{"data":[{"ActionabilityDocID":{"value":"AC021","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"NF2","properties":{"GeneFunction":{"value":"neurofibromin 2 (merlin)"},"HGNCId":{"value":"HGNC:7773"},"GeneOMIM":{"value":"607379"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"101000"}}]}}}}]},"Syndrome":{"value":"Neurofibromatosis Type II","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"101000"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"607379"}}]},"Overview":{"value":"Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Affected individuals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and, very rarely, astrocytomas. Posterior subcapsular lens opacities that rarely progress to a visually significant cataract are the most common ocular findings and may be the first sign of NF2. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy, a squint (third nerve palsy), or hand/foot drop."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Neurofibromatosis 2"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Neurofibromatosis 2 [Mesh]","properties":{"NumberOfHits":{"value":25},"Date":{"value":"2014-06-20"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":4,"items":[{"SearchString":{"value":"Neurofibromatosis 2","properties":{"NumberOfHits":{"value":8},"Date":{"value":"2014-06-20"}}}},{"SearchString":{"value":"Neurofibromatosis","properties":{"NumberOfHits":{"value":7},"Date":{"value":"2014-06-20"}}}},{"SearchString":{"value":"Bilateral Acoustic Neurofibromatosis","properties":{"NumberOfHits":{"value":8},"Date":{"value":"2014-06-20"}}}},{"SearchString":{"value":"Central Neurofibromatosis","properties":{"NumberOfHits":{"value":8},"Date":{"value":"2014-06-20"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2014-06-20"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2014-06-20"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2014-06-20"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2014-06-20"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Vestibular schwannoma","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"MRI/Screening"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"In the past, the estimated prevalence of neurofibromatosis 2 (NF2) was estimated at 1:210,000. However, a recent 2010 study estimated a higher prevalence of 1:60,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000163"}},{"Reference":{"value":"/coll/reference_model/doc/RF000164"}},{"Reference":{"value":"/coll/reference_model/doc/RF000165"}},{"Reference":{"value":"/coll/reference_model/doc/RF000166"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"NF2 is characterized by the development of nervous system tumors (schwannomas and meningiomas), ocular abnormalities, and skin tumors. Bilateral vestibular schwannomas occur in 95% of adult patients; vestibular schwannoma growth rates are extremely variable, both between patients and over time in the same patient. Schwannomas typically affect both vestibular nerves, leading to hearing loss and deafness, tinnitus, dizziness and imbalance.\n\nWhile the tumors caused by NF2 are not malignant, their anatomical location and multiplicity lead to great morbidity and early mortality."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000165"}},{"Reference":{"value":"/coll/reference_model/doc/RF000166"}},{"Reference":{"value":"/coll/reference_model/doc/RF000163"}},{"Reference":{"value":"/coll/reference_model/doc/RF000164"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Average age of onset in individuals with NF2 is 18 to 24 years (range birth to 70 years). Nearly all affected individuals develop bilateral vestibular schwannomas by age 30. The average age of death is 36 years; actuarial survival from correct diagnosis is 15 years. NF2 has no racial or ethnic predilections.\n\nChildhood-onset NF2 typically presents with non-8th nerve tumors and non-vestibular symptoms, while adult-onset NF2 typically presents with vestibular symptoms.  Age at diagnosis, presence of intracranial meningiomas, type of treatment center and type of NF2 mutation are informative predictors of the risk of mortality. Age at diagnosis is, by far, the strongest single predictor."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000165"}},{"Reference":{"value":"/coll/reference_model/doc/RF000166"}},{"Reference":{"value":"/coll/reference_model/doc/RF000163"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM848","properties":{"Key Text":{"value":"Initial medical evaluations"},"Tier":{"value":"4"},"Recommendation Text":{"value":"At diagnosis, the following evaluations are recommended: head MRI, hearing evaluation including BAER, ophthalmologic evaluation, cutaneous evaluation, and a genetics consultation."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000163"}}]}}}},{"Patient Management":{"value":"ACPM851","properties":{"Key Text":{"value":"Specialty-center patient management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"NF2 patients should be managed in specialty centers. NF2 patients who are managed at specialty centers have a significantly lower risk of mortality than those who are treated at non-specialty centers (relative risk 0.34, 95% CI 0.12-0.98)."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000166"}}]}}}},{"Patient Management":{"value":"ACPM850","properties":{"Key Text":{"value":"Audiologist referral"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Hearing preservation and augmentation are important in the management of individuals with NF2; all affected individual and their families should be referred to an audiologist."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000167"}}]}}}},{"Patient Management":{"value":"ACPM849","properties":{"Key Text":{"value":"Pre-surgery imaging"},"Tier":{"value":"3"},"Recommendation Text":{"value":"A cervical spine scan should be performed before cranial surgery to prevent complications from manipulation under anesthesia. Lumbosacral imaging should be performed before regional analgesia is given."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000163"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU454","properties":{"Key Text":{"value":"MRI/Screening"},"Tier":{"value":"2"},"Recommendation Text":{"value":"MRI screening every 2 years for patients less than 20 and every 3 years for older patients should be sufficient for at-risk patients without tumors.  The initial MRI scan could be at 10-12 years of age, or earlier in severely affected families. In 10% of cases, individuals with NF2 become symptomatic before 10 years of age. Once tumors are present, MRI screening should be at least annual until the individual growth rate is established. Annual audiological tests, including auditory brainstem response, may be useful.  A full annual neurological examination is a wise precaution, with a spinal MRI every 2-3 years unless no tumors are present on the initial scan."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000166"}},{"Reference":{"value":"/coll/reference_model/doc/RF000167"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM306","properties":{"Key Text":{"value":"Familial genetic testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Children of affected patients should be considered at 50% risk of NF2 and screening for NF2 can start at birth. All NF2 patients and their families should have access to genetic testing; presymptomatic genetic testing is an integral part of the management of NF2, allowing for presymptomatic clinical screening."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000166"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"Prevalence of NF2 mutations was not identified."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE429","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Penetrance is close to 100%. Virtually all individuals who have a pathogenic germline mutation develop the disease in an average lifetime."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Vestibular schwannoma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000163"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR174","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":""},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN197","properties":{"Key Text":{"value":"Vestibular schwannoma growth rates are extremely variable, both between patients and over time in the same patient. Growth rates are highly variable even among multiple NF2 patients of similar ages in the same family."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000163"}},{"Reference":{"value":"/coll/reference_model/doc/RF000165"}},{"Reference":{"value":"/coll/reference_model/doc/RF000166"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI199","properties":{"Key Text":{"value":"Management of NF2 requires a variety of non-invasive screening tests."},"References":{"value":null}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC195","properties":{"Key Text":{"value":"Regular screening (MRI, neurological, audiology) is recommended beginning at diagnosis, or earlier for family members. These screenings are above and beyond general population recommendations."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers Present":{"value":0,"items":[]}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Vestibular schwannoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"MRI/Screening","properties":{"Overall Score":{"value":"10BB"},"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]},"FinalScoreOfScorers":{"value":3,"items":[{"FinalScoreOfScorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Vestibular schwannoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"MRI/Screening","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Vestibular schwannoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"MRI/Screening","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Vestibular schwannoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"MRI/Screening","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":3,"items":[{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Vestibular schwannoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"MRI/Screening","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"Scorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Vestibular schwannoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"MRI/Screening","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Vestibular schwannoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"MRI/Screening","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36019},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-10"},"ReleasedBy":{"value":"hunterj","properties":{"First Name":{"value":"Jessica"},"Last Name":{"value":"Hunter"}}}}}}}},
{"ActionabilityDocID":{"value":"AC025","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"PTEN","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:9588"},"GeneOMIM":{"value":"601728"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"158350"}}]}}}}]},"Syndrome":{"value":"PTEN Hamartoma Tumor Syndrome - Cowden Syndrome","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"158350"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules, and present by the late 20s."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"PTEN Hamartoma Tumor Syndrome (Cowden Syndrome)"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Hamartoma Syndrome, Multiple OR PTEN Hamartcoma Tumor Syndrome with Granular Cell Tumor [MeSH]","properties":{"NumberOfHits":{"value":5},"Date":{"value":"2014-07-11"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":5,"items":[{"SearchString":{"value":"PTEN Hamartoma Tumor Syndrome","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2014-07-11"}}}},{"SearchString":{"value":"Hamartoma Tumor Syndrome","properties":{"NumberOfHits":{"value":3},"Date":{"value":"2014-07-11"}}}},{"SearchString":{"value":"Cowden Syndrome","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2014-07-11"}}}},{"SearchString":{"value":"MULTIPLE HAMARTOMA SYNDROME","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2014-07-11"}}}},{"SearchString":{"value":"PTEN","properties":{"NumberOfHits":{"value":3},"Date":{"value":"2014-07-11"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2014-07-11"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2014-07-11"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2014-07-11"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2014-07-11"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Breast cancer","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Regular screening"}}]}}}},{"Outcome":{"value":"Thyroid cancer","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Thyroid ultrasounds"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"The true prevalence of Cowden syndrome (CS) is unknown."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}},{"Reference":{"value":"/coll/reference_model/doc/RF000172"}},{"Reference":{"value":"/coll/reference_model/doc/RF000173"}},{"Reference":{"value":"/coll/reference_model/doc/RF000174"}},{"Reference":{"value":"/coll/reference_model/doc/RF000175"}},{"Reference":{"value":"/coll/reference_model/doc/RF000176"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"CS is part of the PTEN hamartoma tumor syndrome (PHTS) spectrum. CS is a cancer syndrome associated with a high risk of hamartomas and/or cancerous lesions in various organs and tissues, including the skin, mucous membranes, breast, thyroid, endometrium, and brain.  Macrocephaly is a common manifestation.\r\rHamartomatous polyps of the colon and other intestines also occur.\r\rRenal cell carcinoma and malignant melanoma may be minor component neoplasias of CS."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}},{"Reference":{"value":"/coll/reference_model/doc/RF000173"}},{"Reference":{"value":"/coll/reference_model/doc/RF000175"}},{"Reference":{"value":"/coll/reference_model/doc/RF000174"}},{"Reference":{"value":"/coll/reference_model/doc/RF000176"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s. By the third decade, 99% of affected individuals develop the mucocutaneous stigmata, as well as acral and plantar keratoses.\r\rThe average age of breast cancer diagnosis is between 38 and 46 years. \r\rThe median age of epithelial thyroid cancer onset is 37 years. Elevated risk for endometrial cancer, colorectal cancer, and renal cell carcinoma starts in the late 30s and early 40s."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}},{"Reference":{"value":"/coll/reference_model/doc/RF000173"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM853","properties":{"Key Text":{"value":""},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"Information on the effectiveness of the patient management recommendations below was not available."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}},{"Patient Management":{"value":"ACPM852","properties":{"Key Text":{"value":"Initial examinations"},"Tier":{"value":"4"},"Recommendation Text":{"value":"At diagnosis: individuals should undergo a physical examination, paying particular attention to skin, mucous membranes, thyroid, and breasts; urinalysis; and medical genetics consultation. Individuals diagnosed after ages 35 and 40 should undergo colonoscopy and renal imaging, respectively. Women diagnosed after age 30 should undergo breast screening and transvaginal ultrasound."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000173"}}]}}}},{"Patient Management":{"value":"ACPM855","properties":{"Key Text":{"value":"Dermatologic management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Dermatologic management may be indicated for some patients."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}}]}}}},{"Patient Management":{"value":"ACPM856","properties":{"Key Text":{"value":"Risk reducing surgery"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Risk-reduction mastectomy and hysterectomy should be discussed on a case-by-case basis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}}]}}}},{"Patient Management":{"value":"ACPM854","properties":{"Key Text":{"value":"Patient education"},"Tier":{"value":"2"},"Recommendation Text":{"value":"CS patients should be educated about the signs and symptoms of cancer."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU456","properties":{"Key Text":{"value":"Annual examinations"},"Tier":{"value":"2"},"Recommendation Text":{"value":"CS patients should undergo annual comprehensive examinations."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}}]}}}},{"Surveillance":{"value":"ACSU458","properties":{"Key Text":{"value":"Breast awareness"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Women should be breast aware starting at age 18, including periodic, consistent breast self-exam. Clinical breast exam, every 6-12 months, should begin at age 25, or 5-10 years before the earliest known breast cancer in the family."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}}]}}}},{"Surveillance":{"value":"ACSU457","properties":{"Key Text":{"value":"Breast Screening"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Women should undergo annual mammography and breast MRI screening starting at age 30-35 or individualized based on earliest age of onset in the family."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}},{"Reference":{"value":"/coll/reference_model/doc/RF000177"}}]}}}},{"Surveillance":{"value":"ACSU460","properties":{"Key Text":{"value":"Endometrial screening"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Women should consider annual random endometrial biopsies and/or ultrasound beginning at age 30-35."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}}]}}}},{"Surveillance":{"value":"ACSU459","properties":{"Key Text":{"value":"Thyroid ultrasounds"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals with CS should receive annual thyroid ultrasounds starting at age 18 or 5-10 years before the earliest known thyroid cancer in the family, whichever is earlier."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}}]}}}},{"Surveillance":{"value":"ACSU455","properties":{"Key Text":{"value":"Colonoscopy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals with CS should undergo colonoscopy, starting at age 35, then every 5 years, or more frequently if patient is symptomatic or polyps are found."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}}]}}}},{"Surveillance":{"value":"ACSU461","properties":{"Key Text":{"value":"Renal ultrasound"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Consider renal ultrasound starting at age 40, then every 1-2 years."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM307","properties":{"Key Text":{"value":"Patient management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Genetic counseling and consideration of genetic testing is recommended for at-risk relatives. An individual with a known deleterious PTEN mutation in a close family member who does not undergo gene testing should be followed according to the same guidelines as a carrier of a PTEN mutation."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA375","properties":{"Key Text":{"value":"Removal of cutaneous lesions"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Because of the propensity for rapid tissue regrowth, it is recommended that cutaneous lesions be excised only if malignancy is suspected or symptoms are significant."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000173"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"Information on the prevalence of PTEN mutations was not available."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null}}},"Penetrances":{"value":4,"items":[{"Penetrance":{"value":"ACPE431","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s. By the third decade, 99% of affected individuals develop the mucocutaneous stigmata."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast cancer"}},{"Outcome":{"value":"Thyroid cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000173"}},{"Reference":{"value":"/coll/reference_model/doc/RF000103"}}]}}}},{"Penetrance":{"value":"ACPE432","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Among individuals meeting the diagnostic criteria for CS, the cumulative lifetime risk of any cancer is 89%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}}]}}}},{"Penetrance":{"value":"ACPE433","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"The lifetime risk of breast cancer for females with a PTEN pathogenic variant is 77-85%, with 50% penetrance by age 50."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000173"}},{"Reference":{"value":"/coll/reference_model/doc/RF000176"}}]}}}},{"Penetrance":{"value":"ACPE430","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"Lifetime risk of epithelial thyroid cancer ranges from 21-38%."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Thyroid cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000173"}},{"Reference":{"value":"/coll/reference_model/doc/RF000103"}},{"Reference":{"value":"/coll/reference_model/doc/RF000176"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR175","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":""},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN198","properties":{"Key Text":{"value":"The high variability in disease expression is highlighted by the fact that clinical diagnosis in an individual is based on three of eight possible major diagnostic criteria, or two major criteria and three of eleven possible minor criteria."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000103"}}]},"Tier":{"value":"2"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI200","properties":{"Key Text":{"value":"Management of CS includes regular invasive and non-invasive screening tests and the possible recommendation of prophylactic organ removal for affected women."},"References":{"value":null}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC196","properties":{"Key Text":{"value":"Given the age of development of cancers in CS patients, general population screening would not allow for prophylactic measures to be taken. 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{"ActionabilityDocID":{"value":"AC026","properties":{"Status":{"value":"Released"},"Genes":{"value":2,"items":[{"Gene":{"value":"TSC1","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:12362"},"GeneOMIM":{"value":"191100"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"191100"}}]}}}},{"Gene":{"value":"TSC2","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:12363"},"GeneOMIM":{"value":"613254"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"613254"}}]}}}}]},"Syndrome":{"value":"Tuberous Sclerosis Complex (TSC)","properties":{"OmimIDs":{"value":2,"items":[{"OmimID":{"value":"191100"}},{"OmimID":{"value":"613254"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Tuberous sclerosis complex (TSC) is a rare, slowly progressive disorder characterized by pervasive benign tumors in the brain, skin, kidneys, heart, lungs, retina, and other organs. These tumors present in a range of numbers, sizes, and locations, which may lead to early and severe symptoms, or which may result in mild symptoms that are undiagnosed or misdiagnosed well into adulthood."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Tuberous sclerosis complex"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":5,"items":[{"SearchString":{"value":"\"Tuberous Sclerosis\"[Mesh] limited to practice guidelines, meta-analysis, systematic reviews","properties":{"NumberOfHits":{"value":34},"Date":{"value":"2015-07-21"}}}},{"SearchString":{"value":"Targeted:  (\"Tuberous Sclerosis\"[Mesh]) AND \"Risk\"[Mesh]","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-07-21"}}}},{"SearchString":{"value":"Targeted:  Search term: (\"Tuberous Sclerosis\"[Mesh]) AND \"Penetrance\"[Mesh]","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-07-21"}}}},{"SearchString":{"value":"(Bibliographic references)","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-07-21"}}}},{"SearchString":{"value":"(Stage 1 search)","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-07-21"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"'tuberous'","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-07-21"}}}},{"SearchString":{"value":"'tcr'","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-07-21"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-07-21"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-07-21"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-07-21"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"'tuberous,' 'sclerosis,' 'TSC'","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-07-21"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":3,"items":[{"Outcome":{"value":"SEGA development","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"mTOR inhibitor treatment"}}]}}}},{"Outcome":{"value":"Morbidity and mortality from masses","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Imaging to detect masses when intervention is effective"}}]}}}},{"Outcome":{"value":"LAM development in women","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"mTOR inhibitor treatment"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 10000"},"Notes":{"value":"TSC affects approximately one in 6000 births, with a prevalence of one in 11,000 to 14,000 after the age of 10 years."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000142"}},{"Reference":{"value":"/coll/reference_model/doc/RF000143"}},{"Reference":{"value":"/coll/reference_model/doc/RF000144"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Tuberous sclerosis complex (TSC) is a rare, slowly progressive disorder characterized by disorganized cellular growth, abnormal differentiation, and the  pervasive formation of benign tumors in the brain, skin, kidneys, heart, lungs, retina, and other organs. These  masses consist of cysts, lesions, nodules, or tubers that present in a range of numbers, sizes, and locations; which may lead to early and severe symptoms, or which may result in mild symptoms that are undiagnosed or misdiagnosed well into adulthood.  Kidney manifestations include angiomyolipomas (AMLs) with complications of hemorrhagic rupture, cortical cysts, chronic renal insufficiency (due to AMLs or polycystosis), and malignant lesions. Adult women with TSC may develop pulmonary lymphangioleiomyomatosis (LAM), which can lead to terminal respiratory insufficiency. Brain lesions include subependymal nodules (SEN), cortical tubers, and subependymal giant cell astrocytomas (SEGAs) affecting 80%, 90%, and 5-15% of TSC patients, respectively.  When SEGAs develop they produce complications either through growth and invasion of surrounding cerebral tissue or through blockage of the flow of cerebrospinal fluid. Development and progression of benign brain tumors including tubers, SEN, and SEGAs may be associated with epilepsy, intellectual disability, and behavioral disorders such as autism and ADHD.  Prevalence rates of autism spectrum disorder (ASD) in TSC range from 24% to 60% with an approximately equal male to female ratio. In adulthood, high rates of anxiety symptoms and depressed mood are reported.   Disfiguring skin lesions are common, but do not result in serious medical problems. Eye lesions are occasionally symptomatic."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000142"}},{"Reference":{"value":"/coll/reference_model/doc/RF000144"}},{"Reference":{"value":"/coll/reference_model/doc/RF000145"}},{"Reference":{"value":"/coll/reference_model/doc/RF000146"}},{"Reference":{"value":"/coll/reference_model/doc/RF000147"}},{"Reference":{"value":"/coll/reference_model/doc/RF000148"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Tuberous sclerosis complex (TSC) exhibits variability in clinical findings both among and within families. Females tend to have milder disease than males. Any organ system can be involved and TSC2 mutations produce a more severe phenotype than TSC1 mutations.  Patients with mild symptoms tend to live long, productive lives, while individuals with more severe forms of TSC may have serious disabilities. \r\rIn at least two-thirds of cases, TSC is diagnosed in the first year of life when an infant with TSC presents with epileptic seizures; cortical tumors may be detected. Cardiac rhabdomyoma may also be present particularly in the neonatal period, requiring surveillance until regression during childhood. Epilepsy is a major manifestation in childhood and may be accompanied by behavioral and neuropsychiatric manifestations that continue into adulthood. The leading cause of premature death (32.5%) among individuals with TSC is a complication of severe intellectual disability (e.g. status epilepticus and bronchopneumonia).  Renal disease is the second leading cause of early death (27.5%). Kidney damage affects 48-80% of patients, developing mainly before 20 years of age but with consequences that must be managed well into adulthood. Whether TSC is a risk factor for development of malignant kidney tumors is a subject of debate; such tumors occur in TSC at a rate of 0.5-4%. Although present in a minority of cases, SEGAs tend to develop in adolescence or very early adulthood and may remain dormant or enlarge at any time, causing significant morbidity and mortality. The mean age of diagnosis for women who develop TSC LAM is 28 years."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000142"}},{"Reference":{"value":"/coll/reference_model/doc/RF000143"}},{"Reference":{"value":"/coll/reference_model/doc/RF000146"}},{"Reference":{"value":"/coll/reference_model/doc/RF000148"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM857","properties":{"Key Text":{"value":"Evaluation at diagnosis"},"Tier":{"value":"2"},"Recommendation Text":{"value":"At diagnosis all individuals should undergo magnetic resonance imaging (MRI) of the brain, abdominal imaging, renal function tests, blood pressure assessment, echocardiogram, and a detailed dermatologic, dental and ophthalmologic exam. Also, a baseline pulmonary function test, 6-minute walk test, and high-resolution tomography (HRCT) in women 18 years or older."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000142"}},{"Reference":{"value":"/coll/reference_model/doc/RF000147"}},{"Reference":{"value":"/coll/reference_model/doc/RF000149"}}]}}}},{"Patient Management":{"value":"ACPM862","properties":{"Key Text":{"value":"Psycho-social evaluation at diagnosis"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Newly diagnosed adults should undergo an assessment of cognitive, behavioral, and vocational profiles to determine a based profile for future evaluations. Psychosocial needs should be also determined."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000149"}}]}}}},{"Patient Management":{"value":"ACPM859","properties":{"Key Text":{"value":"SEGA assessment and intervention"},"Tier":{"value":"2"},"Recommendation Text":{"value":"SEGAs associated with increasing ventricular enlargement, or with unexplained changes in neurological status or neuropsychiatric symptoms, require intervention (surgical resection or medical therapy with mTOR inhibitors) or more frequent clinical monitoring and reimaging. In two large prospective studies, the mTOR inhibitor everolimus significantly decreased the volume (>50%) of SEGAs in 35% to 42% at 6 months of treatment."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000149"}},{"Reference":{"value":"/coll/reference_model/doc/RF000150"}}]}}}},{"Patient Management":{"value":"ACPM858","properties":{"Key Text":{"value":"Educating patients regarding acute symptoms"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should be informed of the risk and clinical signs of a hemorrhagic rupture of an AML and the nearest medical centers able to treat these acute ruptures should be identified. Patients with LAM should be educated and warned regarding the signs and risk of pneumothorax and told to seek urgent medical attention in the event of symptoms."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000142"}},{"Reference":{"value":"/coll/reference_model/doc/RF000147"}}]}}}},{"Patient Management":{"value":"ACPM860","properties":{"Key Text":{"value":"Development and treatment of respiratory symptoms-LAM"},"Tier":{"value":"2"},"Recommendation Text":{"value":"The onset of respiratory symptoms (unexplained dyspnea, pneumothorax) should result in pulmonary imaging regardless of the sex of the patient. In select patients, treatment with an mTOR inhibitor may be used to stabilize or improve pulmonary function.   In a 1-year randomized double-blind placebo-controlled trial of sirolimus in 89 patients with LAM, the between-group difference in the mean change in FEV(1) was about 11% of baseline, favoring sirolimus.  The sirolimus group improved in measures of forced vital capacity, quality of life, and functional performance, although not in the 6-miniute walk test."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000142"}},{"Reference":{"value":"/coll/reference_model/doc/RF000147"}},{"Reference":{"value":"/coll/reference_model/doc/RF000149"}}]}}}},{"Patient Management":{"value":"ACPM861","properties":{"Key Text":{"value":"Risks during pregnancy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with TSC who would like to become pregnant should have a genetic consultation before any conception and should be informed of risks during pregnancy."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000142"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU467","properties":{"Key Text":{"value":"Ongoing surveillance"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Ongoing periodic surveillance is needed after initial diagnosis for optimal care and prevention of secondary complications associated with TSC."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000149"}}]}}}},{"Surveillance":{"value":"ACSU465","properties":{"Key Text":{"value":"Monitoring for TSC-specific neuropsychiatric features"},"Tier":{"value":"2"},"Recommendation Text":{"value":"It is imperative to monitor for TSC-specific neuropsychiatric features and their impact on daily living at each follow-up clinic visit, with a minimum frequency of once per year."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000149"}}]}}}},{"Surveillance":{"value":"ACSU466","properties":{"Key Text":{"value":"Screening, monitoring, and treatment of renal lesions"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Annual screening and monitoring of renal lesions and blood pressure is indicated in all patients with TSC. Preventive treatment such as mTOR inhibitor therapy for AMLs meeting appropriate criteria may be considered. In a double-blind, placebo-controlled, phase III trial of patients with TSC or sporadic LAM, the AML response rate was 42% (33 of 79 [95% CI 31-53%]) for the mTOR everolimus and 0% (0 of 39 [0-9%]) for placebo (response rate difference 42% [24-58%]; p<0·0001)."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000142"}},{"Reference":{"value":"/coll/reference_model/doc/RF000149"}}]}}}},{"Surveillance":{"value":"ACSU462","properties":{"Key Text":{"value":"Skin survey"},"Tier":{"value":"2"},"Recommendation Text":{"value":"A skin survey should be performed annually to assess skin lesions. Early intervention is indicated for bleeding, symptomatic, or potentially disfiguring lesions."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000149"}}]}}}},{"Surveillance":{"value":"ACSU464","properties":{"Key Text":{"value":"Imaging for pulmonary LAM"},"Tier":{"value":"2"},"Recommendation Text":{"value":"HRCT imaging for pulmonary LAM should be repeated in previously asymptomatic women every 5-10 years after baseline or at least by 30 to 40 years of age."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000142"}},{"Reference":{"value":"/coll/reference_model/doc/RF000147"}},{"Reference":{"value":"/coll/reference_model/doc/RF000149"}}]}}}},{"Surveillance":{"value":"ACSU463","properties":{"Key Text":{"value":"Surveillance for SEGAs"},"Tier":{"value":"2"},"Recommendation Text":{"value":"For early detection, MRI surveillance for SEGAs should be performed every 1-3 years until age 25, or more frequently in developmentally or cognitively disabled patients who cannot reliably report symptoms. Individuals without SEGAs by the age of 25 years do not need continued surveillance, but those with asymptomatic tumors should continue to be monitored by MRI for life because of the possibility of growth."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000149"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM308","properties":{"Key Text":{"value":"Assessment of proband first-degree relatives"},"Tier":{"value":"2"},"Recommendation Text":{"value":"First-degree relatives of affected individuals should be offered clinical assessment and, where a mutation has been identified in the index case, genetic testing."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000149"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA378","properties":{"Key Text":{"value":"Avoid smoking"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with LAM should refrain from smoking."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000147"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA376","properties":{"Key Text":{"value":"Avoid estrogenic treatments"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with TSC who have renal AMLs and/or pulmonary LAM should avoid estrogenic treatments, which are risk factors for AML progression and/or spontaneous rupture, and for more rapid degeneration of respiratory function in LAM. For those without symptoms, counseling on smoking risks and estrogen use should also occur in adolescents and adults"},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000142"}},{"Reference":{"value":"/coll/reference_model/doc/RF000149"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA377","properties":{"Key Text":{"value":"Avoid nephrectomy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Nephrectomy should be avoided due to the high incidence of complications and risk of renal insufficiency or failure."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000149"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":"Two thirds of affected individuals have the altered TSC1 or TSC2 gene as the result of a de novo mutation."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000143"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"No information on population prevalence of genetic mutations was found.  About 30% of patients with definite clinical TSC and an identifiable mutation have a TSC1 mutation; the rest have a TSC2 mutation."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000143"}},{"Reference":{"value":"/coll/reference_model/doc/RF000151"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC048","properties":{"Recommendation":{"value":"Approximately 15-20% of persons with TSC have no mutation identified."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000143"}},{"Reference":{"value":"/coll/reference_model/doc/RF000151"}}]}}}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE434","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"Not provided"},"Notes":{"value":"In a study of 103 clinically diagnosed TSC patients (all with seizure onset at less than 3 years of age), 90% of whom had confirmed TSC1 or TSC2 mutations, it was estimated that 40% of individuals had ASD. (Tier 5)"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"SEGA development"}},{"Outcome":{"value":"Morbidity and mortality from masses"}},{"Outcome":{"value":"LAM development in women"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000152"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC053","properties":{"Recommendation":{"value":"In three studies of TSC patients selected first by clinical diagnosis and then by TSC1 or TSC2 mutation, the following characteristics were documented. \n\n•Median age at diagnosis was 10 to 13 years; overall range was 0 to 64 years.\n\n•Skin involvement included: hypomelanotic macules (92-96% of individuals), facial angiofibromas (63-80%), shagreen patches (44-55%), forehead plaques (33-41%), and ungual fibromas (20-37%).\n\n•SENs occurred in 89-95%, cortical or subcortical tubers occurred in 88-91%, and SEGAs occurred in 12-31% of all individuals with TSC-related mutations.\n\n•80-95% of individuals with mutations had seizures, and 48-76% had intellectual disability.\n\n•Renal AMLS affected 42-56% and renal cysts (any grade) affected 23-27% of adults."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000153"}},{"Reference":{"value":"/coll/reference_model/doc/RF000154"}},{"Reference":{"value":"/coll/reference_model/doc/RF000155"}}]}}}}]}}}},{"Penetrance":{"value":"ACPE435","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"5"},"Notes":{"value":"In two studies of TSC patients selected first by clinical diagnosis and then by TSC1 or TSC2 mutation, LAM occurred in 12-39% of adult females with TSC."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"LAM development in women"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000156"}},{"Reference":{"value":"/coll/reference_model/doc/RF000154"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR176","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was found."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN199","properties":{"Key Text":{"value":"The TSC clinical phenotype is extremely variable. Some individuals have only superficial skin problems or mild seizures while others show severe physical effects and profound intellectual disability.  Variability has also been noted in monozygotic twins."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000144"}},{"Reference":{"value":"/coll/reference_model/doc/RF000146"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI201","properties":{"Key Text":{"value":"Because of the variability of TSC, non-invasive but comprehensive investigations of different organ systems are needed, like a neurological examination, MRI of the brain, cardiology examination, ultrasound of the heart, ophthalmological examination, dermatological examination, and ultrasound or CT-scan of the abdomen. Some patients may require treatment with mTOR inhibitors, which may be accompanied by adverse events of moderate risk such as infection, metabolic disturbances, hematologic abnormalities, non-infectious pneumonitis, and renal dysfunction."},"References":{"value":null}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC197","properties":{"Key Text":{"value":"TSC has a highly variable phenotype with only one third of patients having the classical triad of epilepsy, learning difficulties, and facial angiofibromas. Those who do not have epilepsy or learning difficulties may have mild cutaneous features of TSC that can be overlooked. Diverse, non-specific, clinical manifestations as well as a high probability of a spontaneous mutation can cause some individuals with TSC to go unrecognized or misdiagnosed for years."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000143"}},{"Reference":{"value":"/coll/reference_model/doc/RF000147"}},{"Reference":{"value":"/coll/reference_model/doc/RF000148"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"bieseckerl"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"strandet"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"sobreiran"}}]}}},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"SEGA 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The condition manifests as liver disease more commonly in children and younger adults; other major symptomology may include neurologic disease (e.g. movement disorders or rigid dystonia), mood disturbances, difficulty with motor skills, and psychiatric manifestations (e.g. depression, phobias, compulsive behaviors, aggression, or antisocial behavior).  Kayser-Fleischer rings (deposits of copper in the cornea) are often present in patients with neurologic symptoms and may be found in those without neurologic symptoms but do not cause ocular difficulties. Clinical features of Wilson disease overlap with other liver diseases such as autoimmune liver diseases, and with neurologic symptoms characteristic of a variety of other neurologic disorders, resulting in potential for misdiagnosis. As a result, Wilson disease must be excluded in any patient with unexplained liver disease along with neurological or neuropsychiatric disorder."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000010"}},{"Reference":{"value":"/coll/reference_model/doc/RF000011"}},{"Reference":{"value":"/coll/reference_model/doc/RF000012"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Decreased copper excretion results in hepatic copper accumulation and injury, release of copper into the bloodstream, and copper deposition in other organs such as brain, kidneys, and cornea. After a presymptomatic period, approximately 40% of patients present acutely with liver failure, hemolytic anemia, or both, or more chronically with liver conditions such as chronic hepatitis, portal hypertension, or cirrhosis. In other patients, liver disease remains subclinical and neuropsychiatric symptoms develop, reflecting ongoing copper deposition in other organs.  Clinically evident liver disease may precede neurologic manifestations by as much as 10 years, and most patients with neurologic symptoms have some degree of liver disease. However, neurological, behavioral, and/or psychiatric signs are present in almost 50% of patients at any one time, and present before motor signs in 20% of cases. Neuropsychiatric presentation can be extremely subtle, and intermitted for many years, but may also develop very rapidly, leading within a few months to complete disability. Wilson disease is uniformly fatal without treatment, with most patients dying from liver disease and a minority from complications of progressive neurologic disease.  The majority of patients present between ages 5 and 35 but the oldest patients have been diagnosed in their early 70s. Symptoms at any age are frequently nonspecific and the spectrum of disease at presentation is highly variable."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000011"}},{"Reference":{"value":"/coll/reference_model/doc/RF000012"}},{"Reference":{"value":"/coll/reference_model/doc/RF000013"}},{"Reference":{"value":"/coll/reference_model/doc/RF000015"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM865","properties":{"Key Text":{"value":"Evaluation at diagnosis"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of the disease and treatment needs of an individual diagnosed with Wilson disease, the following evaluations are recommended following initial diagnosis: biochemical testing and imaging of the liver, upper GI endoscopy to exclude or confirm esophageal varices, detailed clinical neurologic assessment, assessment of kidney function, medical genetics consultation."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000010"}}]}}}},{"Patient Management":{"value":"ACPM864","properties":{"Key Text":{"value":"Recommended treatment of presymptomatic patients"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Treatment of presymptomatic patients can be accomplished with a chelating agent or with zinc. Treatment is lifelong and should not be discontinued (including during pregnancy)."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000011"}},{"Reference":{"value":"/coll/reference_model/doc/RF000012"}}]}}}},{"Patient Management":{"value":"ACPM863","properties":{"Key Text":{"value":"Effectiveness evidence for chelation/zinc therapy"},"Tier":{"value":"1"},"Recommendation Text":{"value":"In a systematic review of 10 studies of chelation therapy in asymptomatic patients (1 randomized comparative effectiveness trial, 5 prospective and 4 retrospective cohort studies), mean age at diagnosis of Wilson disease was 10 to 11 years, age range was 1.5 to 39 years. Clinical effectiveness was defined as the ability of the interventional drug to prevent clinical symptoms related to Wilson disease over the mean evaluation periods of 57 months (range 12-186) and 81 months (range 12-144) for D-penicillamine and zinc, respectively. Both D-penicillamine (chelator) and zinc were effective in 70/70 (100%) and 66/66 (100%) of presymptomatic patients, respectively.  However, given the average age of onset, the lack of untreated comparison groups, or an explanation in the review for why these followup periods were reported, it is unclear whether patients would have progressed without treatment."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000013"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU472","properties":{"Key Text":{"value":"Routine monitoring"},"Tier":{"value":"2"},"Recommendation Text":{"value":"For routine monitoring, serum copper and ceruloplasmin, liver biochemistries and international normalized ratio, complete blood count and urinalysis (especially for those on chelation therapy), as well as physical and neurological examination should be performed regularly, at least twice annually. Patients receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000011"}},{"Reference":{"value":"/coll/reference_model/doc/RF000012"}}]}}}},{"Surveillance":{"value":"ACSU471","properties":{"Key Text":{"value":"Copper excretion"},"Tier":{"value":"2"},"Recommendation Text":{"value":"The 24-hour urinary excretion of copper while on medication should be measured yearly, or more frequently if there are questions on compliance or if dosage of medications is adjusted. The serum unbound copper may be another useful parameter for monitoring therapy."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000011"}},{"Reference":{"value":"/coll/reference_model/doc/RF000012"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM311","properties":{"Key Text":{"value":"Screening siblings"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Siblings of any patient newly diagnosed with WD should be screened for WD and offspring of patients should be tested by serum ceruloplasmin concentration after age one year unless consanguinity is present."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000010"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA382","properties":{"Key Text":{"value":"Copper in diet 1"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should avoid intake of foods and water with high concentrations of copper, especially during the first year of treatment."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000012"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA381","properties":{"Key Text":{"value":"Copper in diet 2"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Diets deficient in copper may delay the onset of the disease and control disease progression."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000011"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"},"Notes":{"value":"Wilson disease is inherited in an autosomal recessive manner.  Most patients are compound heterozygotes.  Clinical disease is not known to occur in carriers."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000010"}},{"Reference":{"value":"/coll/reference_model/doc/RF000012"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 5000"},"Tier":{"value":"5"},"Notes":{"value":"Traditionally, estimates for carrying one copy of a mutation in ATP7B have been 1 in 90 individuals. A recent UK study of newborn blood spots suggests this prevalence may be substantially higher at 1 in 18 to 25 individuals (depending on the categorization of variant pathogenicity); the corresponding number of homozygotes would be 1 in 2,500 to 7,026 individuals."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000014"}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE439","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"No estimates of penetrance were found."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Liver disease"}}]},"References":{"value":null}}}},{"Penetrance":{"value":"ACPE440","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"No estimates of penetrance were found."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neuropsychiatric disease"}}]},"References":{"value":null}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR178","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was found."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN201","properties":{"Key Text":{"value":"Wilson disease can manifest as hepatic, neurologic, hematologic, or psychiatric disturbances, or a combination of these, in individuals ranging in age from three years to over 60 years. 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D-penicillamine in particular, although extensively used, is associated with severe early (e.g. sensitivity reactions, fever, proteinuria) and late side effects (e.g. significant bone marrow toxicity, nephrotoxicity, lupus-like syndrome, dermatological toxicities, and, rarely, myasthenia gravis, polymyositis, serous retinitis) requiring the drug to be discontinued in approximately 30% of patients."},"References":{"value":null}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC199","properties":{"Key Text":{"value":"Acute or chronic hepatitis with Wilson's disease presents similarly to any other acute or chronic cases of hepatitis. 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{"ActionabilityDocID":{"value":"AC037","properties":{"Status":{"value":"Released"},"Genes":{"value":4,"items":[{"Gene":{"value":"DNAJB11","properties":{"GeneFunction":{"value":"DnaJ heat shock protein family (Hsp40) member B11"},"HGNCId":{"value":"HGNC:14889"},"GeneOMIM":{"value":"611341"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"618061"}}]}}}},{"Gene":{"value":"GANAB","properties":{"GeneFunction":{"value":"glucosidase, alpha; neutral AB"},"HGNCId":{"value":"HGNC:4138"},"GeneOMIM":{"value":"104160"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"600666"}}]}}}},{"Gene":{"value":"PKD1","properties":{"GeneFunction":{"value":"polycystin 1, transient receptor potential channel interacting"},"HGNCId":{"value":"HGNC:9008"},"GeneOMIM":{"value":"601313"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"173900"}}]}}}},{"Gene":{"value":"PKD2","properties":{"GeneFunction":{"value":"polycystin 2, transient receptor potential cation channel"},"HGNCId":{"value":"HGNC:9009"},"GeneOMIM":{"value":"173910"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"613095"}}]}}}}]},"Syndrome":{"value":"Autosomal Dominant Polycystic Kidney Disease","properties":{"OmimIDs":{"value":4,"items":[{"OmimID":{"value":"173900"}},{"OmimID":{"value":"613095"}},{"OmimID":{"value":"600666"}},{"OmimID":{"value":"618061"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":""},"Acronyms":{"value":4,"items":[{"Acronym":{"value":"PDK1"}},{"Acronym":{"value":"PDK2"}},{"Acronym":{"value":"GANAB"}},{"Acronym":{"value":"DNAJB11"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":0,"items":[]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":0,"items":[]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":0,"items":[]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-07-27"},"Notes":{"value":""},"Label":{"value":""}}}},{"SearchString":{"value":"OMIM update","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2018-11-05"},"Notes":{"value":""},"Label":{"value":""}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":0,"items":[]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":0,"items":[]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Progression to ESRD","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacologic management of renal function"}}]}}}},{"Outcome":{"value":"Neurologic disability or death due to ICA","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICA surveillance"}}]}}}},{"Outcome":{"value":"Morbidity due to thoracic aortic disease","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"TAAD surveillance to guide surgical intervention"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 500"},"Notes":{"value":"Estimates of population prevalence of autosomal dominant polycystic kidney disease (ADPKD) have varied widely depending on methodology from 1:400 to a more modest 2.7:10,000. It is estimated to affect approximately 300,000 persons in the United States."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}},{"Reference":{"value":"/coll/reference_model/doc/RF000042"}},{"Reference":{"value":"/coll/reference_model/doc/RF000867"}},{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000869"}},{"Reference":{"value":"/coll/reference_model/doc/RF000870"}},{"Reference":{"value":"/coll/reference_model/doc/RF000871"}},{"Reference":{"value":"/coll/reference_model/doc/RF000872"}},{"Reference":{"value":"/coll/reference_model/doc/RF000873"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"ADPKD is a late-onset, multisystem disorder characterized by bilateral renal cysts; cysts in other organs including the liver, seminal vesicles, pancreas, and arachnoid membrane; cardiovascular abnormalities including intracranial aneurysms (ICAs), dilatation of the aortic root, thoracic aortic dissection (TAAD), left ventricular hypertrophy, diastolic dysfunction, and mitral valve prolapse (MVP); and abdominal wall hernias. Renal manifestations due to the development of renal cysts include hypertension, abdominal fullness and pain, renal insufficiency and progression to end-stage renal disease (ESRD); renal stones, urinary tract infection (UTI) and cyst infection also can develop. Cysts that manifest in the liver, seminal vesicles, pancreas, and arachnoid membrane are typically asymptomatic and rarely result in clinical manifestations or complications; these complications can include cyst hemorrhage, infection, or rupture. Women may have higher risk pregnancies."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}},{"Reference":{"value":"/coll/reference_model/doc/RF000042"}},{"Reference":{"value":"/coll/reference_model/doc/RF000867"}},{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000869"}},{"Reference":{"value":"/coll/reference_model/doc/RF000870"}},{"Reference":{"value":"/coll/reference_model/doc/RF000871"}},{"Reference":{"value":"/coll/reference_model/doc/RF000873"}},{"Reference":{"value":"/coll/reference_model/doc/RF000874"}},{"Reference":{"value":"/coll/reference_model/doc/RF000875"}},{"Reference":{"value":"/coll/reference_model/doc/RF000876"}},{"Reference":{"value":"/coll/reference_model/doc/RF000877"}},{"Reference":{"value":"/coll/reference_model/doc/RF000878"}},{"Reference":{"value":"/coll/reference_model/doc/RF000604"}},{"Reference":{"value":"/coll/reference_model/doc/RF000879"}},{"Reference":{"value":"/coll/reference_model/doc/RF000880"}},{"Reference":{"value":"/coll/reference_model/doc/RF000881"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Although all individuals with ADPKD develop renal cysts, substantial variability occurs in severity of renal disease and other manifestations.  Because the disease is progressive, few cysts may be evident during childhood or young adulthood, especially for those with mild phenotypes. Hypertension usually onsets before detectable renal decline; renal decline (detected as increased serum creatine) usually begins about 12 years prior to ESRD.  The prevalence of liver cysts, the most common extrarenal manifestation, increases with age. Hypertension is often diagnosed late in the disease course, and cardiovascular disease is the main cause of death. In general, women with ADPKD that have normal blood pressure and kidney function have a favorable course during pregnancy. Polycystic liver disease (PLD) develops at a younger age in women than men and is more severe in women who have had multiple pregnancies; multiple pregnancies may also be associated with greater risk of renal decline. However, males have a higher incidence of ESRD and more severe renal disease. Genotype is predictive of phenotype. Pathogenic variants in GANAB cause mild cystic kidney disease, usually without a decline in renal function, with a range of liver involvement (none to severe). Pathogenic variants in DNAJB11 result in small renal cysts, usually without renal enlargement; liver cysts are present in about half of patients. DNAJB11-related ADPKD is associated with progression to renal insufficiency or ESRD most often after the 6th decade.  Approximately 50% of individuals with PKD1-related ADPKD have end-stage renal disease (ESRD) by age 60 years. The mean age of onset of ESRD is age 58 for PKD1-related ADPKD (range: infancy to 80 years) and age 79 for PKD2-related ADPKD, with a lower probability of reaching ESRD in PKD2-related ADPKD."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}},{"Reference":{"value":"/coll/reference_model/doc/RF000042"}},{"Reference":{"value":"/coll/reference_model/doc/RF000867"}},{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000869"}},{"Reference":{"value":"/coll/reference_model/doc/RF000871"}},{"Reference":{"value":"/coll/reference_model/doc/RF000874"}},{"Reference":{"value":"/coll/reference_model/doc/RF000876"}},{"Reference":{"value":"/coll/reference_model/doc/RF000877"}},{"Reference":{"value":"/coll/reference_model/doc/RF000878"}},{"Reference":{"value":"/coll/reference_model/doc/RF000884"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1220","properties":{"Key Text":{"value":"Multidisciplinary care"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Multidisciplinary care is recommended, with all relevant specialties in one center or clinic based on evidence in rare disease settings in general."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000874"}},{"Reference":{"value":"/coll/reference_model/doc/RF000882"}},{"Reference":{"value":"/coll/reference_model/doc/RF000883"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC293","properties":{"Recommendation":{"value":"Consultation with a clinical geneticist and/or genetic counselor is recommended if the nephrologist is not an expert in inherited disorders."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000042"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1226","properties":{"Key Text":{"value":"Initial assessment"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Initial assessment should include renal and liver imaging to determine the extent of disease."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Progression to ESRD"}},{"Outcome":{"value":"Morbidity due to thoracic aortic disease"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}},{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000873"}},{"Reference":{"value":"/coll/reference_model/doc/RF000874"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC290","properties":{"Recommendation":{"value":"Other initial evaluations recommended are standardized blood pressure screening, measurement of blood lipid concentrations, cardiographic studies in individuals with murmurs, systolic clicks, or family history of thoracic aortic dissections, and urine studies."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000042"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1218","properties":{"Key Text":{"value":"ICA screening"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Head magnetic resonance angiography (MRA) or CT angiography is recommended at the time of diagnosis in individuals with a family history of ICA or subarachnoid hemorrhage (SAH). Some recommendations indicate this screening can also be considered in patients with symptoms suggestive of ICA, a job or hobby where loss of consciousness may be lethal, preparation for major elective surgery, or extreme anxiety regarding the risk of having an ICA."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic disability or death due to ICA"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}},{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000604"}},{"Reference":{"value":"/coll/reference_model/doc/RF000880"}}]}}}},{"Patient Management":{"value":"ACPM1227","properties":{"Key Text":{"value":"Thoracic aortic replacement"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Thoracic aortic replacement is indicated in patients with ADPKD."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Morbidity due to thoracic aortic disease"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000042"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC291","properties":{"Recommendation":{"value":"Evidence on effectiveness of thoracic aortic replacement is not available for patients with ADPKD. Based on guidelines for Marfan syndrome, prophylactic surgical repair of the aorta is recommended for aortic diameters >5.0 cm, though some guidelines indicate repair at >4.0 or >4.5 cm with special consideration for the rate of aortic diameter expansion, progressive aortic regurgitation, family history of aortic dissection, and the height of the patient.Timely repair of aortic aneurysms among patients with Marfan syndrome prolongs survival such that it approaches that of age-matched controls."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000046"}},{"Reference":{"value":"/coll/reference_model/doc/RF000885"}},{"Reference":{"value":"/coll/reference_model/doc/RF000049"}},{"Reference":{"value":"/coll/reference_model/doc/RF000050"}},{"Reference":{"value":"/coll/reference_model/doc/RF000045"}},{"Reference":{"value":"/coll/reference_model/doc/RF000047"}},{"Reference":{"value":"/coll/reference_model/doc/RF000886"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1225","properties":{"Key Text":{"value":"Antihypertensive therapies"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Antihypertensive therapies to treat hypertension are recommended with a suggested blood pressure target of ≤130/80mmHg or ≤140/90 mmHg, depending on guideline. Guidelines recommend that angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB). Sodium restricted diets should be used in combination."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Progression to ESRD"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}},{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000874"}},{"Reference":{"value":"/coll/reference_model/doc/RF000879"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC288","properties":{"Recommendation":{"value":"A recent systematic review of antihypertensive therapies in ADPKD found that ACEi significantly reduced diastolic BP but had uncertain effects on mortality, ESRD, kidney volumes, GFR, creatinine levels and albuminuria. Both this systematic review and a separate meta-analysis found that ACEi did not produce different effects on kidney function (as measured by eGFR) when compared with beta blockers or ARBs."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000869"}},{"Reference":{"value":"/coll/reference_model/doc/RF000887"}}]}}}},{"RecommendationID":{"value":"REC289","properties":{"Recommendation":{"value":"Patients should be educated regarding risk factors, specifically hypertension, for disease progression. A longitudinal study of a hypertension education program showed that the proportion of patients with a controlled BP and the use of ACEi therapy increased from baseline over the course of the program."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000874"}},{"Reference":{"value":"/coll/reference_model/doc/RF000888"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1224","properties":{"Key Text":{"value":"Lipid lowering agents"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Lipid lowering agents (LLA) are recommended following care recommendations for those with CKD. There is limited and conflicting evidence on the effectiveness of LLA therapies in ADPKD. This recommendation was made on the basis of a meta-analysis in patients with CDK of any etiology (n=28,276), which found that LLA therapy reduced the risk of death, major cardiovascular events, and myocardial infarction by 20%. However, the effect of LLA therapy on renal dysfunction was uncertain."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Progression to ESRD"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000879"}}]}}}},{"Patient Management":{"value":"ACPM1222","properties":{"Key Text":{"value":"Tolvaptan"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Some guidelines recommend treatment with tolvaptan for patients who have CKD, are at risk of rapidly progressive renal disease, and fulfill guideline-specific criteria; others recommend this treatment in a research study setting or cite insufficient evidence for a recommendation."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Progression to ESRD"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000873"}},{"Reference":{"value":"/coll/reference_model/doc/RF000874"}},{"Reference":{"value":"/coll/reference_model/doc/RF000879"}},{"Reference":{"value":"/coll/reference_model/doc/RF000881"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC292","properties":{"Recommendation":{"value":"In a meta-analysis of controlled trials examining treatments to slow progression of ADPKD, a single trial (N = 1445) of tolvaptan was identified. The meta-analysis reported that this study showed that use of tolvaptan compared to placebo in patients with ADPKD slowed the rate of total kidney volume (TKV) growth (from 5.5% to 2.8% per year) and reduced the rates of worsening kidney function (2 vs 5 events per 100 person-years of follow-up) but did not do further calculations. A Cochrane systematic review reported that high dose tolvaptan significantly reduced systolic and diastolic blood pressure in comparison to low-dose tolvaptan but found no other significant differences in included studies for other outcomes comparing tolvaptan to placebo or high vs. low dose tolvaptan."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000869"}},{"Reference":{"value":"/coll/reference_model/doc/RF000889"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1221","properties":{"Key Text":{"value":"Sodium restricted diet"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with ADPKD should restrict their sodium intake to <100 mmol/day, as it has been shown to reduce blood pressure in a single randomized, double-blind, placebo-controlled, cross-over trial investigating the impact of sodium intake on ADPKD with hypertension, although it was limited by sample size."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Progression to ESRD"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000888"}}]}}}},{"Patient Management":{"value":"ACPM1223","properties":{"Key Text":{"value":"Patient education regarding aggravation of polycystic liver disease"},"Tier":{"value":"2"},"Recommendation Text":{"value":"All women of reproductive potential should receive counseling including potential aggravation of polycystic liver disease (PLD) with exogenous estrogen or progesterone exposures and pregnancy."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000874"}},{"Reference":{"value":"/coll/reference_model/doc/RF000890"}}]}}}},{"Patient Management":{"value":"ACPM1219","properties":{"Key Text":{"value":"Pregnancy recommendations"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Pregnant women with ADPKD should be monitored for the development of UTIs and hypertensive women should be followed as a high-risk pregnancy. Compared to a control cohort of patients diagnosed with simple cyst, pregnant ADPKD patients (N = 54; all diagnosed by ultrasound) had higher risks for gestational hypertension (12.0% vs 3.9%) and UTI (14.1% vs 0.7%) during their pregnancies. Increased fetal prematurity rates were found in preeclamptic women with ADPKD as compared with normotensive ADPKD women (28% vs 10%). More maternal complications occurred in women with PKD than in their unaffected family members (35% versus 19% P < 0.001) with preexisting hypertension being the most important risk factor for a maternal complication to occur."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Progression to ESRD"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}},{"Reference":{"value":"/coll/reference_model/doc/RF000867"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU648","properties":{"Key Text":{"value":"ICA screening"},"Tier":{"value":"2"},"Recommendation Text":{"value":"The guideline recommended frequency of ICA surveillance by MRA/CT angiography can vary among those with a negative result from their initial screening from no additional imaging, to imaging every 5-10 years, imaging in selective populations, or imaging in the event of symptom onset or prior to ESRD. Decision modeling has indicated that screening and treatment of ICAs in patients with ADPKD increases the life expectancy without neurological disability by 1 year. Detection of ICA should be followed by referral to neurosurgeon or expert center and allows for management by watchful waiting or surgery.  No randomized controlled trials have been conducted to determine the optimal management of ICAs."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic disability or death due to ICA"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}},{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000874"}},{"Reference":{"value":"/coll/reference_model/doc/RF000604"}},{"Reference":{"value":"/coll/reference_model/doc/RF000880"}}]}}}},{"Surveillance":{"value":"ACSU647","properties":{"Key Text":{"value":"TAAD screening"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Screening for TAAD using either echocardiography or chest MRI examination every two to three years is indicated for first-degree relatives of individuals with TAAD."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Morbidity due to thoracic aortic disease"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000042"}}]}}}},{"Surveillance":{"value":"ACSU649","properties":{"Key Text":{"value":"Blood pressure monitoring"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Ambulatory or home blood pressure monitoring is recommended for early diagnosis of hypertension."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Progression to ESRD"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}}]}}}},{"Surveillance":{"value":"ACSU646","properties":{"Key Text":{"value":"Monitoring disease progression"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Guidelines differ on how to monitor disease progression, with some guidelines recommending routine measurement of renal function by eGFR and others by either once yearly measurement of TKV by MRI, CT, or ultrasound, or assessing TKV by MRI only in clinical trials."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Progression to ESRD"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}},{"Reference":{"value":"/coll/reference_model/doc/RF000873"}},{"Reference":{"value":"/coll/reference_model/doc/RF000891"}}]}}}},{"Surveillance":{"value":"ACSU650","properties":{"Key Text":{"value":"Follow-up interval"},"Tier":{"value":"2"},"Recommendation Text":{"value":"ADPKD adults without renal failure should have yearly follow-up visits. Follow-up in other patients should be scheduled according to CKD stage."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Progression to ESRD"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}}]}}}}]},"Family Managements":{"value":null,"items":[]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA542","properties":{"Key Text":{"value":"Caffeine"},"Tier":{"value":"3"},"Recommendation Text":{"value":"It is recommended that patients avoid caffeine in large amounts."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA543","properties":{"Key Text":{"value":"Smoking"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should stop or avoid starting active smoking and avoid passive smoking. Smokers with ADPKD have a statistically significant increased risk for ESRD (odds ratio, 3.5-5.8; CI: 2.0-17)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Progression to ESRD"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000888"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":"Biallelic PKD1- or PKD2-related ADPKD has been reported in individuals with very early-onset ADPKD. Digenic ADPKD (pathogenic variants in both PKD1 and PKD2) has been described in individuals with more severe renal disease than was reported in heterozygous relatives."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}},{"Reference":{"value":"/coll/reference_model/doc/RF000042"}},{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000871"}},{"Reference":{"value":"/coll/reference_model/doc/RF000874"}},{"Reference":{"value":"/coll/reference_model/doc/RF000875"}},{"Reference":{"value":"/coll/reference_model/doc/RF000876"}},{"Reference":{"value":"/coll/reference_model/doc/RF000877"}},{"Reference":{"value":"/coll/reference_model/doc/RF000878"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 500"},"Tier":{"value":"3"},"Notes":{"value":"Among ADPKD cases with a known pathogenic variant, PKD1, PKD2, GANAB and DNAJB11 account for 78%, 15%, ~0.3%, and ~0.1% of these cases, respectively. However, approximately 7% of individuals who undergo comprehensive mutation screening of these genes have no pathogenic variant identified.  This indicates that pathogenic variants in PKD1, PKD2, GANAB, or DNAJB11 are likely to have a similar, although slightly lower, summed prevalence as that estimated for ADPKD, or between 2.7:10,000 to 1:400."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Progression to ESRD"}},{"Outcome":{"value":"Neurologic disability or death due to ICA"}},{"Outcome":{"value":"Morbidity due to thoracic aortic disease"}}]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}},{"Reference":{"value":"/coll/reference_model/doc/RF000042"}},{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000869"}},{"Reference":{"value":"/coll/reference_model/doc/RF000870"}},{"Reference":{"value":"/coll/reference_model/doc/RF000873"}},{"Reference":{"value":"/coll/reference_model/doc/RF000874"}}]}}},"Penetrances":{"value":6,"items":[{"Penetrance":{"value":"ACPE634","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"ADPKD has a high penetrance for renal cysts, with virtually all patients developing bilateral renal cysts. Penetrance is reduced for ESRD and varies by genotype. The mean age of onset of ESRD is age 58 for PKD1-related ADPKD (range: infancy to 80 years) with a penetrance of 50% by age 60. Penetrance of ESRD in other genotypes was not specified, though the following comparisons were made: ESRD average age of onset is 79 for PKD2-related ADPKD, with a lower probability of reaching ESRD in PKD2-related ADPKD.  DNAJB11-related ADPKD is associated with progression to renal insufficiency or ESRD most often after the 6th decade.  Pathogenic variants in GANAB are not typically associated with a decline in renal function."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Progression to ESRD"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}},{"Reference":{"value":"/coll/reference_model/doc/RF000042"}},{"Reference":{"value":"/coll/reference_model/doc/RF000869"}},{"Reference":{"value":"/coll/reference_model/doc/RF000874"}},{"Reference":{"value":"/coll/reference_model/doc/RF000875"}},{"Reference":{"value":"/coll/reference_model/doc/RF000876"}},{"Reference":{"value":"/coll/reference_model/doc/RF000877"}},{"Reference":{"value":"/coll/reference_model/doc/RF000878"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC082","properties":{"Recommendation":{"value":"A study of 333 patients with pathogenic variant-associated ADPKD found that in those with PKD1-related ADPKD, 34% (N=110 patients) reached ESRD by a mean age of 54.3 years. In those with PKD2-related ADPKD, 14% (N = 40 patients) reached ESRD by a mean age of 74.0 years."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000902"}}]}}}}]}}}},{"Penetrance":{"value":"ACPE636","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"According to MRI results, hepatic cysts have a prevalence of up to 94% by age 46."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000042"}}]}}}},{"Penetrance":{"value":"ACPE637","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"1"},"Notes":{"value":"Systematic reviews of ADPKD patient cohorts have found ICA prevalence rates of 10-11.5%. One systematic review included data from two cohorts of patients (total N = 88 patients) who were not found to have an ICA at the time of baseline evaluation. In these patients, 1 patient (0.13%) had an ICA rupture in the study observation time (792-person years across all individuals)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic disability or death due to ICA"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000871"}},{"Reference":{"value":"/coll/reference_model/doc/RF000892"}}]}}}},{"Penetrance":{"value":"ACPE639","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"2"},"Notes":{"value":"The rupture of an ICA in those with clinically diagnosed ADPKD is associated with a mortality rate of 30-40% and a disability rate of 30%. Risk of rupture depends on additional clinical factors."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic disability or death due to ICA"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}}]}}}},{"Penetrance":{"value":"ACPE638","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"MVP occurs in up to 25% of individuals."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000874"}}]}}}},{"Penetrance":{"value":"ACPE635","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Multiple pregnancies (>3) have been reported to be associated with a greater risk for decline in kidney function."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000874"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR259","properties":{"Key Text":{"value":"2-3"},"Notes":{"value":"Individuals diagnosed with ADPKD and with a family history of hemorrhagic stroke or ICA (ruptured or unruptured) were 2.33 (95% CI: 1.60-3.38) times more likely to have an aneurysm than those individuals diagnosed with ADPKD and without a family history of stroke or ICA."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000871"}}]},"Tier":{"value":"1"}}}},{"Relative Risk":{"value":"RR258","properties":{"Key Text":{"value":">3"},"Notes":{"value":"In a large population-based cohort study of ADPKD patients (n = 2076) individuals diagnosed with ADPKD have a 5.49-fold (95% CI 2.86-10.52) greater risk for aortic aneurysm and dissection in comparison to non-ADPKD counterparts (n = 20760) after adjusting for age, sex, and comorbidities."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000893"}}]},"Tier":{"value":"5"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN289","properties":{"Key Text":{"value":"Marked discordant renal disease severity among affected family members has been well documented suggesting a role for other genetic and environmental modifiers."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000874"}}]},"Tier":{"value":"3"}}}},{"Expressivity Note":{"value":"EN290","properties":{"Key Text":{"value":"Recent studies have found that truncating variants of PKD1 and PKD2 are associated with more severe disease."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000042"}},{"Reference":{"value":"/coll/reference_model/doc/RF000874"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI296","properties":{"Key Text":{"value":"In experienced centers, elective repair of TAAD, depending on location of aneurysm, carries a mortality of at least 1-5%."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000046"}},{"Reference":{"value":"/coll/reference_model/doc/RF000045"}}]}}}},{"Nature of Intervention":{"value":"NOI293","properties":{"Key Text":{"value":"A meta-analysis reported the mortality rate after surgical treatment of ICA to be 12.7%. A randomized controlled trial found the combined morbidity (dependency) or mortality associated with ICA surgical treatment to be 23.7%-30.6% depending on procedure type."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000880"}}]}}}},{"Nature of Intervention":{"value":"NOI294","properties":{"Key Text":{"value":"A meta-analysis of the use of LLA in CKD of any etiology noted adverse events of elevated creatine kinase and liver dysfunction."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000879"}}]}}}},{"Nature of Intervention":{"value":"NOI295","properties":{"Key Text":{"value":"Adverse events associated with tolvaptan use were increased thirst, dry mouth, and liver enzyme levels. It has the potential to induce fatal liver toxicity and requires regular monitoring of liver enzymes. Patients may require considerable assistance in order to manage the aquaretic side effects of tolvaptan. Tolvaptan is only available through a restricted distribution and monitoring program due to these possible side effects."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000868"}},{"Reference":{"value":"/coll/reference_model/doc/RF000869"}},{"Reference":{"value":"/coll/reference_model/doc/RF000879"}},{"Reference":{"value":"/coll/reference_model/doc/RF000881"}},{"Reference":{"value":"/coll/reference_model/doc/RF000889"}},{"Reference":{"value":"/coll/reference_model/doc/RF000894"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC288","properties":{"Key Text":{"value":"ICAs are usually asymptomatic. The rupture of an ICA results in a SAH, which may cause death or disability."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000043"}}]},"Tier":{"value":"2"}}}},{"Chance to Escape Clinical Detection":{"value":"CDEC289","properties":{"Key Text":{"value":"TAAD’s are largely asymptomatic until a sudden and catastrophic event, including aortic rupture or dissection, occurs, and is rapidly fatal in a large proportion of patients."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000045"}}]},"Tier":{"value":"2"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers 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guide surgical intervention","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Progression to ESRD","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacologic management of renal function","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"due to complex management and possible adverse effects"}}}}}}]}}}},{"Outcome":{"value":"Neurologic disability or death due to ICA","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0A","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICA surveillance","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity due to thoracic aortic disease","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"TAAD surveillance to guide surgical intervention","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"extrapolated from Marfan"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"strandet","properties":{"First Name":{"value":"Tasha"},"Last Name":{"value":"Strande"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Progression to ESRD","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacologic management of renal function","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Neurologic disability or death due to ICA","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICA surveillance","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Morbidity due to thoracic aortic disease","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"TAAD surveillance to guide surgical intervention","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Progression to ESRD","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacologic management of renal function","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":"The only real data specific to ESRD are for tolvaptan, and those are scant."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Due to potential for tolvaptan side effects."}}}}}}]}}}},{"Outcome":{"value":"Neurologic disability or death due to ICA","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":"Am presuming that ICAs nearly always lead to neurologic disability - would go with 1 if that's not the case."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICA surveillance","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"Based on decision modeling showing increased life expectancy w/o euro disability of 1 yr."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity due to thoracic aortic disease","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"TAAD surveillance to guide surgical intervention","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":"Not much data, but should be effective way to detect TAAD and intervene via thoracic aortic replacement."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Progression to ESRD","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacologic management of renal function","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Neurologic disability or death due to ICA","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICA surveillance","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Morbidity due to thoracic aortic disease","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"TAAD surveillance to guide surgical intervention","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Progression to ESRD","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3B","properties":{"Notes":{"value":"I am thinking this is not a tier 4-- we surely have quality evidence for penetrance on renal disease"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacologic management of renal function","properties":{"Effectiveness":{"value":"2","properties":{"Notes":{"value":"There is an excellent section on interventions that can preserve renal function and reduce cyst development in GeneReviews. I think these should be summarized here for reviewers to know what is out there."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Neurologic disability or death due to ICA","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"1","properties":{"Notes":{"value":"10% if prevalence not incidence.  having and ICA is not a problem unless it ruptures.  That is what we need data on. from Zhou: Fifteen studies with 1,490 participants with ADPKD were pooled to study about the prevalence of intracranial aneurysm in participants with ADPKD, and the prevalence rate was found to be 10% (95% CI 7-13%). Studies from China, Japan and Europe (Germany, Poland) reported a higher prevalence of intracranial aneurysm. Having a family history of haemorrhagic stroke or intracranial aneurysm was a risk factor for aneurysm occurrence. Twenty-three percent (95% CI 15-31%) of the participants had multiple aneurysms. Most of the aneurysms were small (<6 mm) and located in the anterior circulation. Five studies with 171 participants (83 with 106 aneurysms at baseline and 88 without) were analyzed to understand the natural history of aneurysms, with an incidence of aneurysm growth, new aneurysm and aneurysm rupture of 1.84% (followed up for 435 person-years), 0.57% (1,227 person-years) and 0.13% (792 person-years) respectively. Very low incidence of rupture, hence disability or death.  \nCagnazzo: Our systematic review included 16 articles with a total of 563 patients with ADPKD and intracranial aneurysms. The prevalence of unruptured aneurysms was 11.5% (95% CI = 10.1-13%), whereas 1.9% (95% CI = 1.3-2.6%) of aneurysms were ruptured"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICA surveillance","properties":{"Effectiveness":{"value":"Not Scored","properties":{"Notes":{"value":"again, where is the information on whether this leads to useful interventions."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"the intervention is the imaging not the operations, right?"}}}}}}]}}}},{"Outcome":{"value":"Morbidity due to thoracic aortic disease","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"TAAD surveillance to guide surgical intervention","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Fix the Thoracic aortic replacement statement.  This should say When the aortic root diameter reaches 55-60 mm, replacement of the aorta is indicated."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"the intervention is the imaging, not the interventions, right"}}}}}}]}}}}]}}}},{"Scorer":{"value":"murugumanickam","properties":{"First Name":{"value":"Murugu"},"Last Name":{"value":"Manickam"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Progression to ESRD","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3A","properties":{"Notes":{"value":"surprised by Tier 4 for progression to ESRD; there is variation between gene, variant and even within a family. Correlation with cysts number and size."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacologic management of renal function","properties":{"Effectiveness":{"value":"0A","properties":{"Notes":{"value":"Tolvaptan and HTN treatment both have some controversy to prevent ESRD"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Neurologic disability or death due to ICA","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"1B","properties":{"Notes":{"value":"ICA incidence is 10-11% but rupture appears rare"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICA surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity due to thoracic aortic disease","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"TAAD surveillance to guide surgical intervention","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"Did reduce one because it is extraction from Marfan syndrome"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"jenniferposey","properties":{"First Name":{"value":"Jennifer"},"Last Name":{"value":"Posey"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Progression to ESRD","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacologic management of renal function","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":"Based on Tolvaptan data"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Neurologic disability or death due to ICA","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0A","properties":{"Notes":{"value":"Actual likelihood of poor outcome due to ICA unclear"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICA surveillance","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity due to thoracic aortic disease","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"TAAD surveillance to guide surgical intervention","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"Extrapolating from Marfan"}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"2.0.0","properties":{"Notes":{"value":""},"Public Notes":{"value":""},"kbRevision-PairedKB":{"value":36929},"ReasonCode":{"value":"Q4","properties":{"Reason":{"value":"Scoring pairs updated with major updates in the report"}}},"Date":{"value":"2019-03-21"},"ReleasedBy":{"value":"marianjgilmore","properties":{"First Name":{"value":"Mari"},"Last Name":{"value":"Gilmore"}}}}}}}},
{"ActionabilityDocID":{"value":"AC039","properties":{"Status":{"value":"Released"},"Genes":{"value":5,"items":[{"Gene":{"value":"PKP2","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:9024"},"GeneOMIM":{"value":"602861"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"609040"}}]}}}},{"Gene":{"value":"DSP","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:3052"},"GeneOMIM":{"value":"125647"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"607450"}}]}}}},{"Gene":{"value":"DSC2","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:3036"},"GeneOMIM":{"value":"125645"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"610476"}}]}}}},{"Gene":{"value":"TMEM43","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:28472"},"GeneOMIM":{"value":"612048"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"604400"}}]}}}},{"Gene":{"value":"DSG2","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:3049"},"GeneOMIM":{"value":"125671"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"610193"}}]}}}}]},"Syndrome":{"value":"Arrhythmogenic Right Ventricular Dysplasia","properties":{"OmimIDs":{"value":5,"items":[{"OmimID":{"value":"609040"}},{"OmimID":{"value":"607450"}},{"OmimID":{"value":"610476"}},{"OmimID":{"value":"604400"}},{"OmimID":{"value":"610193"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle; with time, it may also involve the left ventricle. The presentation of disease is highly variable even within families."},"Acronyms":{"value":5,"items":[{"Acronym":{"value":"Arrhythmogenic right ventricular  dysplasia 9"}},{"Acronym":{"value":"Arrhythmogenic right ventricular  dysplasia 8"}},{"Acronym":{"value":"Arrhythmogenic right ventricular  dysplasia 11"}},{"Acronym":{"value":"Arrhythmogenic right ventricular  dysplasia 5"}},{"Acronym":{"value":"Arrhythmogenic right ventricular  dysplasia 10"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"\"Arrhythmogenic Right Ventricular Dysplasia\"[Mesh] limited to Guideline, Systematic Reviews","properties":{"NumberOfHits":{"value":18},"Date":{"value":"2015-07-14"}}}},{"SearchString":{"value":"\"Defibrillators, Implantable\"[Mesh] AND replacement (specific search for battery life)","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-07-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"by disease:  cardiovascular diseases:  'arrhythmia' and 'genetic'","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-07-14"}}}},{"SearchString":{"value":"by disease:  Congenital, Hereditary, and Neonatal Diseases and Abnormalities:  'arrhythmia'","properties":{"NumberOfHits":{"value":15},"Date":{"value":"2015-07-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-07-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":6},"Date":{"value":"2015-07-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-07-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"arrhythmogenic; dysplasia; cardiomyopathy; arvd; arvc","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-07-14"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"ICD implantation"}},{"Intervention":{"value":"Anti-arrhythmic therapy"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 1000"},"Notes":{"value":"The prevalence is estimated to be approximately 1 per 1,000 to 5,000 individuals in the general population worldwide.  Higher numbers may be found in specific regions."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000025"}},{"Reference":{"value":"/coll/reference_model/doc/RF000026"}},{"Reference":{"value":"/coll/reference_model/doc/RF000284"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Arrhythmogenic right ventricular dysplasia or cardiomyopathy (here referred to as ARVD) is characterized by structural and functional abnormalities of the right ventricle, with or without concomitant left ventricular disease.  Clinical diagnosis is based on demonstration of characteristic electrocardiogram (ECG), arrhythmic, structural, and/or histological abnormalities along with family history of sudden cardiac death (SCD) or a disease-causing mutation."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000029"}},{"Reference":{"value":"/coll/reference_model/doc/RF000284"}},{"Reference":{"value":"/coll/reference_model/doc/RF000028"}},{"Reference":{"value":"/coll/reference_model/doc/RF000025"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years.   Among 100 ARVD patients from a US registry, the most common presenting symptoms were palpitations, syncope, and sudden cardiac death in 27%, 26%, and 23% of patients, respectively.  Estimates of the annual incidence of SCD vary from 0.08% to 9%. In the early 'concealed' phase, individuals are often asymptomatic, but may still be at risk of SCD, especially during exertion. However, SCD with no apparent provocation is not uncommon.  In the symptomatic phase, individuals present with arrhythmias and right ventricular morphological abnormalities discernible by conventional imaging. Later, diffuse disease may result in heart failure while ventricular arrhythmias may or may not be present."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000029"}},{"Reference":{"value":"/coll/reference_model/doc/RF000284"}},{"Reference":{"value":"/coll/reference_model/doc/RF000031"}},{"Reference":{"value":"/coll/reference_model/doc/RF000028"}},{"Reference":{"value":"/coll/reference_model/doc/RF000030"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM872","properties":{"Key Text":{"value":"Antiarrhythmic medication (beta-blockers, the anti-arrhythmic beta-blocker sotalol, amiodarone)"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Antiarrhythmic medication (beta-blockers, the anti-arrhythmic beta-blocker sotalol, amiodarone) can be used to prevent ventricular arrhythmias.  In one study of patients with ARVD neither beta blocker therapy (n=58) nor sotalol (n=38) were protective against ventricular arrhythmias. However, amiodarone was associated with lower risk for any clinically relevant arrhythmias. Larger studies are needed to confirm this finding."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000284"}}]}}}},{"Patient Management":{"value":"ACPM871","properties":{"Key Text":{"value":"Implantable cardioverter defibrillators"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Implantable cardioverter defibrillators (ICD) can be effective for the prevention of SCD in ARVD patients with extensive disease, 1 or more affected family members with SCD, or undiagnosed syncope when VT or VF has not been excluded as the cause of syncope, who are receiving chronic optimal medical therapy. However, there is not clear consensus among guidelines on the specific risk factors that identify those ARVD patients in whom the probability of SCD is sufficiently high to warrant an ICD for primary prevention. Individualized decisions for primary prevention of SCD must be based on experience, judgment, and the available data."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000005"}},{"Reference":{"value":"/coll/reference_model/doc/RF000031"}},{"Reference":{"value":"/coll/reference_model/doc/RF000030"}}]}}}},{"Patient Management":{"value":"ACPM869","properties":{"Key Text":{"value":"Implantable cardioverter defibrillators"},"Tier":{"value":"1"},"Recommendation Text":{"value":"In a systematic review of 18 cohort studies enrolling 610 patients who had received an ICD for primary or secondary prevention of SCD, the appropriate and inappropriate annual ICD intervention rates were 9.5% and 3.7%, respectively."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000032"}}]}}}},{"Patient Management":{"value":"ACPM870","properties":{"Key Text":{"value":"Electrophysiological testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Electrophysiological (EP) testing might be useful for risk assessment of SCD in patients with ARVD. The prognostic role of EP testing in patients presenting with isolated PVCs or NSVT is not known. The response to EP testing may be influenced by the severity of the disease. In one study EP testing in 17 patients with \"mild\" dysplasia and induced VT only in patients with spontaneous sustained VT. VT was induced in 90% of 12 patients with spontaneous sustained VT. The positive predictive value for recurrent VT was only 55%. In a second study, sustained VT could not be induced in 20 patients presenting with NSVT. In this study, inducibility was 88% in 24 of 27 patients presenting with sustained VT."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000030"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU475","properties":{"Key Text":{"value":"Clinical screening for cardiomyopathy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Clinical screening for cardiomyopathy is recommended at yearly intervals after age 10 to age 50 in asymptomatic individuals known to carry a disease-causing mutation(s) or at any time that signs or symptoms appear. Consider repeat screening at 1 year for any abnormal clinical screening test. Recommended screening consists of clinical history and physical exam; electrocardiogram and echocardiogram; Holter monitoring; and imaging. In an analysis of a registry of ARVD patients, all 69 patients who were diagnosed with ARVD while living demonstrated one or more ECG abnormality characteristic of ARVD.  In another study, MRI was found to be 100% sensitive to those meeting ARVD diagnostic criteria."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000033"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM315","properties":{"Key Text":{"value":"Mutation-specific genetic testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Mutation-specific genetic testing is recommended for appropriate family members following the identification of the ARVD-causative mutation in an index case."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000029"}},{"Reference":{"value":"/coll/reference_model/doc/RF000034"}},{"Reference":{"value":"/coll/reference_model/doc/RF000026"}}]}}}},{"Family Management":{"value":"ACFM317","properties":{"Key Text":{"value":"Clinical screening for cardiomyopathy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Clinical screening for cardiomyopathy (as described in Surveillance) is recommended in asymptomatic at-risk relatives who are known to carry the disease-causing mutation(s)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000034"}},{"Reference":{"value":"/coll/reference_model/doc/RF000033"}}]}}}},{"Family Management":{"value":"ACFM316","properties":{"Key Text":{"value":"Screening in the absence of genetic testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"In situations where genetic testing has not been performed or has not identified a disease causing mutation, screening is recommended at least every 5 years starting at age 10. Whether screening may be discontinued is uncertain as the age of complete penetrance is not known."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000034"}},{"Reference":{"value":"/coll/reference_model/doc/RF000033"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA384","properties":{"Key Text":{"value":"High-intensity endurance exercise"},"Tier":{"value":"3"},"Recommendation Text":{"value":"ARVD is present in 4% to 22% of athletes with sudden cardiac death. There is some debate over whether high-intensity endurance exercise can cause development of ARVD and therefore should be avoided."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000284"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":"Autosomal recessive has also been described. Up to 57% of persons with ARVD have been shown to have compound heterozygosity or digenic heterozygosity."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000284"}},{"Reference":{"value":"/coll/reference_model/doc/RF000031"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Tier":{"value":"3"},"Notes":{"value":"Overall yield of genetic testing for all available genes in probands who meet diagnostic criteria for ARVD approximates 50% with the majority of mutations (11-51%) occurring in PKP2. Exceptions include a founder mutation in the TMEM43 gene in the Newfoundland, Canada population.\n\nInformation on the prevalence of genetic mutations associated with ARVD in the general population was not available."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000284"}},{"Reference":{"value":"/coll/reference_model/doc/RF000025"}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE442","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"Not provided"},"Notes":{"value":"In a study of 35 PKP2 mutation carriers among 9 unrelated families (including probands) 49% met criteria for ARVD. Excluding probands, 31% were clinically diagnosed with ARVD. (Tier 3)\n\nClinical evaluation of 24 family members of 9 probands, all with DSG2 mutations, demonstrated penetrance of 58 to 75% depending on diagnostic criteria.  (Tier 3)\n\nIn 15 unrelated families from Newfoundland, penetrance was 100% in males and females carrying the S358L variant in the TMEM43 gene by ages 63 and 76 years, respectively.  (Tier 3)\n\nIn a single family with DSP mutation carriers, penetrance was estimated at 50%.  (Tier 3)\n\nPenetrance is age-related and often incomplete as late as 50-60 years of age.   (Tier 3)"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Sudden cardiac death"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000036"}},{"Reference":{"value":"/coll/reference_model/doc/RF000037"}},{"Reference":{"value":"/coll/reference_model/doc/RF000034"}},{"Reference":{"value":"/coll/reference_model/doc/RF000035"}},{"Reference":{"value":"/coll/reference_model/doc/RF000284"}}]}}}},{"Penetrance":{"value":"ACPE443","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"Information on the penetrance of SCD is limited.   In a study of 130 probands fulfilling clinical criteria for ARVD, there were 7 SCDs (4.4%) over a mean followup of 8 years.  In a study of 100 persons in 9 families with genetically confirmed ARVD (diagnosed clinically or via autopsy), 31 experienced sudden cardiac death.  In a study of 11 families with members at risk for mutations in TMEM43, 31% of 197 individuals at high risk of a mutation died of SCD. In these last two studies, no time frame for observation was provided. (Tier 3)\n\nStudies of genetic variation in ARVD-related genes in healthy population controls suggest that variants that would be considered rare and pathogenic may be common and penetrance depends on type of mutation."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Sudden cardiac death"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000284"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR180","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information on relative risk was not available."},"References":{"value":null,"items":[]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC011","properties":{"Recommendation":{"value":""},"Tier":{"value":"Not provided"},"References":{"value":null,"items":[]}}}}]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN203","properties":{"Key Text":{"value":"Disease expression is variable with regard to age at onset and severity."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000029"}},{"Reference":{"value":"/coll/reference_model/doc/RF000034"}},{"Reference":{"value":"/coll/reference_model/doc/RF000028"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC024","properties":{"Recommendation":{"value":"ARVD patients carrying more than one disease-associated mutation may show a more severe phenotype characterized by a younger age of onset and worse prognosis."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000025"}}]}}}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI205","properties":{"Key Text":{"value":"Interventions include non-invasive surveillance, long-term pharmacotherapy, and possible ICD implantation which may be associated with moderate risk and burden.\n\nBased on data from the National ICD Registry, more than 25% of procedures are to replace devices."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000038"}}]},"Tier":{"value":"Not provided"}}}},{"Nature of Intervention":{"value":"NOI206","properties":{"Key Text":{"value":"Among patients receiving replacement ICDs between 2005 and 2010 and reported to the National ICD Registry, the median time to replacement was 4.6 years (25-75% Interquartile Range 3.7-5.8) for all types of replaced devices."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000039"}}]},"Tier":{"value":"Not provided"}}}},{"Nature of Intervention":{"value":"NOI207","properties":{"Key Text":{"value":"In one study of 132 ARVD patients followed for a mean of 39 months, 16% of patients per year experienced an inappropriate ICD shock. In a second study, 23% of patients received inappropriate shocks during a mean follow-up period of almost 7 years."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000040"}},{"Reference":{"value":"/coll/reference_model/doc/RF000041"}}]},"Tier":{"value":"Not provided"}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC201","properties":{"Key Text":{"value":"SCD may be the first manifestation of disease. Among 100 ARVD patients from a US registry, 23% of cases were identified after SCD. Establishing a presymptomatic diagnosis among family members allows monitoring for disease development and genetic counseling."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000284"}},{"Reference":{"value":"/coll/reference_model/doc/RF000030"}}]},"Tier":{"value":"2"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2016-07-22"},"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"bieseckerl"}},{"Scorer":{"value":"williamsm"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"strandet"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"jensenb"}}]}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"ICD 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{"ActionabilityDocID":{"value":"AC040","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"SCN5A","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:10593"},"GeneOMIM":{"value":"600163"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"601144"}}]}}}}]},"Syndrome":{"value":"Brugada Syndrome","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"601144"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Brugada is characterized by ST segment elevation in the right precordial electrocardiogram leads and a high incidence of sudden death in patients with structurally normal hearts. The syndrome typically manifests in adulthood."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Brugada Syndrome"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"((\"Brugada Syndrome\"[Mesh]) OR \"NAV1.5 Voltage-Gated Sodium Channel\"[Mesh]) OR \"SCN5A protein, human\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":11},"Date":{"value":"2015-04-10"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":3,"items":[{"SearchString":{"value":"Brugada syndrome","properties":{"NumberOfHits":{"value":7},"Date":{"value":"2015-04-10"}}}},{"SearchString":{"value":"SCN5A","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-04-10"}}}},{"SearchString":{"value":"Sudden Unexplained Nocturnal Death Syndrome","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-04-10"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-04-10"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-04-10"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-04-10"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"NA","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-04-10"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"No"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"Yes","properties":{"Exception Made":{"value":"Yes","properties":{"Note why exception made":{"value":"AWG decided Brugada syndrome was an important clinical condition and warranted further assessment. JEH"}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 5000"},"Notes":{"value":"The prevalence of Brugada syndrome is difficult to estimate due to the recent identification of the disorder and the difficulty in diagnosis. Available prevalence estimates vary around the world, from 1/700-1/800 in certain endemic areas of Asia to 1/3,300-1/10,000 in Europe and the United States."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000285"}},{"Reference":{"value":"/coll/reference_model/doc/RF000002"}},{"Reference":{"value":"/coll/reference_model/doc/RF000003"}},{"Reference":{"value":"/coll/reference_model/doc/RF000286"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Brugada syndrome is characterized by a distinctive ECG pattern of sinus tachycardia (ST) segment elevation in the V1-V3 leads (termed \"type 1 abnormality\") in the absence of gross structural abnormalities.  Patients have a high risk for ventricular arrhythmias, which can result in syncope or sudden cardiac death. Clinical presentations may also include sudden infant death syndrome (SIDS) and the sudden unexpected nocturnal death syndrome (SUNDS). Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome. Electrical storms, multiple episodes of ventricular arrhythmias over a short period of time, are malignant but rare in patients."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000286"}},{"Reference":{"value":"/coll/reference_model/doc/RF000003"}},{"Reference":{"value":"/coll/reference_model/doc/RF000005"}},{"Reference":{"value":"/coll/reference_model/doc/RF000002"}},{"Reference":{"value":"/coll/reference_model/doc/RF000285"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Brugada syndrome presents primarily during adulthood, with syncope as the most common presenting feature. Age at diagnosis ranges from 2 days to 85 years. The mean age of sudden death is approximately 40 years. Both sexes are at a high risk for ventricular arrhythmias and sudden death, though the vast majority of those affected are male. Patients who have easily induced sustained ventricular arrhythmias, a spontaneous type 1 ECG pattern (compared to pharmacologically-induced), and a history of syncope have a worse prognosis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000285"}},{"Reference":{"value":"/coll/reference_model/doc/RF000003"}},{"Reference":{"value":"/coll/reference_model/doc/RF000286"}},{"Reference":{"value":"/coll/reference_model/doc/RF000005"}},{"Reference":{"value":"/coll/reference_model/doc/RF000006"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM877","properties":{"Key Text":{"value":"ICD"},"Tier":{"value":"2"},"Recommendation Text":{"value":"An implantable cardioverter defibrillator (ICD) is reasonable for patients with Brugada syndrome, though some guidelines only recommend ICD implantation for those with certain risk factors such as a history of syncope and/or documented ventricular tachycardia that has not resulted in cardiac arrest.  ICD should also be considered in patients with a spontaneous type 1 ECG pattern. In the absence of a spontaneous type 1 ECG pattern, an implantable loop recorder (ILR) should be considered. A cohort study of 220 patients with Brugada and a history of syncope reported an appropriate ICD shock rate of 10% over 3 years."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000007"}},{"Reference":{"value":"/coll/reference_model/doc/RF000005"}},{"Reference":{"value":"/coll/reference_model/doc/RF000006"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC195","properties":{"Recommendation":{"value":"Two additional cohort studies reported appropriate shock rates of 19%, 16%, and 12% for patients with a history of syncope, patients with a type 1 ECG pattern, and asymptomatic patients, respectively."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000009"}},{"Reference":{"value":"/coll/reference_model/doc/RF000008"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM876","properties":{"Key Text":{"value":"ICD"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Treatment of asymptomatic individuals is controversial and recommendations vary, but include observation until the first symptom develops and placement of an ICD in individuals with a family history of sudden cardiac death or when electrophysiological study indicates a likelihood of arrhythmias."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000285"}}]}}}},{"Patient Management":{"value":"ACPM873","properties":{"Key Text":{"value":"Quinidine"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Quinidine is recommended to prevent primary symptoms, and has been shown to restore ST-segment elevation and decrease the incidence of arrhythmias.  In one study, of 19 patients treated for 6 to 219 months and followed 0.5 to 22 years, none had an arrhythmic event. In another study, syncope occurred in 2 of 21 patients treated an average of 17 months."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000285"}}]}}}},{"Patient Management":{"value":"ACPM874","properties":{"Key Text":{"value":"Quinidine"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Women experiencing arrhythmic events due to hormone changes during pregnancy can be treated with quinidine to normalize the ECG pattern. In a case study of a young pregnant woman, oral quinidine inhibited the recurrence of ventricular tachyarrhythmia."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000285"}}]}}}},{"Patient Management":{"value":"ACPM875","properties":{"Key Text":{"value":"Management during anesthesia"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Because perioperative pharmacological and physiological changes may precipitate malignant arrhythmias, specific management is required for patients under anesthesia."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000003"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU477","properties":{"Key Text":{"value":"ECG"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish extent of disease and individual needs after initial diagnosis, patients are recommended to undergo an ECG, induction with sodium channel blockers among those with a type 2 or type 3 pattern on ECG, electrophysiological study, and medical genetics consultation."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000285"}}]}}}},{"Surveillance":{"value":"ACSU476","properties":{"Key Text":{"value":"ECG"},"Tier":{"value":"3"},"Recommendation Text":{"value":"At-risk patients with a family history or a known pathogenic variant should undergo ECG monitoring every one to two years."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000285"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM318","properties":{"Key Text":{"value":"Risk stratification"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Serial ECGs and a pharmacological drug challenge can assist in risk stratification in individuals with a family history of Brugada syndrome."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000003"}}]}}}},{"Family Management":{"value":"ACFM319","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"3"},"Recommendation Text":{"value":"If the pathogenic variant is known, relatives at risk should undergo genetic testing to identify those who should undertake preventive measures as well as rule out risk for those not carrying the pathogenic variant."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000285"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA386","properties":{"Key Text":{"value":"Avoidance of Medications"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should avoid certain antiarrhythmic, psychotropic, and anesthetic drugs that can induce cardiac arrhythmias. Other agents to avoid include acetylcholine, alcohol toxicity, cocaine, and ergonovine."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000002"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA385","properties":{"Key Text":{"value":"Avoid fever and electrolyte disturbances"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Patients should also avoid or quickly mitigate high fever and electrolyte disturbances."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000285"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Pathogenic mutations in SCN5A account for 15-30% of Brugada syndrome cases."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000285"}},{"Reference":{"value":"/coll/reference_model/doc/RF000003"}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE444","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"Among individuals with a pathogenic variant in SCN5A, approximately 20-30% have a type 1 ECG pattern and approximately 80% manifest the characteristic ECG change when challenged with a sodium channel blocker."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Sudden cardiac death"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000285"}}]}}}},{"Penetrance":{"value":"ACPE445","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"4"},"Notes":{"value":"The majority of patients remain asymptomatic, while 20-30% experience syncope and 8-12% experience at least one cardiac arrest (potentially leading to sudden death)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000286"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR181","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information on relative risk was not available."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN204","properties":{"Key Text":{"value":"Information on variable expressivity was not available."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI208","properties":{"Key Text":{"value":"Identified interventions include the implantation of an ICD, which would involve invasive surgery."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC202","properties":{"Key Text":{"value":"Brugada syndrome is typically diagnosed with ECG, a screening procedure not typically recommended for asymptomatic adults with apparently low risk of coronary heart disease. It is very likely this disorder could go unrecognized and present in a patient as ventricular arrhythmia and cardiac arrest, resulting in sudden death in 8-12% of affected individuals."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000285"}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"sobreiran"}},{"Scorer":{"value":"bieseckerl"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"jensenb"}}]}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD implantation","properties":{"Overall 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{"ActionabilityDocID":{"value":"AC041","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"FLCN","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:27310"},"GeneOMIM":{"value":"607273"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"135150"}}]}}}}]},"Syndrome":{"value":"Birt-Hogg-Dubé syndrome","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"135150"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include cutaneous manifestations (fibrofolliculomas, trichodiscomas/angiofibromas, perifollicular fibromas, and acrochordons), pulmonary cysts/history of pneumothorax, and various types of renal tumors. Disease severity can vary significantly even within the same family."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Birt-Hogg-Dube Syndrome"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":3,"items":[{"SearchString":{"value":"\"Birt-Hogg-Dube Syndrome\"[Mesh]","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-03-30"}}}},{"SearchString":{"value":"\"Hereditary Renal Cancer Associated 1\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-03-30"}}}},{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":3},"Date":{"value":"2016-03-30"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-03-30"}}}},{"SearchString":{"value":"FLCN","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-03-30"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-03-30"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2016-03-30"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-03-30"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"HuGE Review[StudyType]>>Kidney Diseases, NEOPLASMS[Mesh]","properties":{"NumberOfHits":{"value":11},"Date":{"value":"2016-03-30"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity and mortality from masses","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Imaging to detect renal masses when intervention is effective"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"The prevalence of Birt-Hogg-Dubé syndrome (BHDS) is estimated at 1 in 200,000 but the exact incidence is unknown. There have been more than 100 families from various populations affected by BHDS."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000287"}},{"Reference":{"value":"/coll/reference_model/doc/RF000254"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"BHDS is a rare condition characterized by renal tumors of varying histologic subtypes, cutaneous benign tumors of the hair follicle (fibrofolliculomas), and pulmonary cysts, which can manifest as spontaneous pneumothoraces.  Cutaneous perifollicular fibromas, acrochordons, and angiofibromas have also been associated with BHDS, but only fibrofolliculomas are specific for BHDS. Other findings have included thyroid nodules and cysts, a few cases of thyroid cancer, colorectal cancer, benign parotic oncocytoma, cutaneous-type oral papules, and various other tumor types.  BHDS has been reported to be associated with cutaneous melanoma, but whether the risk in individuals with BHDS is increased compared to the general population is unclear."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000287"}},{"Reference":{"value":"/coll/reference_model/doc/RF000254"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Skin lesions typically develop during the third or fourth decade of life, and most often have a distribution on the face, neck, and anterior trunk.  Fibrofolliculomas increase in size and number with age but are not malignant. Later onset correlates with a milder skin phenotype. Women tend to have smaller and fewer lesions than men.  While skin lesions usually have an earlier onset than renal tumors, some patients have presented with pulmonary and/or renal involvement without skin lesions.\n\nLung cysts are mostly bilateral and multifocal, and do not cause pulmonary symptoms.  However, lung cysts predispose to a high risk of spontaneous, often recurrent, pneumothorax, which may present without symptoms or with dyspnea and chest pain. Families with confirmed FLCN mutations have been described in which pulmonary involvement appears to be the only disease manifestation.\n\nRenal cell tumors occur in a significant proportion of clinically-diagnosed BHDS patients with a wide age range of onset (median age, 48 years; range, 31 to 71). Unusually, BHDS-related renal tumors have different histologic subtypes. For example, in one study of 130 tumors from 30 BHDS patients, the renal histology included 34% chromophobe, 5% oncocytoma, 50% chromophobe/oncocytic hybrid, 9% clear cell, and 2% papillary. Only renal oncocytoma is considered benign. Most renal tumors associated with BHDS are bilateral, multifocal, and slow growing, and may affect morbidity more than mortality."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000287"}},{"Reference":{"value":"/coll/reference_model/doc/RF000254"}},{"Reference":{"value":"/coll/reference_model/doc/RF000255"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM878","properties":{"Key Text":{"value":"Establish extent of disease and needs"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with BHDS, the following evaluations are recommended:\n\n• Detailed dermatologic examination; punch biopsy of suspected cutaneous lesion\n\n• High-resolution computed tomography (HRCT) or CT of the chest for visualization of pulmonary cysts. Individuals with symptoms/signs of pneumothorax should immediately undergo chest x-ray and CT with appropriate followup.\n\n• Baseline abdominal/pelvic CT scan with contrast or MRI to screen for renal tumor. Renal ultrasound examination may distinguish cystic from solid renal lesions.\n\n• Medical genetics consultation"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000254"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU478","properties":{"Key Text":{"value":"Renal imaging"},"Tier":{"value":"3"},"Recommendation Text":{"value":"There is no consensus on clinical surveillance; current recommendations are provisional:\n\n•Beginning at age 18 years, or later when a BHDS diagnosis is established, annual MRI of the kidneys is optimal to assess for lesions (unless family history suggests earlier testing).  FLCN-confirmed individuals without a family history of kidney tumors who have had 2-3 consecutive tumor-free MRI examinations may be screened every 2 years. Discovery of any suspicious lesion <1 cm in diameter should result in a return to an annual interval for screening.\n\n  -     Renal lesions <3 cm in diameter are monitored by periodic imaging.  Rapidly growing lesions and/or those with potentially associated symptoms require a more individualized approach. Once the largest tumor reaches 3 cm in maximal diameter, referral to a urologic surgeon is appropriate in order to evaluate the need for nephron-sparing surgery.\n\n   -      In a prospective study, 124 clinically or genetically diagnosed individuals with BHDS were followed by surveillance.  Of these, 34 (27%) had renal tumors detected at an average age of 50 years.  Of 10 with tumors >3cm and treated surgically at one institution, 5 remained disease-free, 3 had small renal tumors (2 in the non-operated kidney), and 2 died of metastatic renal cancer (predominantly clear cell) at a median of 38 months. No other patients have had metastatic disease since.\n\n•Full body skin examination at routine intervals to evaluate any suspicious pigmented lesions for melanoma should be considered."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000254"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM320","properties":{"Key Text":{"value":"Genetic testing when family-specific variant is known"},"Tier":{"value":"4"},"Recommendation Text":{"value":"When the family-specific pathogenic variant is known, genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces unnecessary surveillance of members who have not inherited the pathogenic variant."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000254"}}]}}}},{"Family Management":{"value":"ACFM321","properties":{"Key Text":{"value":"Clinical surveillance of asymptomatic at-risk relatives"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Early recognition of clinical manifestations may allow timely intervention and improve outcome. Therefore, clinical surveillance of asymptomatic at-risk relatives for early detection is appropriate."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000254"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA388","properties":{"Key Text":{"value":"Environmental exposures"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Cigarette smoking, high ambient pressures, which may precipitate spontaneous pneumothorax, and radiation exposure should be avoided."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000254"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA387","properties":{"Key Text":{"value":"Total nephrectomy"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Total nephrectomy should be avoided in order to decrease morbidity by preserving functioning renal tissue."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000254"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"FLCN (previously known as BHD) is the only gene known to be associated with BHDS. Population prevalence of FLCN mutations was not reported. FLCN mutations are found in 88-93% of clinically diagnosed individuals, depending on the analysis method."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000254"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE446","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"5"},"Notes":{"value":"In one study of 89 individuals (from 51 families; median age 54 years) with an FLCN germline pathogenic variant:\n\n• 84% had fibrofolliculoma \n• 84% had pulmonary cysts on chest CT \n• 38% had a history of spontaneous pneumothorax \n• 34% had renal tumors.\n\n\n In a separate review of published cases with FLCN germline mutations:\n• 85% (122 of 143) had fibrofolliculoma\n• 87% (95 of 109) had lung cysts\n• 33% (57 of 171) reported a history of spontaneous pneumothorax \n• 20% (35 of 177) had renal tumors.   \n\n\nExcluding reports from the National Cancer Institute Clinical Center from this series: \n• 73% had fibrofolliculoma, \n• 77% had lung cysts \n• 40% had spontaneous penumothorax\n• 6.5% (5 of 77) had renal tumors."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Morbidity and mortality from masses"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000256"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR182","properties":{"Key Text":{"value":">3"},"Notes":{"value":"By comparison to unaffected family members, individuals with BHDS have risks of developing renal tumors and spontaneous pneumothorax that are 7- and 50-fold higher, respectively."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000254"}}]},"Tier":{"value":"3"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN205","properties":{"Key Text":{"value":"Disease 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Clinical CPVT is defined by premature ventricular contractions or ventricular tachycardia during exercise stress testing. Absent emotional or physical stress, CPVT patients have a normal resting ECG."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000029"}},{"Reference":{"value":"/coll/reference_model/doc/RF000053"}},{"Reference":{"value":"/coll/reference_model/doc/RF000289"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000029"}},{"Reference":{"value":"/coll/reference_model/doc/RF000289"}},{"Reference":{"value":"/coll/reference_model/doc/RF000056"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM879","properties":{"Key Text":{"value":"Beta blockers"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Beta-blockers are recommended for symptomatic patients with CPVT and may be effective in asymptomatic patients with a genetic diagnosis. In a study of 101 CPVT patients, including 50 probands, diagnosed clinically or by genetic mutation in the RYR2 or CASQ2 gene, 81 were administered beta-blockers.  Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05) In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (HR, 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000057"}},{"Reference":{"value":"/coll/reference_model/doc/RF000058"}},{"Reference":{"value":"/coll/reference_model/doc/RF000030"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU480","properties":{"Key Text":{"value":"Holter recordings and exercise tests"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Holter recordings and exercise tests should be repeated periodically to assure that the degree of sinus tachycardia that precedes the onset of arrhythmias is known so that in daily life it can be avoided as much as possible."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000058"}},{"Reference":{"value":"/coll/reference_model/doc/RF000030"}}]}}}},{"Surveillance":{"value":"ACSU479","properties":{"Key Text":{"value":"Resting ECG"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Resting ECG is also recommended surveillance."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000289"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM322","properties":{"Key Text":{"value":"Mutation-specific genetic testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the CPVT-causative mutation in an index\rcase.  Early CPVT genetic evaluation facilitates pre-symptomatic diagnosis, appropriate\rcounseling, and initiation of prophylactic beta blocker therapy. Due to instances of SIDS associated with RYR2 mutations, confirmatory genetic testing should be performed at birth in families with known mutations."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000029"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA389","properties":{"Key Text":{"value":"Strenuous exercise, stress"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with a diagnosis of CPVT should limit/avoid competitive sports, strenuous exercise, exposure to stressful environments, and use of digoxin."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000059"}},{"Reference":{"value":"/coll/reference_model/doc/RF000058"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":"The proportion of de novo RYR2 mutations is estimated at approximately 40%."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000289"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Tier":{"value":"2"},"Notes":{"value":"Approximately 60% of CPVT index cases have a RYR2 mutation."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000029"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC049","properties":{"Recommendation":{"value":"The prevalence of RYR2 mutations is unknown."},"Tier":{"value":"Not provided"},"References":{"value":null,"items":[]}}}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE447","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Clinical penetrance for ventricular arrhythmia ranges from 25 to 100%, with an average of 70 to 80%."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Sudden cardiac death"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000060"}}]}}}},{"Penetrance":{"value":"ACPE448","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"5"},"Notes":{"value":"In one study of 30 clinically identified probands and 118 family members, RyR2 mutations were confirmed in 14 probands and 9 family member carriers.  Among these 23, 7 SCDs occurred in individuals less than or equal to ,  ≤ 40 years of age (30%).  No observational time frame was reported."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Sudden cardiac death"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000061"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR183","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information on relative risk was not available."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN206","properties":{"Key Text":{"value":"Age at onset is variable extending into adulthood and severity of disease symptoms among different individuals can range from minor dizziness and faintness to the possible outcome of sudden death."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000289"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI210","properties":{"Key Text":{"value":"Interventions include non-invasive surveillance and long-term use of beta-blockers."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC204","properties":{"Key Text":{"value":"Although the mean age of onset of CPVT symptoms occurs in childhood, onset well into adulthood has been reported. 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{"ActionabilityDocID":{"value":"AC044","properties":{"Status":{"value":"Released"},"Genes":{"value":2,"items":[{"Gene":{"value":"F8","properties":{"HGNCId":{"value":"HGNC:3546"},"GeneOMIM":{"value":"300841"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"306700"}}]}}}},{"Gene":{"value":"F9","properties":{"HGNCId":{"value":"HGNC:3551"},"GeneOMIM":{"value":"300746"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"306900"}}]}}}}]},"Syndrome":{"value":"Hemophilia A and B","properties":{"OmimIDs":{"value":2,"items":[{"OmimID":{"value":"306900"}},{"OmimID":{"value":"306700"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"X-linked recessive bleeding disorder"},"Acronyms":{"value":10,"items":[{"Acronym":{"value":"Hemophilia"}},{"Acronym":{"value":"HEMA"}},{"Acronym":{"value":"Classic hemophilia"}},{"Acronym":{"value":"Factor VIII deficiency"}},{"Acronym":{"value":"Hemophilia B"}},{"Acronym":{"value":"HEMB"}},{"Acronym":{"value":"Christmas 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IX\\\"[Mesh]","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-07-27"},"searchURL":{"value":"http://www.ncbi.nlm.nih.gov/pubmed/?term=(((%22Hemophilia+A%22%5BMesh%5D)+OR+%22Hemophilia+B%22%5BMesh%5D)+OR+%22Factor+VIII%22%5BMesh%5D)+OR+Factor+IX%5BMesh%5D"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"MedGen","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Hemophilia 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Clearinghouse","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"f8","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2016-07-27"},"searchURL":{"value":"https://www.guideline.gov/search?q=F8"}}}},{"SearchString":{"value":"F9","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-07-27"},"searchURL":{"value":"https://www.guideline.gov/search?q=F9"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":"Enter notes here..."},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":"Enter value here..."}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":0,"items":[]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Males: Severe/prolonged hemorrhage","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development of comprehensive management plan based on activity levels"}}]}}}},{"Outcome":{"value":"Females: Severe/prolonged hemorrhage","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development of comprehensive management plan based on activity levels"}}]}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 10000"},"Notes":{"value":"It is estimated that there are roughly 400,000 individuals worldwide and 17,000 males in the US with hemophilia due to factor VIII (Hemophilia A or HEMA) or factor IX (Hemophilia B or HEMB) deficiency. HEMA is more common than HEMB, representing 80-85% of all patients with hemophilia. Age-adjusted prevalence rates in US males, similar to worldwide rates, have been estimated as 1/10,000 for HEMA and 1/35,000 for HEMB. The incidence of HEMA and HEMB in the US was estimated to be 1/5032 live male births."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000276"}},{"Reference":{"value":"/coll/reference_model/doc/RF000277"}},{"Reference":{"value":"/coll/reference_model/doc/RF000292"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"HEMA and HEMB are X-linked disorders that typically affect males while females are most commonly carriers. As many as 1/3 of all cases (depending on hemophilia type) are the result of spontaneous mutation, and thus patients will lack a prior family history. Both disorders are characterized by deficiencies in coagulation factors that promote blood clotting, which results in abnormal bleeding. Signs include easy bruising; spontaneous bleeding or bleeding for no apparent/known reason, particularly in the joints, muscles, and soft tissues; and excessive bleeding following trauma or surgery. Bleeding can be immediate due to impaired clot formation or delayed due to clot instability. Some bleeding can be life-threatening and require immediate treatment."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000280"}},{"Reference":{"value":"/coll/reference_model/doc/RF000279"}},{"Reference":{"value":"/coll/reference_model/doc/RF000277"}},{"Reference":{"value":"/coll/reference_model/doc/RF000276"}},{"Reference":{"value":"/coll/reference_model/doc/RF000292"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Disease severity is correlated with the level of factor VIII or IX clotting activity, with a normal range of about 50-150% for both. In the US, it is estimated that roughly 43%, 26%, and 31% of patients with hemophilia are classified as severe, moderate, and mild: \n\n  • Severe (<1% clotting activity): Patients are typically diagnosed prior to age 2.  Patients experience prolonged bleeding or excessive pain and swelling from joint bleeds, minor injuries, surgery, and tooth extractions. Without treatment, spontaneous bleeding is common (mostly in the joints and muscles), with an average frequency of 2-5 episodes per month. \n\n  • Moderate (1-5% clotting activity): Patients are typically diagnosed prior to age 5 or 6. They seldom have spontaneous bleeding but prolonged or delayed oozing may be triggered by relatively minor trauma if untreated. The frequency of episodes varies from once a month to once a year. \n\n  • Mild (6-40% clotting activity): Patients are often diagnosed later in life. They do not have spontaneous bleeding and may not bleed excessively until they experience trauma, tooth extractions, or surgery. The frequency of bleeding varies from once a year to once every ten years.\n\nFemale carriers may experience milder symptoms of abnormal bleeding. Roughly 10% of carriers with factor clotting levels <35% for factor VIII and <30% for factor IX are at similar risk for bleeding as males with mild hemophilia. A few carriers may have clotting factor levels in the moderate or severe range due to extremely skewed X-inactivation. In addition, more subtle abnormal bleeding may be seen with clotting factor activity in the ranges of 35-60% for factor VIII and 30-60% for factor IX. Women are at particular risk of bleeding complications during menstruation and, especially for HEMB, during and following childbirth. Menorrhagia is the most common bleeding symptom in women and may be the first or only presenting symptom.\n\nThe leading cause of death related to bleeding is intracranial hemorrhage. The major cause of disability from bleeding is from chronic joint disease. Prophylactic treatment with clotting factor concentrates normalizes life expectancy and reduces chronic disease."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000292"}},{"Reference":{"value":"/coll/reference_model/doc/RF000276"}},{"Reference":{"value":"/coll/reference_model/doc/RF000280"}},{"Reference":{"value":"/coll/reference_model/doc/RF000279"}},{"Reference":{"value":"/coll/reference_model/doc/RF000277"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM881","properties":{"Key Text":{"value":"Evaluations after diagnosis"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with hemophilia, the following evaluations are recommended:\n\n  • A personal and family history of bleeding to help predict disease severity\n\n  • A joint and muscle evaluation, particularly if the individual describes a history of hemarthrosis or deep-muscle hematomas\n\n  • Baseline CBC and platelet count, especially if there is a history of nose bleeds, GI bleeding, mouth bleeding; or in women, menorrhagia or postpartum hemorrhage\n\n  • Medical genetics consultation, particularly if a new diagnosis in the family and for females of childbearing years."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000279"}},{"Reference":{"value":"/coll/reference_model/doc/RF000280"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC196","properties":{"Recommendation":{"value":"Prophylaxis with factor replacement is the main form of therapy in young patients with severe disease and prevents bleeding and joint destruction. Prophylaxis is not recommended for mild disease."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000292"}},{"Reference":{"value":"/coll/reference_model/doc/RF000277"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM887","properties":{"Key Text":{"value":"Patient management at home"},"Tier":{"value":"2"},"Recommendation Text":{"value":"All patients should be taught to self-administer at home under supervision and monitoring by a hemophilia specialist. Patients should treat acute bleeding episodes as quickly as possible, preferably within 2 hours. Treatment consists of factor IX concentrate for HEMB and desmopressin for mild to possibly moderate cases of HEMA, in responsive patients, or factor VIII concentrate."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000292"}},{"Reference":{"value":"/coll/reference_model/doc/RF000277"}}]}}}},{"Patient Management":{"value":"ACPM884","properties":{"Key Text":{"value":"Patient identification for emergencies"},"Tier":{"value":"2"},"Recommendation Text":{"value":"To facilitate appropriate management in emergency situations, all patients should carry easily accessible identification indicating the diagnosis, severity of the bleeding disorder, inhibitor status, type of treatment product used, initial dosage for treatment of severe, moderate, and mild bleeding, and contact information of the treating physician/clinic."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000292"}},{"Reference":{"value":"/coll/reference_model/doc/RF000277"}}]}}}},{"Patient Management":{"value":"ACPM882","properties":{"Key Text":{"value":"Surgery management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"A hemophilia patient requiring surgery is best managed at or in consultation with a comprehensive hemophilia treatment center to ensure care by healthcare professionals with experience treating patients with bleeding disorders."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000293"}},{"Reference":{"value":"/coll/reference_model/doc/RF000292"}}]}}}},{"Patient Management":{"value":"ACPM885","properties":{"Key Text":{"value":"Pre-surgery factor treatment"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Infusion of factor concentrates/hemostatic agents may be necessary before invasive diagnostic procedures, endoscopy with biopsy, surgery, and during the post-operative period."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000293"}},{"Reference":{"value":"/coll/reference_model/doc/RF000292"}},{"Reference":{"value":"/coll/reference_model/doc/RF000276"}}]}}}},{"Patient Management":{"value":"ACPM886","properties":{"Key Text":{"value":"Oral hygiene"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Good oral hygiene is essential to prevent periodontal disease and dental caries, which predispose to gum bleeding. Patients should undergo an enhanced regimen of preventive dental care (brushing, flossing, and fluoride treatment) as well as regular dental exams with a general dental practitioner. Oral injections, deep dental cleanings, tooth extraction, and oral surgery should be done in consultation with hemophilia specialists."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000293"}},{"Reference":{"value":"/coll/reference_model/doc/RF000292"}},{"Reference":{"value":"/coll/reference_model/doc/RF000276"}}]}}}},{"Patient Management":{"value":"ACPM883","properties":{"Key Text":{"value":"Physical activites"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Regular exercise and other activities to stimulate psychomotor development should be encouraged to promote strong muscles, develop balance and coordination, improve fitness, and maintain a healthy body weight. Non-contact and low-impact sports are encouraged. An active lifestyle improves muscle tone and balance to prevent falls and improve range of joint movement. Two small studies have also shown a reduction in bleeding tendency with exercise. A study of 11 hemophiliac boys showed a decrease in mean prothrombin time across all patients, while 4 mild cases had increased factor VIII activity.  A separate study of 8 patients indicated that 7 showed significantly reduced muscle bleeds after 13 months on a home exercise program."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000292"}},{"Reference":{"value":"/coll/reference_model/doc/RF000277"}},{"Reference":{"value":"/coll/reference_model/doc/RF000281"}}]}}}},{"Patient Management":{"value":"ACPM889","properties":{"Key Text":{"value":"Vaccinations"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with hemophilia should be vaccinated. Immunization to hepatitis A and B is especially important for all persons with hemophilia."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000293"}},{"Reference":{"value":"/coll/reference_model/doc/RF000292"}},{"Reference":{"value":"/coll/reference_model/doc/RF000277"}}]}}}},{"Patient Management":{"value":"ACPM888","properties":{"Key Text":{"value":"Enzyme assay in carrier females"},"Tier":{"value":"2"},"Recommendation Text":{"value":"In females known to be carriers, it is important to assay their factor VII or factor IX levels to establish whether they are at increased risk of bleeding."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000277"}}]}}}},{"Patient Management":{"value":"ACPM880","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Pregnancy in carriers of hemophilia should be managed by a multidisciplinary team including an obstetrician, hematologist, and anesthetist. A pregnancy and delivery plan should be formulated to meet the needs of the patient. Pregnancy management should include:\n\n  • Assessment of family and personal bleeding history.\n\n  • Knowledge of fetal gender enables appropriate management of labor and delivery to reduce the risk of bleeding in a potentially affected infant.  Invasive fetal monitoring techniques (e.g., fetal scalp electrodes and blood sampling), vacuum extractions, mid-cavity or difficult forceps deliveries, and prolonged labor should be avoided for an affected male fetus or when the fetal sex or coagulation status of the male fetus is unknown. Delivery should be achieved by the least traumatic method and early recourse to cesarean section should be considered.\n\n  • Cord blood should be collected from all male neonates to assess clotting factor levels for identification and early management. In addition, until the affected status is known, intramuscular injections and venipunctures should be avoided, vitamin K should be given orally, routine immunizations should be given intradermally or subcutaneously, heel pricks should be avoided, and circumcision should be delayed. \n\n  • Clotting factor levels should be assessed at booking and at 28 and 34 weeks gestation to allow appropriate management of labor and delivery and to assess the need for prophylactic treatment.\n\n  • The risk of postpartum hemorrhage (PPH) can be reduced by active monitoring of factor levels during the third stage of labor.  In addition, factor levels should be monitored and adjusted appropriately post-delivery for at least 3 days, or 5 days for a cesarean delivery. In carriers, the incidence of primary (<24 hours) and secondary (>24 hours) PPH is 22% and 11%, respectively, compared to 5-8% and 0.8% in the general population, respectively.  Evidence that active monitoring improves outcomes was not available."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000292"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000277"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU481","properties":{"Key Text":{"value":"Comprehensive care setting"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with hemophilia are best managed in a comprehensive care setting with a multidisciplinary team of healthcare professionals with experience in treating bleeding disorders. Patients should meet with their team regularly for a complete hematologic, serologic, musculoskeletal, and psychosocial assessment and to develop, audit, and refine their comprehensive management plan. The frequency of assessments depends on the severity of hemophilia. Analysis of a cohort of 2950 patients with hemophilia indicated that treatment via a hemophilia treatment center that provided comprehensive care was associated with reduced mortality (RR=0.6, 95% CI=0.5-0.8)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000293"}},{"Reference":{"value":"/coll/reference_model/doc/RF000292"}},{"Reference":{"value":"/coll/reference_model/doc/RF000277"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM323","properties":{"Key Text":{"value":"Enzyme assay"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Immediate female relatives (mother, sisters, and daughters) of a person with hemophilia should have their clotting factor level checked, especially prior to any invasive intervention, childbirth, or if any symptoms occur."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000292"}}]}}}},{"Family Management":{"value":"ACFM324","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Where available and possible, genetic testing for carrier status should be offered to at-risk female family members of people with hemophilia to facilitate genetic counseling."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000292"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA393","properties":{"Key Text":{"value":"Drugs that affect platelet function"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Drugs that affect platelet function, such as aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), should be avoided. Paracetamol/acetaminophen, cyclo-oxygenase-2 (COX-2) inhibitors, or opioids are recommended alternatives for analgesia."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000293"}},{"Reference":{"value":"/coll/reference_model/doc/RF000292"}},{"Reference":{"value":"/coll/reference_model/doc/RF000277"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA390","properties":{"Key Text":{"value":"Intramuscular injections"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Avoid all intramuscular injections (administer vaccines subcutaneously)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000277"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA392","properties":{"Key Text":{"value":"Cutting into vein"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Never cut down into a vein, except in an emergency, and venous access devices should be avoided whenever possible."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000293"}},{"Reference":{"value":"/coll/reference_model/doc/RF000292"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA391","properties":{"Key Text":{"value":"Risky activities"},"Tier":{"value":"2"},"Recommendation Text":{"value":"High contact and collision sports (e.g., hockey, wrestling) as well as high-velocity activities (e.g., skiing) should be avoided."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000292"}},{"Reference":{"value":"/coll/reference_model/doc/RF000277"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"X-linked"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 10000"},"Tier":{"value":"3"},"Notes":{"value":"Information on the prevalence of genetic mutations associated with HEMA and HEMB in the general population was not available. However, given that virtually all males with mutations associated with hemophilia are affected, the prevalence of mutations in F8 and F9 in males is likely similar to the prevalence rates of HEMA (1/10,000) and HEMB (1/35,000), respectively. In addition, carrier prevalence can be estimated for HEMA (1/5000) and HEMB (1/17,500) based on the prevalence in males."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000276"}},{"Reference":{"value":"/coll/reference_model/doc/RF000277"}},{"Reference":{"value":"/coll/reference_model/doc/RF000292"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE449","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"4"},"Notes":{"value":"All males with pathogenic F8 and F9 variants are affected. Approximately 10% of carrier females will be affected due to factor VIII clotting activity <30% or factor IX clotting activity <35%. In addition, mild bleeding can occur in carriers with low-normal factor activity."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000279"}},{"Reference":{"value":"/coll/reference_model/doc/RF000280"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR184","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information on relative risk was not available."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN207","properties":{"Key Text":{"value":"The nature of hemophilia is consistent among family members with the same mutation. However, other genetic and environmental effects may modify the clinical severity to some extent."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000279"}},{"Reference":{"value":"/coll/reference_model/doc/RF000280"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI211","properties":{"Key Text":{"value":"Interventions identified for HEMA and HEMB include increased surveillance, particularly during surgical or other invasive procedures and childbirth, with the potential for administration of prophylactic agents, such as factor concentrates, to prevent bleeding. Patients often respond variably to the administration of coagulation agents and may develop complications such as alloimmune inhibitors (antibodies) to the clotting factor or allergic reactions.  Inhibitors to F8 or, far less often, F9 proteins can severely impede the effectiveness of treatment. Inhibitor development likely affects only a small proportion of mild/moderate HEMA cases."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000292"}},{"Reference":{"value":"/coll/reference_model/doc/RF000279"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC205","properties":{"Key Text":{"value":"Though patients with moderate or severe hemophilia will likely be detected and diagnosed prior to adulthood, patients with mild hemophilia are often not diagnosed until later in life when they undergo surgery or tooth extraction or experience major trauma."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000279"}},{"Reference":{"value":"/coll/reference_model/doc/RF000280"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2016-07-27"},"Scorers Present":{"value":2,"items":[{"Scorer":{"value":"fakescorer"}},{"Scorer":{"value":"buchanana"}}]}}},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Males: Severe/prolonged hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development of comprehensive management plan based on activity levels","properties":{"Overall Score":{"value":"9CB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Females: Severe/prolonged hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development of comprehensive management plan based on activity levels","properties":{"Overall Score":{"value":"9CB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":0,"items":[]}}},"Scorers":{"value":2,"items":[{"Scorer":{"value":"fakescorer","properties":{"First Name":{"value":"Fake"},"Last Name":{"value":"Scorer"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe/prolonged hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe/prolonged hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"added the gene-disease pairs that were missing\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36042},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-10"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC047","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"GLA","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:4296"},"GeneOMIM":{"value":"300644"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"301500"}}]}}}}]},"Syndrome":{"value":"Fabry Disease","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"301500"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. This enzymatic defect leads to the systemic accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes of vessels, nerves, tissues, and organs throughout the body"},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Fabry Disease"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"(\"Fabry Disease\"[Mesh] OR \"Fabry Disease, Cardiac Variant\" [Supplementary Concept]) OR ( \"alpha-galactosidase A, human\" [Supplementary Concept] OR \"alpha-Galactosidase\"[Mesh] )","properties":{"NumberOfHits":{"value":30},"Date":{"value":"2015-06-24"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":8,"items":[{"SearchString":{"value":"Fabry","properties":{"NumberOfHits":{"value":5},"Date":{"value":"2015-06-24"}}}},{"SearchString":{"value":"GLA","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-06-24"}}}},{"SearchString":{"value":"ANGIOKERATOMA CORPORIS DIFFUSUM","properties":{"NumberOfHits":{"value":5},"Date":{"value":"2015-06-24"}}}},{"SearchString":{"value":"ANDERSON-FABRY DISEASE","properties":{"NumberOfHits":{"value":5},"Date":{"value":"2015-06-24"}}}},{"SearchString":{"value":"ALPHA-GALACTOSIDASE A DEFICIENCY","properties":{"NumberOfHits":{"value":5},"Date":{"value":"2015-06-24"}}}},{"SearchString":{"value":"HEREDITARY DYSTOPIC LIPIDOSIS","properties":{"NumberOfHits":{"value":5},"Date":{"value":"2015-06-24"}}}},{"SearchString":{"value":"GLA DEFICIENCY","properties":{"NumberOfHits":{"value":5},"Date":{"value":"2015-06-24"}}}},{"SearchString":{"value":"CERAMIDE TRIHEXOSIDASE DEFICIENCY","properties":{"NumberOfHits":{"value":5},"Date":{"value":"2015-06-24"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-06-24"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2018-04-26"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-06-24"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Fabry OR GLA AND HuGE Review","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-06-24"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":8,"items":[{"Outcome":{"value":"Cardiovascular disease (males)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy"}}]}}}},{"Outcome":{"value":"Cardiovascular disease (females)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy"}}]}}}},{"Outcome":{"value":"Cerebrovascular events (males)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy"}}]}}}},{"Outcome":{"value":"Cerebrovascular events (females)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy"}}]}}}},{"Outcome":{"value":"End-stage renal disease (males)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy"}}]}}}},{"Outcome":{"value":"End-stage renal disease (females)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy"}}]}}}},{"Outcome":{"value":"Pain crises (males)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy"}}]}}}},{"Outcome":{"value":"Pain crises (females)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"The incidence of Fabry disease has historically been estimated as 1:50,000 to 1:117,000 births; however, more recent studies suggest the incidence may be as high as 1:1,600 to 1:3,100. This likely reflects a broader phenotypic spectrum identified in the last decade with a ratio of 11:1 of persons with the later-onset:classic phenotypes."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000295"}},{"Reference":{"value":"/coll/reference_model/doc/RF000804"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Fabry disease encompasses a spectrum of phenotypes resulting from deficient activity of the enzyme α-galactosidase (α-Gal A) and progressive lysosomal deposition of globotriaosylceramide (GL-3) in cells throughout the body. The classic form occurs in males with less than 1% α-Gal A enzyme activity with periodic crises of severe pain in the extremities, appearance of vascular cutaneous lesions, hypohidrosis (diminished sweating response), proteinuria, and corneal and lenticular opacities. Disease progression can lead to cardiac and/or cerebrovascular disease; mitral insufficiency may be present in childhood and adolescence. Progressive decline in renal function leads to end stage renal disease (ESRD).  Patients may also have gastrointestinal, auditory, pulmonary, vascular, cranial nerve, and psychological manifestations. Cognitive function can be impaired. While, general intellectual and global cognitive functioning appear unaffected, there is evidence for impairment in executive functioning, information processing speed, and attention. An estimated 15-65% have depression, with pain the most common associated factor. \\n\\nHeterozygous females typically have milder and more variable symptoms. In addition, males with a greater than 1%  α-Gal A activity present later and may have either a cardiac variant phenotype, renal variant phenotype, or cerebrovascular disease presenting as stroke or transient ischemic attack. Males and females with the cardiac variant, present with left ventricular hypertrophy (LVH), mitral insufficiency, cardiomyopathy and arrhythmia, with proteinuria but without ESRD. The renal variant phenotype is typically associated with ESRD without the skin or pain symptoms associated with classic Fabry disease."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000295"}},{"Reference":{"value":"/coll/reference_model/doc/RF000807"}},{"Reference":{"value":"/coll/reference_model/doc/RF000805"}},{"Reference":{"value":"/coll/reference_model/doc/RF000806"}},{"Reference":{"value":"/coll/reference_model/doc/RF000804"}},{"Reference":{"value":"/coll/reference_model/doc/RF000064"}},{"Reference":{"value":"/coll/reference_model/doc/RF000067"}},{"Reference":{"value":"/coll/reference_model/doc/RF000066"}},{"Reference":{"value":"/coll/reference_model/doc/RF000065"}},{"Reference":{"value":"/coll/reference_model/doc/RF000069"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Onset of the classic form is generally in childhood or adolescent years (typically age 4-8 years).  Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Heterozygous females typically have a later age of onset than males. Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype. Patients with Fabry disease overall have a lower quality of life (QoL) compared to the general population.  Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespln among affected males (50-57 years) and females (70-72) compared to the normal population. The most common cause of death among both sexes is cardiovascular disease with most patients dying of cardiovascular disease having previously received renal replacement therapy. Before the availability of dialysis and transplantation, death from kidney failure occurred early in the first decade in classically affected males. Those patients with late-onset atypical variants of the disease are generally asymptomatic most of their lives. Those with the cardiac variant generally present in the sixth to eighth decade of life; many are diagnosed as the result of having hypertrophic cardiomyopathy. For those with the renal variant, age at onset is typically after 25 years."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000295"}},{"Reference":{"value":"/coll/reference_model/doc/RF000807"}},{"Reference":{"value":"/coll/reference_model/doc/RF000804"}},{"Reference":{"value":"/coll/reference_model/doc/RF000064"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM890","properties":{"Key Text":{"value":"Baseline evaluation"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should undergo baseline evaluation by a multidisciplinary team. Evaluation should include a complete physical and psychological exam including quality of life, measurement of  α-Gal A levels, and examination of the following systems: renal, cardiac, neurologic, ear/nose/throat, ophthalmologic, pulmonary, gastrointestinal, and skeletal."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000064"}},{"Reference":{"value":"/coll/reference_model/doc/RF000067"}},{"Reference":{"value":"/coll/reference_model/doc/RF000066"}},{"Reference":{"value":"/coll/reference_model/doc/RF000065"}}]}}}},{"Patient Management":{"value":"ACPM894","properties":{"Key Text":{"value":"Registry"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Baseline data and all follow up data should be transferred to a central registry."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000067"}},{"Reference":{"value":"/coll/reference_model/doc/RF000065"}}]}}}},{"Patient Management":{"value":"ACPM892","properties":{"Key Text":{"value":"ERT"},"Tier":{"value":"2"},"Recommendation Text":{"value":"In practice, there is wide variability in the use of ERT even for hemizygotes, with some starting therapy at a young age even without symptoms and others waiting until end organ damage is evident. The decision to initiate ERT should be made according to the clinical judgment of the managing metabolic physician in conjunction with the family of the patient."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Cardiovascular disease (males)"}},{"Outcome":{"value":"Cardiovascular disease (females)"}},{"Outcome":{"value":"Cerebrovascular events (males)"}},{"Outcome":{"value":"Cerebrovascular events (females)"}},{"Outcome":{"value":"End-stage renal disease (males)"}},{"Outcome":{"value":"End-stage renal disease (females)"}},{"Outcome":{"value":"Pain crises (males)"}},{"Outcome":{"value":"Pain crises (females)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000805"}},{"Reference":{"value":"/coll/reference_model/doc/RF000064"}},{"Reference":{"value":"/coll/reference_model/doc/RF000067"}},{"Reference":{"value":"/coll/reference_model/doc/RF000066"}},{"Reference":{"value":"/coll/reference_model/doc/RF000065"}},{"Reference":{"value":"/coll/reference_model/doc/RF000069"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC198","properties":{"Recommendation":{"value":"Limited trial literature has been published regarding the use of ERT for Fabry disease. A systematic review of RCTs of ERT reported on nine studies of 351 patients; however, many of these studies reported only on the effect of ERT on levels of unmetabolized GL-3. Data from 2 trials (n=39) found no statistally significant differences in plasma GL-3 concentration and one trial (n=24) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. However, one trial (n=26) found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (N= 82) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000804"}}]}}}},{"RecommendationID":{"value":"REC197","properties":{"Recommendation":{"value":"The majority of the literature related to ERT has been data generated registries mandated by regulatory authorities. A systematic review and analysis of pooled proportions included 77 cohort studies comprising 15,305 participants followed over a mean of 3.8 years; however, only data from 39 of these studies could be pooled. Within these cohorts 66% of participants were male and had a mean age of 35 years. For the majority of cohorts the phenotype (classic/non-classic) was not reported.  Although the rate of all-cause mortality in the primary analysis was higher in the untreated patients (10.8%), followed by agalsidase alfa (9%), and agalsidase beta (4.4%), there was no significant difference between the groups. Compared with untreated patients, treatment with algalsidase beta resulted in statistically significantly lower proportion of patients with renal complications (6% versus 21%), cardiovascular complications (7% versus 26%), and cerebrovascular complications (3.5% versus 17.8%). The differences between agalsidase alpha and untreated patients were not significantly different."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000808"}}]}}}},{"RecommendationID":{"value":"REC199","properties":{"Recommendation":{"value":"A separate systematic review of trial and observation studies was unable to draw any definitive conclusions about the effect of ERT on patient QoL."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000807"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM891","properties":{"Key Text":{"value":"Management of vascular risk factors"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Due to an increased risk of vascular events, other vascular risk factors (hypertension, dyslipidemia, diabetes mellitus, increased weight) should be aggressively managed."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000064"}},{"Reference":{"value":"/coll/reference_model/doc/RF000067"}}]}}}},{"Patient Management":{"value":"ACPM893","properties":{"Key Text":{"value":"Stroke prevention"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Risk of stroke is elevated in patients with Fabry disease. One cohort study found that among 33 Fabry patients, 24% suffered at least one stroke by the age of 29. In order to reduce stroke risk, aspirin may be offered starting at age 30 for males and age 35 for females.  Adequate intake of vitamins B12, B6, C, and folate should be promoted."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Cerebrovascular events (males)"}},{"Outcome":{"value":"Cerebrovascular events (females)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000064"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU482","properties":{"Key Text":{"value":"General Surveillance"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should undergo regular surveillance including complete physical and psychological exams and surveillance of the following systems: kidney, cardiac, neurologic, ear/nose/throat, ophthalmologic, pulmonary, gastrointestinal, and skeletal. Type and frequency of surveillance vary across systems and with individual patient symptoms."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Cardiovascular disease (males)"}},{"Outcome":{"value":"Cardiovascular disease (females)"}},{"Outcome":{"value":"Cerebrovascular events (males)"}},{"Outcome":{"value":"Cerebrovascular events (females)"}},{"Outcome":{"value":"End-stage renal disease (males)"}},{"Outcome":{"value":"End-stage renal disease (females)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000064"}},{"Reference":{"value":"/coll/reference_model/doc/RF000067"}},{"Reference":{"value":"/coll/reference_model/doc/RF000066"}},{"Reference":{"value":"/coll/reference_model/doc/RF000065"}}]}}}}]},"Family Managements":{"value":null,"items":[]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA395","properties":{"Key Text":{"value":"Smoking avoidance"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Due to the high risk of vascular events patients should be discouraged from smoking."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000064"}},{"Reference":{"value":"/coll/reference_model/doc/RF000067"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA394","properties":{"Key Text":{"value":"Amiodarone avoidance"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Given the potential effects on cellular levels  of α-galactosidase A, amiodarone (an antiarhythmia drug) has been contraindicated in persons with Fabry disease. However, there is little evidence of a detrimental effect and the relative benefit in patients with cardiac arrhythmia should be considered."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000295"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"X-linked"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 5000"},"Tier":{"value":"1"},"Notes":{"value":"Based on 6 studies in newborn screening populations in Europe and Taiwan, the pooled prevalence of newborns with a variant in the GLA gene, which includes variants of undetermined significance, is about 0.04%."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000071"}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE450","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"The incidence of cardiac complications is similar in individuals with the atypical Fabry cardiac variant and individuals with classic Fabry disease."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Cardiovascular disease (males)"}},{"Outcome":{"value":"Cardiovascular disease (females)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000295"}}]}}}},{"Penetrance":{"value":"ACPE451","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"The Fabry Registry and Fabry Outcomes Study reported a median age of symptom onset at 11-13 years for males and 19-23 years for females with pain the most frequent presenting symptom (62-76% males, 41-64% females). The following clinical events were reported for individuals in the registries:\n\nRenal dialysis or transplantation:\n- Males: 13-17% of males \n- Females: 1-2% females \n\nCardiovascular event (arrhythmia, myocardial infarction, angina pectoris, congestive heart failure, significant cardiac procedure)\n- Males: 19% \n- Females: 14% \n\nStroke\n- Males: 7% \n- Females: 5%  \n\nCerebrovascular event (stroke, transient ischemic attack, prolonged reversible ischemic neurologic deficit): \n- Males: 12-15% \n- Females: 11.5-27%"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Cardiovascular disease (males)"}},{"Outcome":{"value":"Cardiovascular disease (females)"}},{"Outcome":{"value":"Cerebrovascular events (males)"}},{"Outcome":{"value":"Cerebrovascular events (females)"}},{"Outcome":{"value":"End-stage renal disease (males)"}},{"Outcome":{"value":"End-stage renal disease (females)"}},{"Outcome":{"value":"Pain crises (males)"}},{"Outcome":{"value":"Pain crises (females)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000295"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR185","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN209","properties":{"Key Text":{"value":"Fabry disease encompasses a spectrum of phenotypes ranging from the severe classic phenotype to atypical forms that often lack many of the classical characteristics of the disease (e.g., skin lesion, sweating abnormalities)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000295"}}]},"Tier":{"value":"3"}}}},{"Expressivity Note":{"value":"EN208","properties":{"Key Text":{"value":"Substaintial intrafamilial and interfamilial variability in age of disease onset and disease progression exists."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000805"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI212","properties":{"Key Text":{"value":"Patient management involves non-invasive, multiple organ system medical screening and potentially the use of enzyme replacement therapy (infused bi-weekly). Infusions tend to be reasonably well tolerated, with reported infusion reactions of about 10%, mostly consisting of fever and transient rigors of mild to moderate intensity.  Within a pooled analysis of registry data, the rates of reported adverse events was 31% for agalsidase alfa and 34% for agalsidase beta. However, these rates were not significantly different from those reported by untreated patients (37%)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000804"}},{"Reference":{"value":"/coll/reference_model/doc/RF000808"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC206","properties":{"Key Text":{"value":"Misdiagnosis in individuals with Fabry is common in clinical care with some patients having a delay of >50 years before the correct diagnosis, and a delay of >20 years between the onset of symptoms and diagnosis being common. Recent studies have found that nearly half of Fabry patients (46%) experience their first stroke before being diagnosed."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000067"}},{"Reference":{"value":"/coll/reference_model/doc/RF000809"}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2018-06-18"},"Scorers Present":{"value":6,"items":[{"Scorer":{"value":"alexanderkatz"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"srego"}},{"Scorer":{"value":"jenniferposey"}},{"Scorer":{"value":"jvengoe"}}]},"Notes":{"value":""}}},"Outcomes":{"value":8,"items":[{"Outcome":{"value":"Cardiovascular disease 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(males)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Pain crises (females)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"jvengoe","properties":{"First Name":{"value":"Jaime"},"Last 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{"ActionabilityDocID":{"value":"AC048","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"APC","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:583"},"GeneOMIM":{"value":"611731"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"175100"}}]}}}}]},"Syndrome":{"value":"Familial Adenomatous Polyposis","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"175100"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":""},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Familial adenomatous polyposis"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":0,"items":[]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":0,"items":[]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2014-05-13"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"FAMILIAL ADENOMATOUS POLYPOSIS 1; FAP1","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2018-04-09"},"Notes":{"value":""},"Label":{"value":""}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2014-05-13"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2014-05-13"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Colorectal cancer (AFAP only)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"FullName":{"value":"Colonoscopy with polypectomy"}}}}]},"FullName":{"value":"Colorectal cancer (AFAP only)"}}}},{"Outcome":{"value":"Colorectal cancer","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"(Procto)colectomy","properties":{"FullName":{"value":"(Procto)colectomy"}}}}]},"FullName":{"value":"Colorectal cancer"}}}},{"Outcome":{"value":"Advanced-stage thyroid cancer","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual surveillance","properties":{"FullName":{"value":"Annual surveillance"}}}}]},"FullName":{"value":"Advanced-stage thyroid cancer"}}}},{"Outcome":{"value":"Upper GI (stomach or duodenum) cancer","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic EGD","properties":{"FullName":{"value":"Periodic EGD"}}}}]},"FullName":{"value":"Upper GI (stomach or duodenum) cancer"}}}},{"Outcome":{"value":"Morbidity from desmoid tumor","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Regular physical exam and imaging","properties":{"FullName":{"value":"Regular physical exam and imaging"}}}}]},"FullName":{"value":"Morbidity from desmoid tumor"}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 10000"},"Notes":{"value":"Estimates of the prevalence of FAP vary from 1:6,850 to 1:37,600 live births."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000183"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000296"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000297"}},{"Reference":{"value":"/coll/reference_model/doc/RF000816"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Classical FAP is characterized by the presence of ≥100 adenomatous polyps, with cases usually developing hundreds to thousands of adenomatous polyps. Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Extracolonic manifestations are variably present and include polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors, desmoid tumors, epidermoid cysts, adrenal gland adenoma, hepatoblastoma, thyroid cancer, and brain tumors. A milder phenotype of the disorder is referred to as attenuated FAP (AFAP), which occurs in approximately 8% of cases and is characterized by a milder course of the disease."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000183"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000296"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000297"}},{"Reference":{"value":"/coll/reference_model/doc/RF000816"}},{"Reference":{"value":"/coll/reference_model/doc/RF000822"}},{"Reference":{"value":"/coll/reference_model/doc/RF000184"}},{"Reference":{"value":"/coll/reference_model/doc/RF000114"}},{"Reference":{"value":"/coll/reference_model/doc/RF000818"}},{"Reference":{"value":"/coll/reference_model/doc/RF000113"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}},{"Reference":{"value":"/coll/reference_model/doc/RF000187"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"The average age of classic FAP diagnosis in patients presenting with symptoms is 35.8 years (range, 4–72 years). Colorectal adenomatous polyps begin to appear, on average, by age 16 (range: 7-36 years). By age 35, 95% of FAP patients have polyps. In virtually all cases, the adenomas will develop into CRC if left untreated. The mean age of CRC diagnosis in untreated individuals is has been reported between 34-50 years; with cancer developing nearly universally by age 50. Although unusual, CRC has been reported as early as 9 years of age. Although rare, asymptomatic individuals in their 50s have been reported. Duodenal cancer and desmoid tumors are the most common causes of death in patients with FAP after colorectal cancer. Duodenal adenocarcinoma occurs has been reported to occur between ages 17 and 81 years, with the mean age of diagnosis between 45 and 52 years. The incidence of desmoid tumors in FAP is highest in the second and third decades of life, with 80% occurring by age 40, and generally occurring within 5 years of colectomy. 5-10% of individuals with FAP experience morbidity and/or mortality from desmoid tumors, with the highest mortality rate reported for intra-abdominal tumors. The mean age of diagnosis of thyroid cancer is 28 years, ranging from 12 to 62 years, with a female preponderance observed. The majority of hepatoblastomas occur prior to age five years and exhibit a male preponderance.\\n\\nWhile the phenotype of AFAP is not well defined, widely used clinical criteria include the following: a delay in onset of adenomatous polyposis and colorectal cancer of 10–25 years compared with classical FAP; <100 adenomatous polyps at 25 years of age or older; and/or a late onset of disease (≥45 years of age) irrespective of polyp number."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000183"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000296"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000822"}},{"Reference":{"value":"/coll/reference_model/doc/RF000184"}},{"Reference":{"value":"/coll/reference_model/doc/RF000113"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM895","properties":{"Key Text":{"value":"Colonoscopy and polypectomy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"The recommendations detailed below are largely applicable to classic and attenuated FAP; however attenuated FAP, with its milder course, may be manageable by colonoscopy and polypectomy and these patients may never require colectomy depending on polyp burden."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal cancer (AFAP only)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000822"}},{"Reference":{"value":"/coll/reference_model/doc/RF000113"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC201","properties":{"Recommendation":{"value":"Recommendations and evidence for classical FAP are presented here."},"Tier":{"value":"Not provided"},"References":{"value":null,"items":[]}}}}]}}}},{"Patient Management":{"value":"ACPM897","properties":{"Key Text":{"value":"Multidisciplinary management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Treatment for FAP should include thorough counseling about the nature of the syndrome and the need for compliance with recommendations for management and surveillance. Patients should be managed ideally by clinicians with expertise in FAP and in the setting of a multidisciplinary team."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal cancer (AFAP only)"}},{"Outcome":{"value":"Colorectal cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000822"}},{"Reference":{"value":"/coll/reference_model/doc/RF000818"}},{"Reference":{"value":"/coll/reference_model/doc/RF000823"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC202","properties":{"Recommendation":{"value":"A systematic review of studies comparing CRC incidence and mortality before and after registry commencement, found 8 studies (3101 individuals) examining CRC incidence and 6 studies examining CRC mortality. Odds ratios for CRC incidence following registration range from 0.09-0.44, with all but one study showing a statistically significant effect. Odds ratios for CRC-related mortality range from 0.11-0.22, all significant."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000114"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM896","properties":{"Key Text":{"value":"Prophylactic (procto)colectomy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Colonscopic clearance of adenomas in patients with classical FAP cannot guarantee that cancer will be prevented; therefore, removal of the at-risk epithelium ((procto)colectomy) is  considered the standard of care, Decisions regarding the timing and type of operation to be performed (including rectal sparing or pouch construction) should be made by the patients after being fully informed about the natural history of the disease in relation to the individual’s polyp burden and the pros and cons of the surgical options. Removal of the colon should be undertaken at a premalignant stage, typically before age 25-30. Nonrandomized studies have demonstrated individual merits of each surgical approach."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000183"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000822"}},{"Reference":{"value":"/coll/reference_model/doc/RF000818"}},{"Reference":{"value":"/coll/reference_model/doc/RF000113"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}},{"Reference":{"value":"/coll/reference_model/doc/RF000824"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC200","properties":{"Recommendation":{"value":"There  remains a risk of adenoma and CRC after colectomy, and the extent of risk is influenced by the type of procedure chosen and type of tissue-sparing. The risk of adenoma has been estimated at 10% - 51% and the risk of cancer less than 1% to about 2% in studies after the modern surgical techniques became available. However, some registries have estimated the risk of mortality from rectal cancer in rectal-sparing procedures (ileorectal anastomosis) to be up to 12.5% for patients with a high rectal polyp burden."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000183"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000822"}},{"Reference":{"value":"/coll/reference_model/doc/RF000818"}},{"Reference":{"value":"/coll/reference_model/doc/RF000113"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}},{"Reference":{"value":"/coll/reference_model/doc/RF000824"}},{"Reference":{"value":"/coll/reference_model/doc/RF000189"}}]}}}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU486","properties":{"Key Text":{"value":"Endoscopic surveillance of the colon"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Endoscopic surveillance (i.e., flexible sigmoidoscopy or colonoscopy) is recommended until the polyp burden necessitates that colectomy is performed. Surveillance is generally recommended annually; however, some guidelines recommend screening every 6 months or every two years. During surveillance, polyp burden should be recorded and several polyps biopsied."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal cancer (AFAP only)"}},{"Outcome":{"value":"Colorectal cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000183"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000822"}},{"Reference":{"value":"/coll/reference_model/doc/RF000818"}},{"Reference":{"value":"/coll/reference_model/doc/RF000113"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}},{"Reference":{"value":"/coll/reference_model/doc/RF000824"}},{"Reference":{"value":"/coll/reference_model/doc/RF000189"}},{"Reference":{"value":"/coll/reference_model/doc/RF000825"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC032","properties":{"Recommendation":{"value":"A systematic review of patients with FAP found that 26 of 27 studies showed a statistically significant reduction in CRC incidence with surveillance (odds ratios ranged from 0.01 to 0.37) in screened patients compared to those who presented symptomatically with polyposis/CRC outside of a screening program. Eight studies examined CRC mortality, all of which showed a significant reduction in CRC mortality (odds ratios ranged from <0.01 to 0.16) in screened (N= 1028) versus symptomatic groups (N= 947). Two studies provided evidence for complete prevention of CRC-related deaths during surveillance, although the duration of follow-up was short (2-4 years)."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000114"}}]}}}}]}}}},{"Surveillance":{"value":"ACSU483","properties":{"Key Text":{"value":"EGD"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Surveillance for gastric and proximal small bowel tumors  with esophagogastroduodenoscopy using forward and side-viewing endoscopes  should begin at age 20 to 30. Most guidelines base the surveillance interval on endoscopic findings (Spigelman score for duodenal adenomatosis staging) at baseline."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Upper GI (stomach or duodenum) cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000183"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000822"}},{"Reference":{"value":"/coll/reference_model/doc/RF000818"}},{"Reference":{"value":"/coll/reference_model/doc/RF000113"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}},{"Reference":{"value":"/coll/reference_model/doc/RF000824"}},{"Reference":{"value":"/coll/reference_model/doc/RF000827"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC031","properties":{"Recommendation":{"value":"While surveillance with selective polypectomy/ampullectomy has been shown to decrease the Spigelman score, and higher Spigelman scores are associated with higher risk of cancer, guidelines note it is unclear if endoscopic prevention of all duodenal cancers is possible."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000183"}},{"Reference":{"value":"/coll/reference_model/doc/RF000818"}}]}}}},{"RecommendationID":{"value":"REC033","properties":{"Recommendation":{"value":"There is some evidence that screen-detection of duodenal cancer may improve survival; FAP patients have been shown to have a median survival after a screen-detected cancer of 8 years (95% CI, 5.9 - not estimated), versus 0.8 years (95% CI, 0.03-1.7) after symptomatic cancer (p < 0.0001)."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000775"}}]}}}},{"RecommendationID":{"value":"REC029","properties":{"Recommendation":{"value":"Malignant progression of fundic gland polyps of the stomach is uncommon and surveillance is considered adequate for monitoring for gastric cancers."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000822"}}]}}}}]}}}},{"Surveillance":{"value":"ACSU485","properties":{"Key Text":{"value":"Annual surveillance for desmoids"},"Tier":{"value":"2"},"Recommendation Text":{"value":"A regular physical exam with evaluation for palpable masses suggestive of desmoids is recommended with consideration for the use of computed tomography or magnetic resonance imaging based on family history."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Morbidity from desmoid tumor"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000822"}},{"Reference":{"value":"/coll/reference_model/doc/RF000113"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC030","properties":{"Recommendation":{"value":"The first line of treatment in patients with large or growing intra-abdominal or abdominal wall tumors is sulindac, usually in combination with tamoxifen, toremifene, or raloxifene. Surgery is reserved for small, well-defined tumors when a clear margin can be obtained; however, even in selected patients recurrence rates are high and the overall benefit of resection is not clear. Chemotherapy or radio therapy may be beneficial."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000183"}},{"Reference":{"value":"/coll/reference_model/doc/RF000818"}},{"Reference":{"value":"/coll/reference_model/doc/RF000113"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}}]}}}}]}}}},{"Surveillance":{"value":"ACSU487","properties":{"Key Text":{"value":"Annual surveillance for thyroid cancer"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Annual surveillance for thyroid cancer should be conducted; however, whether this screening should occur via ultrasound or physical exam is inconsistent across guidelines. There are no prospective studies comparing these screening strategies. A study comparing patients with screen-detected cancer to those with incident cancers showed that screening led to detection of smaller tumors with fewer positive lymph nodes."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Advanced-stage thyroid cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000822"}},{"Reference":{"value":"/coll/reference_model/doc/RF000818"}},{"Reference":{"value":"/coll/reference_model/doc/RF000113"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}}]}}}},{"Surveillance":{"value":"ACSU484","properties":{"Key Text":{"value":"Annual exam"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Annual physical and neurologic examination starting at age 25 to 30 years may be considered for central nervous system (CNS) cancers, but data to support this practice are 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Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Status":{"value":"Complete"},"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Colorectal cancer (AFAP only)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Colorectal 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replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36046},"ReasonCode":{"value":"Q4","properties":{"Reason":{"value":"Scoring pairs updated <strong>with</strong> major updates in the report"}}},"Date":{"value":"2018-08-21"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC056","properties":{"Status":{"value":"Released"},"Genes":{"value":10,"items":[{"Gene":{"value":"ACTC1","properties":{"GeneFunction":{"value":"actin, alpha, cardiac muscle 1"},"HGNCId":{"value":"HGNC:143"},"GeneOMIM":{"value":"102540"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"612098"}}]}}}},{"Gene":{"value":"CSRP3","properties":{"GeneFunction":{"value":"cysteine and glycine rich protein 3"},"HGNCId":{"value":"HGNC:2472"},"GeneOMIM":{"value":"600824"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"612124"}}]}}}},{"Gene":{"value":"MYBPC3","properties":{"GeneFunction":{"value":"myosin binding protein C, cardiac"},"HGNCId":{"value":"HGNC:7551"},"GeneOMIM":{"value":"600958"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"115197"}}]}}}},{"Gene":{"value":"MYH7","properties":{"GeneFunction":{"value":"myosin, heavy chain 7, cardiac muscle, beta"},"HGNCId":{"value":"HGNC:7577"},"GeneOMIM":{"value":"160760"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"192600"}}]}}}},{"Gene":{"value":"MYL2","properties":{"GeneFunction":{"value":"myosin light chain 2"},"HGNCId":{"value":"HGNC:7583"},"GeneOMIM":{"value":"160781"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"608758"}}]}}}},{"Gene":{"value":"MYL3","properties":{"GeneFunction":{"value":"myosin light chain 3"},"HGNCId":{"value":"HGNC:7584"},"GeneOMIM":{"value":"160790"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"608751"}}]}}}},{"Gene":{"value":"PRKAG2","properties":{"GeneFunction":{"value":"protein kinase AMP-activated non-catalytic subunit gamma 2"},"HGNCId":{"value":"HGNC:9386"},"GeneOMIM":{"value":"602743"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"600858"}}]}}}},{"Gene":{"value":"TNNI3","properties":{"GeneFunction":{"value":"troponin I type 3 (cardiac)"},"HGNCId":{"value":"HGNC:11947"},"GeneOMIM":{"value":"191044"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"613690"}}]}}}},{"Gene":{"value":"TNNT2","properties":{"GeneFunction":{"value":"troponin T type 2 (cardiac)"},"HGNCId":{"value":"HGNC:11949"},"GeneOMIM":{"value":"191045"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"115195"}}]}}}},{"Gene":{"value":"TPM1","properties":{"GeneFunction":{"value":"tropomyosin 1 (alpha)"},"HGNCId":{"value":"HGNC:12010"},"GeneOMIM":{"value":"191010"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"115196"}}]}}}}]},"Syndrome":{"value":"Familial Hypertrophic Cardiomyopathy","properties":{"OmimIDs":{"value":10,"items":[{"OmimID":{"value":"115197"}},{"OmimID":{"value":"192600"}},{"OmimID":{"value":"115195"}},{"OmimID":{"value":"613690"}},{"OmimID":{"value":"115196"}},{"OmimID":{"value":"608751"}},{"OmimID":{"value":"612098"}},{"OmimID":{"value":"600858"}},{"OmimID":{"value":"608758"}},{"OmimID":{"value":"612124"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Hypertrophic cardiomyopathy (HCM) is typically defined by the presence of unexplained left ventricular hypertrophy (LVH). Such LVH occurs in a non-dilated ventricle in the absence of other cardiac or systemic disease capable of producing the observed magnitude of increased LV wall thickness, such as pressure overload (e.g., long-standing hypertension, aortic stenosis) or storage/infiltrative disorders (e.g., Fabry disease, amyloidosis). The clinical manifestations of HCM range from asymptomatic LVH to progressive heart failure to sudden cardiac death (SCD), and vary from individual to individual even within the same family. Common symptoms include shortness of breath (particularly with exertion), chest pain, palpitations, orthostasis, presyncope, and syncope. Most often the LVH of HCM becomes apparent during adolescence or young adulthood, although it may also develop late in life, in infancy, or in childhood."},"Acronyms":{"value":9,"items":[{"Acronym":{"value":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4"}},{"Acronym":{"value":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1"}},{"Acronym":{"value":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2"}},{"Acronym":{"value":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7"}},{"Acronym":{"value":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 3"}},{"Acronym":{"value":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 8"}},{"Acronym":{"value":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 11"}},{"Acronym":{"value":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 6"}},{"Acronym":{"value":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 10"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Cardiomyopathy, Hypertrophic, Familial [Mesh]","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-06-07"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":5,"items":[{"SearchString":{"value":"familial hypertrophic cardiomyopathy","properties":{"NumberOfHits":{"value":9},"Date":{"value":"2015-06-07"}}}},{"SearchString":{"value":"CMH","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-06-07"}}}},{"SearchString":{"value":"HCM (restricted to Cardiomyopathy, Hypertrophic)","properties":{"NumberOfHits":{"value":26},"Date":{"value":"2015-06-07"}}}},{"SearchString":{"value":"Hereditary Ventricular Hypertrophy","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-06-07"}}}},{"SearchString":{"value":"Asymmetric Septal Hypertrophy","properties":{"NumberOfHits":{"value":24},"Date":{"value":"2015-06-07"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-06-07"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"HCM","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2017-08-14"},"Notes":{"value":""},"Label":{"value":"HCM"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-06-07"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-06-07"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 500"},"Notes":{"value":"Hypertrophic cardiomyopathy (HCM) is a common genetic cardiovascular disease. The prevalence in the general population is estimated at 1:500, which is equivalent to at least 600,000 people affected in the United States."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000298"}},{"Reference":{"value":"/coll/reference_model/doc/RF000211"}},{"Reference":{"value":"/coll/reference_model/doc/RF000212"}},{"Reference":{"value":"/coll/reference_model/doc/RF000214"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"HCM is a primary cardiac disorder characterized by hypertrophy, usually left ventricle hypertrophy (LVH), in the absence of other loading conditions. Clinical manifestations of HCM range from asymptomatic LVH to progressive heart failure to sudden cardiac death (SCD). Progressive ventricular outflow obstruction may cause palpitation associated with arrhythmia, congestive heart failure, and sudden death. Other symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. Symptoms can be readily provoked by exercise."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000298"}},{"Reference":{"value":"/coll/reference_model/doc/RF000211"}},{"Reference":{"value":"/coll/reference_model/doc/RF000212"}},{"Reference":{"value":"/coll/reference_model/doc/RF000214"}},{"Reference":{"value":"/coll/reference_model/doc/RF000215"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"HCM is a heterogeneous cardiac disease with a diverse clinical presentation and course, presenting in all age groups from infancy to the very elderly; however, LVH often becomes apparent during adolescence or young adulthood. Although HCM was initially thought to be associated with high mortality, it is now recognized that most affected individuals will have a relatively mild course of disease and can achieve normal life expectancy without disability or the necessity for major therapeutic interventions. In some patients, HCM is associated with disease complications that may be profound with the potential to result in disease progression or premature death. An important minority of persons with HCM are at increased risk for SCD (most often occurring in adolescents or young adults) most likely related to ventricular tachycardia/ventricular fibrillation. Approximately 5-10% of individuals with HCM progress to end-stage disease. The annual mortality rate in individuals with end-stage disease is estimated at 11%. Community-based studies suggest an annual mortality rate in the range of 1%. HCM is the commonest structural cause of SCD in individuals less than 35 years, including competitive athletes. There are very few data on the natural histories of individuals who carry a pathogenic variant and have no phenotype, but recent studies suggest a benign clinical course for most clinically unaffected carriers."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000298"}},{"Reference":{"value":"/coll/reference_model/doc/RF000211"}},{"Reference":{"value":"/coll/reference_model/doc/RF000212"}},{"Reference":{"value":"/coll/reference_model/doc/RF000214"}},{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM901","properties":{"Key Text":{"value":"Disease progression"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"No treatments currently exist to prevent or decrease disease development or to reverse established manifestations"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000298"}}]}}}},{"Patient Management":{"value":"ACPM906","properties":{"Key Text":{"value":"Multidisciplinary care"},"Tier":{"value":"2"},"Recommendation Text":{"value":"In all cases of HCM, clinicians should consider evaluation of patients in centers with multidisciplinary teams, with expertise in diagnosis, genetics, risk stratification, and management of heart muscle disease."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}},{"Patient Management":{"value":"ACPM905","properties":{"Key Text":{"value":"SCD risk stratification"},"Tier":{"value":"1"},"Recommendation Text":{"value":"All patients should undergo comprehensive SCD risk stratification at initial evaluation. Patients with multiple risk factors have a substantially increased risk of sudden death sufficient to ward consideration for prophylactic therapy.  In a study of 268 patients with HCM, those with two or more risk factors had a lower six-year survival rate from sudden death than those with one or no risk factors (72% versus 94%). It is possible to identify most high-risk patients by noninvasive clinical markers, and only a small minority of those HCM patients who die suddenly (about 3%) are without any of the currently acknowledged risk markers."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000211"}}]}}}},{"Patient Management":{"value":"ACPM900","properties":{"Key Text":{"value":"SCD risk stratification timing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"SCD risk stratification is reasonable on a periodic basis (12 to 24 months) for patients with HCM who have not undergone ICD therapy. There are no randomized trials or statistically validated prospective prediction models that can be used to guide ICD implantation in patients with HCM. Recommendations are instead based on observational, retrospective cohort studies that have determined the relationship between clinical characteristics and prognosis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000211"}},{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}},{"Patient Management":{"value":"ACPM899","properties":{"Key Text":{"value":"ICD"},"Tier":{"value":"2"},"Recommendation Text":{"value":"It is reasonable to recommend an implantable cardioverter-defibrillator (ICD) for patients with one or more major risk factors for SCD (e.g., history of sudden death presumably due to HCM in a first-degree relative, abnormal blood pressure response during exercise, decreased left-ventricular wall thickness). In an international multicenter registry of HCM patients with ICDs, patients with primary prevention ICDs placed on the basis of 1 or more of the conventional risk markers experienced appropriate ICD therapy at a rate of 4% per year. ICD therapy was effective in terminating VT/VF despite the complex HCM phenotype."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Sudden Cardiac Death"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000211"}},{"Reference":{"value":"/coll/reference_model/doc/RF000212"}},{"Reference":{"value":"/coll/reference_model/doc/RF000214"}},{"Reference":{"value":"/coll/reference_model/doc/RF000007"}},{"Reference":{"value":"/coll/reference_model/doc/RF000031"}},{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC204","properties":{"Recommendation":{"value":"Within the Swedish ICD Registry, all-cause mortality in 342 HCM patients with an ICD was found to be larger than that of the age and sex-matched Swedish general population (standardized mortality ratio: 3.4 (95% CI: 2.4-4.5; p<0.0001) over a mean follow up of 5.4 years. However, ICDs almost eliminated premature arrhythmic death in the population with only two patients dying suddenly (after having ICD turned off or removed). The main cause of death in individuals was still attributed to HCM primary due to heart failure. The genetic cause of HCM in the population was not reported."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000649"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM903","properties":{"Key Text":{"value":"Prevention of endocarditis"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Healthcare professionals should offer people with HCM clear and consistent information about the prevention of infective endocarditis, including the benefits and risks of antibiotic prophylaxis (including why prophylaxis is no longer routinely recommended), the importance of maintaining good oral health, education regarding the symptoms of infective endocarditis, and the risks of invasive procedures including non-medical procedures such as body piercing or tattooing. Any episodes of infection in people at risk for infective endocarditis should be investigated and treated promptly to reduce the risk of endocarditis developing."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000650"}}]}}}},{"Patient Management":{"value":"ACPM907","properties":{"Key Text":{"value":"First trimester abortions"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Pregnant women with HCM seeking pregnancy termination should be referred to a hospital-based provider (with patient permission), with the procedure performed in-hospital after consultation with a cardiologist."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000217"}},{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}},{"Patient Management":{"value":"ACPM902","properties":{"Key Text":{"value":"Beta-blockers and calcium-channel blockers"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with HCM may benefit from beta-blockers and calcium-channel blockers; however, the usefulness of these agents to alter clinical outcomes is not well established for the management of asymptomatic patients with HCM with or without obstruction."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000211"}},{"Reference":{"value":"/coll/reference_model/doc/RF000212"}},{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC203","properties":{"Recommendation":{"value":"A pilot randomized controlled trial examined the use of diltiazem (a calcium channel blocker) in 38 individuals with a pathogenic or likely pathogenic variant in a sarcomere gene with no cardiovascular symptoms or concomitant illnesses. Participants had a mean age of 15.8 years (range: 5 to 39 years) and received a median of 756 days of treatment. This initial study found that while heart rate and blood pressure did not significantly differ between groups, improved early LV remodeling was improved in the diltiazem treatment group (p<0.001). Over the course of the study four participants developed overt HCM (two in each treatment group)."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000651"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM898","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"A diagnosis of HCM is not a contraindication for pregnancy, but female patients should be carefully evaluated in regard to the risk of pregnancy. Expert maternal/fetal medical care and pre-pregnancy risk counseling is advised. Scheduled (induced) vaginal delivery is recommended as the first choice in most patients."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000211"}},{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}},{"Patient Management":{"value":"ACPM904","properties":{"Key Text":{"value":"contraceptive counseling"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Counseling on safe and effective contraception is indicated in all women of fertile age."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU492","properties":{"Key Text":{"value":"Cardiac monitoring"},"Tier":{"value":"1"},"Recommendation Text":{"value":"In individuals with pathogenic variants who do not express the HCM phenotype, it is recommended to perform serial electrocardiogram, transthoracic echocardiogram (TTE), and clinical assessment at periodic intervals (every 1 to 5 years in adults), based on the patient’s age and change in clinical status. One study of 235 found that at first cardiac evaluation almost one-quarter of asymptomatic carriers of MYBPC3 variants were clinically diagnosed with HCM. Risk factors for SCD were frequently present and 11% of carriers were at risk for SCD. A second study more broadly addressing 76 individuals with HCM associated pathologic variants identified through DNA testing found clinical HCM in 41% of those examined."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000211"}},{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}},{"Surveillance":{"value":"ACSU488","properties":{"Key Text":{"value":"Holter monitoring"},"Tier":{"value":"1"},"Recommendation Text":{"value":"24-to-48-hour ambulatory (Holter) electrocardiographic monitoring is recommended for initial evaluation of patients with HCM to detect ventricular tachycardia (VT) and identify patients who may be candidates for ICD and upon development of palpations or lightheadedness. On routine ambulatory (Holter) 24-h ECG monitoring, non-sustained burst of ventricular tachycardia (often asymptomatic) are present in 20-30% of adult HCM patients."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000211"}},{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}},{"Surveillance":{"value":"ACSU490","properties":{"Key Text":{"value":"Diastolic function evaluation"},"Tier":{"value":"2"},"Recommendation Text":{"value":"A comprehensive evaluation of diastolic function is recommended to detect diastolic dysfunction and the assessment of LV filling pressures."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}},{"Surveillance":{"value":"ACSU493","properties":{"Key Text":{"value":"Routine laboratory testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Routine laboratory testing aids the detection of extra-cardiac conditions that cause or exacerbate ventricular dysfunction (for example, thyroid disease, renal dysfunction and diabetes mellitus) and secondary organ dysfunction in patients with severe heart failure. First-line laboratory screening should include hematology, glucose, cardiac enzymes (creatine kinase, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase), renal and liver function tests, pH, electrolytes and uric acid."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}},{"Surveillance":{"value":"ACSU489","properties":{"Key Text":{"value":"Cardiopulmonary exercise testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Irrespective of symptoms, cardiopulmonary exercise testing with simultaneous measurement of respiratory gases (or standard treadmill or bicycle ergometry when unavailable) should be considered to assess the severity and mechanism of exercise intolerance and change in systolic blood pressure."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}},{"Surveillance":{"value":"ACSU491","properties":{"Key Text":{"value":"Pregnancy monitoring"},"Tier":{"value":"2"},"Recommendation Text":{"value":"In pregnant women with HCM, increased surveillance for fetal bradycardia is warranted."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000211"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM325","properties":{"Key Text":{"value":"cascade screening"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Cascade genetic screening after pre-test counselling, is recommended in first degree-adult relatives of patients with definite pathogenic variant."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}},{"Family Management":{"value":"ACFM326","properties":{"Key Text":{"value":"Clinical screening"},"Tier":{"value":"2"},"Recommendation Text":{"value":"First-degree relatives of an affected individual who have not undergone genetic testing, should be clinically screened for HCM. This involves physical examination by a cardiologist, an electrocardiogram, and a transthoracic echocardiogram (TTE). Screening may also include echocardiogram, CK-MM, Holter monitoring, exercise treadmill testing, and MRI. Intervals for screening vary by age (e.g. every 2-3 years until age 30), but should be individually tailored."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000211"}},{"Reference":{"value":"/coll/reference_model/doc/RF000212"}},{"Reference":{"value":"/coll/reference_model/doc/RF000218"}},{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}},{"Family Management":{"value":"ACFM327","properties":{"Key Text":{"value":"Screening children"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Children may be considered for genetic testing starting at age 10 or older. In children whose genetic status is unknown clinical assessment should be considered starting at age 10. Presence of hypertrophy frequently occurs in association with accelerated body growth during the five-year period of the adolescent years. It is common for young affected family members <13 years old to represent “silent” carriers."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000211"}},{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA399","properties":{"Key Text":{"value":"Medications to avoid"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Care should be taken to avoid high dose diuretics, venodilators, and arterial vasodilators to avoid vasodilation because these may exacerbate the degree of ventricular obstruction."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000211"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA398","properties":{"Key Text":{"value":"Competitive sports"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Participation in competitive athletics for asymptomatic, genotype-positive HCM patients without evidence of left ventricular hypertrophy is reasonable, particularly in the absence of a family history of HCM-related sudden death. Those who wish to participate should be advised on an individual basis, taking into account the local legal framework, the underlying variant, and the type of sporting activity. Athletes with a probable or unequivocal clinical expression and diagnosis of HCM (i.e., with the disease phenotype of left ventricular hypertrophy) should not participate in most competitive sports, with the exception of those of low intensity."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000648"}},{"Reference":{"value":"/coll/reference_model/doc/RF000652"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA397","properties":{"Key Text":{"value":"Burst activities"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Avoid burst activities, like sprinting, as well as intense isometric exercise, such as heavy weight lifting; avoid exercise in extreme environmental conditions and maintain adequate hydration."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000211"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"In up to 60% of adolescents and adults with HCM, the disease is an autosomal dominant trait caused by pathogenic variants in cardiac sarcomere protein genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL3). Five to ten percent of adult cases are caused by other genetic disorders including 1% associated with PRKAG2. (Tier 3) \n\nIt is unknown how many cases of HCM are due to pathogenic variants in ACTC1 or CSRP3. (Tier 4)"},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000298"}},{"Reference":{"value":"/coll/reference_model/doc/RF000648"}}]}}},"Penetrances":{"value":4,"items":[{"Penetrance":{"value":"ACPE464","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"5"},"Notes":{"value":"The association with specific genes and HCM prognosis remains controversial."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000653"}}]}}}},{"Penetrance":{"value":"ACPE463","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"5"},"Notes":{"value":"Penetrance of HCM is variable based on the underlying genotype and the age of patient at assessment. Multiple small studies of relatives of HCM probands have found that the penetrance of HCM (based on cardiac evaluation) is over 40% in at least one gene (MYBPC3)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000219"}},{"Reference":{"value":"/coll/reference_model/doc/RF000220"}},{"Reference":{"value":"/coll/reference_model/doc/RF000221"}},{"Reference":{"value":"/coll/reference_model/doc/RF000222"}},{"Reference":{"value":"/coll/reference_model/doc/RF000223"}},{"Reference":{"value":"/coll/reference_model/doc/RF000224"}}]}}}},{"Penetrance":{"value":"ACPE462","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"5"},"Notes":{"value":"One study of 653 HCM patients with an absence of SCD risk factors and no or mild symptoms (aged 10-75) found that over 10 years of follow up the cumulative sudden death risk was 5.9%. During the follow up ICDs were implanted in an additional 6% of patients based on the development of SCD risk factors. The underlying HCM genes were not reported."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Sudden Cardiac Death"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000225"}}]}}}},{"Penetrance":{"value":"ACPE465","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"1"},"Notes":{"value":"A pooled evaluation of found 22.8% (95% CI: 17.3 to 28.2%) of HCM patients with pathogenic variants in sarcomere-encoding genes developed hypertension."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000654"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR191","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":""},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN211","properties":{"Key Text":{"value":"HCM has variable expressivity; clinical manifestations vary from individual to individual even within the same family."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000298"}}]},"Tier":{"value":"Not provided"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI216","properties":{"Key Text":{"value":"Management of HCM includes regular invasive and non-invasive screening tests and the possible recommendation of ICD therapy, which confers appreciable risk.\n\nReported rates of complications include approximately 25% of patients with HCM who experienced inappropriate ICD discharge; 6% to 13% who experienced lead complications (fracture, dislodgment, oversensing); 4% to 5% who developed a device-related infection; and approximately 2% to 3% who experienced bleeding or thrombosis complications."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000211"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC209","properties":{"Key Text":{"value":"General population screening recommendations are inadequate for individuals with HCM. SCD may be the first manifestation of disease."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000298"}}]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Overall Score":{"value":"10NN"},"Effectiveness":{"value":"3N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":7,"items":[{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"1"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"1"}}}}]}}}}]}}}}]}}},"Scorers":{"value":7,"items":[{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"3N","properties":{"Notes":{"value":"The new study from Magnusson is very interesting and specific to the outcome of SCD. Single study, but good-sized numbers and decent length of f/u. Clearly doesn't affect increased risk for all cause mortality."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":"I'm a little confused as to why we're only scoring SCD. While the failure associated with HCM isn't as pronounced as with DCM, it is an issue..."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"I could be talked into a more robust score for efficacy"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"I could be talked into a less acceptable score (\"1) given the inherent problems of an ICD."}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":"Several prevalences; I took the highest."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"2  or 3 here"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Sudden Cardiac Death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"ICD Implantation","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"2.0.3","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36048},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-11"},"ReleasedBy":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"}}}}}}}},
{"ActionabilityDocID":{"value":"AC057","properties":{"Status":{"value":"Released"},"Genes":{"value":3,"items":[{"Gene":{"value":"LDLR","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:6547"},"GeneOMIM":{"value":"606945"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"143890"}}]}}}},{"Gene":{"value":"APOB","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:603"},"GeneOMIM":{"value":"107730"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"144010"}}]}}}},{"Gene":{"value":"PCSK9","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:20001"},"GeneOMIM":{"value":"607786"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"603776"}}]}}}}]},"Syndrome":{"value":"Heterozygous Familial Hypercholesterolemia","properties":{"OmimIDs":{"value":3,"items":[{"OmimID":{"value":"143890"}},{"OmimID":{"value":"603776"}},{"OmimID":{"value":"144010"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":""},"Acronyms":{"value":2,"items":[{"Acronym":{"value":"Familial Hypercholesterolemia"}},{"Acronym":{"value":"Autosomal Dominant Hypercholesterolemia 3"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"\"Hyperlipoproteinemia Type II\"[Mesh]","properties":{"NumberOfHits":{"value":60},"Date":{"value":"2015-04-14"}}}},{"SearchString":{"value":"((((\"low density lipoprotein receptor, human\" [Supplementary Concept]) OR \"Apolipoproteins B\"[Mesh]) OR \"PCSK9 protein, human\" [Supplementary Concept])) AND \"Hypercholesterolemia\"[Mesh]","properties":{"NumberOfHits":{"value":7},"Date":{"value":"2015-04-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":5,"items":[{"SearchString":{"value":"Familial hypercholesterolemia","properties":{"NumberOfHits":{"value":24},"Date":{"value":"2015-04-14"}}}},{"SearchString":{"value":"Autosomal dominant hypercholesterolemia","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-04-14"}}}},{"SearchString":{"value":"LDLR","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-04-14"}}}},{"SearchString":{"value":"APOB","properties":{"NumberOfHits":{"value":14},"Date":{"value":"2015-04-14"}}}},{"SearchString":{"value":"PCSK9","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-04-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-04-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":3},"Date":{"value":"2018-05-08"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-04-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-04-14"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular events","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oral hypercholesterolemia treatment to FH appropriate goal"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 500"},"Notes":{"value":"The prevalence of heterozygous familial hypercholesterolemia (HeFH) is most commonly estimated at 1:200-500, though estimates from 1/67 to 1/1000 have been reported. HeFH has been estimated to affect between 14 and 34 million individuals worldwide."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000781"}},{"Reference":{"value":"/coll/reference_model/doc/RF000782"}},{"Reference":{"value":"/coll/reference_model/doc/RF000783"}},{"Reference":{"value":"/coll/reference_model/doc/RF000300"}},{"Reference":{"value":"/coll/reference_model/doc/RF000095"}},{"Reference":{"value":"/coll/reference_model/doc/RF000784"}},{"Reference":{"value":"/coll/reference_model/doc/RF000785"}},{"Reference":{"value":"/coll/reference_model/doc/RF000075"}},{"Reference":{"value":"/coll/reference_model/doc/RF000096"}},{"Reference":{"value":"/coll/reference_model/doc/RF000786"}},{"Reference":{"value":"/coll/reference_model/doc/RF000787"}},{"Reference":{"value":"/coll/reference_model/doc/RF000788"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"HeFH is associated with a lifelong elevation of serum low-density lipoprotein cholesterol (LDL-C) with levels generally 350-550 mg/dL. The major clinical manifestations of FH result from prolonged exposure to high levels of LDL-C leading to the development of atherosclerotic lesions in the heart, brain, and peripheral arteries. This leads to an increased risk of cardiovascular disease (CVD), most commonly coronary artery disease (CAD). Symptoms of ischemia may occur due the restriction of blood flow; however, acute complications such as myocardial infarction (MI) and sudden cardiac death can occur as the first manifestations of CVD. Other manifestations may include xanthomas around the eyelids and within tendons of the elbows, hands, knees, and feet and corneal arcus."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000781"}},{"Reference":{"value":"/coll/reference_model/doc/RF000782"}},{"Reference":{"value":"/coll/reference_model/doc/RF000783"}},{"Reference":{"value":"/coll/reference_model/doc/RF000300"}},{"Reference":{"value":"/coll/reference_model/doc/RF000785"}},{"Reference":{"value":"/coll/reference_model/doc/RF000075"}},{"Reference":{"value":"/coll/reference_model/doc/RF000786"}},{"Reference":{"value":"/coll/reference_model/doc/RF000788"}},{"Reference":{"value":"/coll/reference_model/doc/RF000789"}},{"Reference":{"value":"/coll/reference_model/doc/RF000790"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"If left untreated, men and women with HeFH typically develop CAD by ages 55 and 60, respectively. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment. HeFH patients with tendon xanthomas have higher risk of CVD compared to FH patients without xanthomas (OR=3.20, 95% CI: 2.12-4.82)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000781"}},{"Reference":{"value":"/coll/reference_model/doc/RF000782"}},{"Reference":{"value":"/coll/reference_model/doc/RF000783"}},{"Reference":{"value":"/coll/reference_model/doc/RF000300"}},{"Reference":{"value":"/coll/reference_model/doc/RF000785"}},{"Reference":{"value":"/coll/reference_model/doc/RF000096"}},{"Reference":{"value":"/coll/reference_model/doc/RF000786"}},{"Reference":{"value":"/coll/reference_model/doc/RF000788"}},{"Reference":{"value":"/coll/reference_model/doc/RF000790"}},{"Reference":{"value":"/coll/reference_model/doc/RF000079"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM911","properties":{"Key Text":{"value":"Statins"},"Tier":{"value":"1"},"Recommendation Text":{"value":"The initial treatment for individuals with FH, irrespective of their calculated cardiovascular risk, should be a high intensity statin with an aim of a reduction of at least 50% in LDL-C concentration from baseline. Statin treatment is lifelong. No studies have examined the use of statins vs placebo in adults with FH. However, high and moderate quality RCTs from populations without FH have found that high-intensity statins reduce non-fatal MI (RR: 0.46, 95% CI: 0.37-0.59). Statins have also been shown to have a small (non-clinically important) effect on reducing 5-year all cause (RR: 0.90, 95% CI: 0.80-1.00), CV mortality (RR: 0.73, 95% CI: 0.61-0.88), and stroke (RR: 0.80, 95% CI: 0.70-0.91)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000784"}},{"Reference":{"value":"/coll/reference_model/doc/RF000791"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC206","properties":{"Recommendation":{"value":"Based on a meta-analysis of 4 observational studies, individuals with HeFH in the pre-statin era exhibited a higher risk for stroke compared with the general population (OR: 7.66, 95% CI: 6.06-9.68, p<0.01) but a lower odds for stroke following the generalization of statin therapy (OR: 0.25, 95% CI: 0.18-0.36, p<0.01)."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000781"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM908","properties":{"Key Text":{"value":"Ezetimibe"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Ezetimibe monotherapy is recommended as an option for treating primary HeFH in adults in whom initial statin therapy is contraindicated. No trials of ezetimibe in individuals with FH have been published. An RCT (IMPROVE-IT trial) of ezetimibe plus simvastatin vs simvastatin alone in 18,144 patients with stabilized acute coronary syndrome found a 6.4% relative risk reduction at 6 years a composite of cardiovascular death, major coronary event, or non-fatal stroke compared with simvastatin alone (HR: 0.94, 95% CI: 0.89-0.99)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000784"}},{"Reference":{"value":"/coll/reference_model/doc/RF000791"}},{"Reference":{"value":"/coll/reference_model/doc/RF000792"}}]}}}},{"Patient Management":{"value":"ACPM914","properties":{"Key Text":{"value":"Bile acid sequestrants (resin) and fibrates"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Adults with FH and contraindications to statin or ezetimibe should be offered a referral to a specialist with expertise in FH for consideration for treatment with either a bile acid sequestrant (resin) or a fibrate. RCTs have found that bile acid sequestrants (2 RCTs, N= 248 with FH) and fibrates (2 RCTs, N= 208 with FH) can results in similar reductions in LDL-C and total cholesterol compared to placebo as treatment with statins."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000784"}}]}}}},{"Patient Management":{"value":"ACPM915","properties":{"Key Text":{"value":"PCSK9 inhibitors"},"Tier":{"value":"1"},"Recommendation Text":{"value":"PCSK9 inhibitors may be considered in HeFH, particularly in patients for whom a statin is contraindicated."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000791"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC205","properties":{"Recommendation":{"value":"Four RCTs (N=598) found a mean decrease in LDL-C of 8-57% (Alirocumab) and 44-61% (Evolocumab) compared to placebo in HeFH individuals already on a high-dose statin plus ezetimibe in 12 weeks."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000793"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM913","properties":{"Key Text":{"value":"Specialist care"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Healthcare professionals should offer adults with FH a referral to specialists with expertise in FH and cardiology if they are assessed to be at very high risk of a coronary event base on: established or suspected CHD, family history of premature CHD, or two or more other CV risk factors."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000784"}},{"Reference":{"value":"/coll/reference_model/doc/RF000075"}},{"Reference":{"value":"/coll/reference_model/doc/RF000794"}},{"Reference":{"value":"/coll/reference_model/doc/RF000795"}}]}}}},{"Patient Management":{"value":"ACPM910","properties":{"Key Text":{"value":"ECG"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Given that asymptomatic coronary disease may not be detected without routine investigation. In individual instances, an ECG should be considered as a baseline investigation for adults with FH. However, evidence is lacking regarding clinical outcomes based on routine investigation."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000784"}},{"Reference":{"value":"/coll/reference_model/doc/RF000096"}}]}}}},{"Patient Management":{"value":"ACPM909","properties":{"Key Text":{"value":"Lifestyle"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Lifestyle advice should be provided as a component of medical management, and not a substitute for lipid-modifying drug therapy, including: individualized nutritional advice and physical activity advice, limiting alcohol consumption, stress reduction, and support for weight loss in line with national guidance for the general population. The aim of these interventions is not to lower LDL-C, but to confer a cardioprotective effect. However, there is no evidence that these interventions improve clinical outcomes in adults with FH."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000784"}},{"Reference":{"value":"/coll/reference_model/doc/RF000785"}},{"Reference":{"value":"/coll/reference_model/doc/RF000075"}},{"Reference":{"value":"/coll/reference_model/doc/RF000096"}},{"Reference":{"value":"/coll/reference_model/doc/RF000786"}},{"Reference":{"value":"/coll/reference_model/doc/RF000788"}},{"Reference":{"value":"/coll/reference_model/doc/RF000790"}},{"Reference":{"value":"/coll/reference_model/doc/RF000795"}}]}}}},{"Patient Management":{"value":"ACPM912","properties":{"Key Text":{"value":"Obstetric care"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Shared care arrangements, to include expertise in cardiology and obstetrics, should be made for women with FH who are considering pregnancy or are pregnant, including: assessment of CHD risk, particularly to exclude aortic stenosis."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000784"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU494","properties":{"Key Text":{"value":"Annual review"},"Tier":{"value":"2"},"Recommendation Text":{"value":"All people with FH should be offered a regularly structured review that is carried out at least annual including an update of family pedigree, changes in CHD status of relatives, assessment of any symptoms of CHD, smoking status, fasting lipid profile, discussion about concordance with medication, possible side effects of treatment, and changes in lifestyle or lipid-modifying drug therapy that may be required."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000784"}}]}}}}]},"Family Managements":{"value":null,"items":[]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA400","properties":{"Key Text":{"value":"Smoking cessation"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals with FH should be strongly discouraged from smoking or advised to stop smoking given the greatly increased risk for CHD."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000784"}},{"Reference":{"value":"/coll/reference_model/doc/RF000075"}},{"Reference":{"value":"/coll/reference_model/doc/RF000786"}},{"Reference":{"value":"/coll/reference_model/doc/RF000788"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Codominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 500"},"Tier":{"value":"5"},"Notes":{"value":"Population screening of 50,762 individuals in a US health care system identified pathogenic variants associated with FH in 1:256 in unselected individuals; however, this may be an overestimate as it was based on screening within a single health care delivery system."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000796"}}]}}},"Penetrances":{"value":5,"items":[{"Penetrance":{"value":"ACPE467","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Based on studies of individuals selected based on clinical criteria in the pre-statin era, untreated males are at 50% risk for a fatal or non-fatal coronary event by age 50 years, and women are at 30% risk by 60 years."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000300"}}]}}}},{"Penetrance":{"value":"ACPE468","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Incomplete penetrance is noted for those heterozygous for a APOB pathogenic variant."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000300"}}]}}}},{"Penetrance":{"value":"ACPE470","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Recent findings suggest that only 73% of those with a heterozygous LDLR pathogenic variant have an LDL level >130 mg/dL, suggesting lower penetrance than previously proposed."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000300"}}]}}}},{"Penetrance":{"value":"ACPE466","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"While penetrance up to 90% is noted for some pathogenic variants in PCSK9, the penetrance for other PCSK9 pathogenic variants remains largely unknown."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000300"}}]}}}},{"Penetrance":{"value":"ACPE469","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"5"},"Notes":{"value":"In a US health-system based screening study of individuals with a pathogenic variant associated with FH, 44.7% would have been judged unlikely to have a diagnosis of FH based on Dutch Lipid Clinic Criteria without information about their pathogenic variant."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000796"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR193","properties":{"Key Text":{"value":">3"},"Notes":{"value":"In a Danish population-based study of patients with FH (selected on clinical criteria) versus non-FH patients, the odds ratios for CAD were 10.3 (95% CI: 7.8–13.8) and 13.2 (95% CI: 10.0–17.4) in subjects treated and not treated with lipid-lowering therapy, respectively."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000789"}}]},"Tier":{"value":"1"}}}},{"Relative Risk":{"value":"RR194","properties":{"Key Text":{"value":">3"},"Notes":{"value":"In an analysis of 12 existing observational studies (N=26,025), individuals high LDL cholesterol (≥190 mg/dl) had six-fold higher risk for CAD (OR: 6.0; 95% CI: 5.2–6.9) compared to those without a high LDL. When limited those with high LDL cholesterol and an FH pathogenic variant, there was a twenty-two-fold increased risk (OR: 22.3; 95% CI: 10.7–53.2)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000300"}}]},"Tier":{"value":"3"}}}},{"Relative Risk":{"value":"RR192","properties":{"Key Text":{"value":">3"},"Notes":{"value":"Within a US health-system based screening study individuals with an FH variant had a higher risk of CAD (OR: 2.6, 95%CI: 2.0-3.5) and premature CAD (OR: 3.7, 95% CI: 2.6 to 5.2)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000796"}}]},"Tier":{"value":"5"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN212","properties":{"Key Text":{"value":"Despite this high risk of CVD compared with unaffected individuals, the clinical course of atherosclerotic cardiovascular disease in FH subjects is variable."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000788"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI217","properties":{"Key Text":{"value":"Interventions for HeFH include: surveillance (echocardiogram), clinical monitoring, and medication. Statins have possible adverse events of elevated liver enzymes, myopathy, and potential fetal teratogenicity. Adverse reactions with ezetimibe monotherapy are generally gastrointestinal and usually mild, when taken with a statin adverse events may include: elevated liver enzymes, headache, and myalgia. Trials of PCSK9 inhibitors indicate that there is no significant difference in the frequency of adverse events compared to those on placebo."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000784"}},{"Reference":{"value":"/coll/reference_model/doc/RF000793"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC210","properties":{"Key Text":{"value":"HeFH is often unrecognized until the inaugural cardiovascular event due to inconsistent screening practices and general unawareness regarding the diagnosis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000785"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final 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Thus, I think this warrants a \"3\".\n\nParenthetically, it's a little odd that under Natural History, it says that \"On average, individuals with HeFH experience their first coronary event at age 42\" but also says \"If left untreated, men and women with HeFH typically develop CAD by ages 55 and 60, respectively\". One would typically have CAD prior to having a coronary event, of course. So I'm puzzled by that (I should have caught it when we reviewed the summary, probably)."}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oral hypercholesterolemia treatment to FH appropriate goal","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":"I scored it as moderately effective since it reduces the risk of MI by ~50%, which seems to me to not qualify for \"highly\" effective..."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"Statins are generally well tolerated"}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular 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Over 300 families with HLRCC have been reported."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000319"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome characterized by a predisposition to cutaneous and uterine leiomyomas and, in some families, to renal cell cancer. Benign cutaneous leiomyomas are common, present as multiple or single nodules that are skin colored to light brown, and are usually localized to the trunk and extremities but may also appear on the face.  They are usually sensitive to touch and/or cold temperature and may be painful.  Uterine Leiomyomas (fibroids) are associated with symptoms of pelvic pain and irregular or heavy menstrual bleeding.  Renal tumors may present with back pain, hematuria, or may be asymptomatic.  These tumors are usually unilateral and solitary; most are type 2 with a characteristic papillary architecture but other tumor types are also found."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000319"}},{"Reference":{"value":"/coll/reference_model/doc/RF000320"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"The majority of individuals with HLRCC (76%) present with a single or multiple cutaneous leiomyomas. Cutaneous leiomyomas usually present at an average age of 25 (range 10 to 47 years), and tend to increase in size and number with age. Uterine leiomyomas have been reported in 77% of women with HLRCC and appear at an average age of 30 (range 18 to 52 years) with symptoms preceding discovery. Fibroids tend to be numerous and large with earlier onset, and may require intervention (hysterectomy or myomectomy) at a younger age than fibroids seen in the general population. The renal carcinomas associated with HLRCC behave aggressively and have a poor prognosis compared with other forms of hereditary RCC. Only a small proportion of individuals with HLRCC develop renal cell cancer (RCC) at a median age of detection of 44 years. In contrast to other hereditary renal cancer syndromes, renal cancers associated with HLRCC are more aggressive, often rapidly progressing to metastatic disease and death.  In one study about 10-16% of those with HLRCC who presented with multiple cutaneous leiomyomas had renal tumors and nine of these 13 individuals died from metastatic disease within 5 years of diagnosis.\n\nTry this."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000319"}},{"Reference":{"value":"/coll/reference_model/doc/RF000320"}},{"Reference":{"value":"/coll/reference_model/doc/RF000088"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM917","properties":{"Key Text":{"value":"Establish the extent of disease and management needs"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and management needs in an individual diagnosed with HLRCC, the following evaluations are recommended:  detailed  dermatologic examination for evaluation of extent of disease and lesions suspicious for cutaneous leiomyosarcoma to include biopsy for histologic confirmation; baseline pelvic examination, pelvic MRI and/or transvaginal pelvic ultrasound to screen for uterine fibroids; baseline renal ultrasound and MRI to screen for renal tumors (or abdominal CT scan with contrast if MRI contraindicated); consultation with a medical geneticist and/or genetic counselor."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000319"}}]}}}},{"Patient Management":{"value":"ACPM916","properties":{"Key Text":{"value":"Renal cancer surgery"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Because of the aggressive nature of renal cancers associated with HLRCC excision of these malignancies requires earlier and more extensive surgery than other hereditary renal cancers. Total nephrectomy should be strongly considered in individuals with a detectable renal mass."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000319"}},{"Reference":{"value":"/coll/reference_model/doc/RF000320"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU495","properties":{"Key Text":{"value":"General surveillance recommendations"},"Tier":{"value":"4"},"Recommendation Text":{"value":"There is no consensus on clinical surveillance; provisional recommendations state that individuals with a clinical diagnosis of HLRCC and those with heterozygous pathogenic FH variants and no clinical manifestations should undergo:\n  \n- full skin examination annually to every 2 years; \n- annual gynecologic consultation; \n- and yearly examination with abdominal MRI for those with normal baseline or followup abdominal MRI (or abdominal CT scan with contrast if MRI contraindicated).\n \nSuspicious lesions detected at a previous examination should be followed with a CT scan with and without contrast (with or without the addition of renal ultrasound or PET-CT)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000319"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC034","properties":{"Recommendation":{"value":"Annual pelvic examination of patients 21 years of age or older is recommended for all women, based on expert opinion."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000586"}}]}}}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM328","properties":{"Key Text":{"value":"Evaluate relatives at risk"},"Tier":{"value":"4"},"Recommendation Text":{"value":"It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000319"}}]}}}},{"Family Management":{"value":"ACFM329","properties":{"Key Text":{"value":"Clinical surveillance of relatives at risk"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Clinical surveillance of asymptomatic at-risk relatives for early detection may allow timely intervention and improve outcomes. 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Some have HLRCC as the result of de novo gene mutation."},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"4"},"Notes":{"value":"Genetic prevalence is unknown.  FH is the only gene known to be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC), and 70% to 90% of individuals with clinically diagnosed HLRCC have identifiable sequence variants in FH. Deletions and duplications also account for an additional small proportion."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000319"}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE471","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Based on the outcomes of cutaneous leiomyomas, uterine leiomyomas, or renal tumor, penetrance of HLRCC is considered to be very high."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Renal cancer"}},{"Outcome":{"value":"Advanced uterine pathology"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000319"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC060","properties":{"Recommendation":{"value":"A French National Cancer Institute study of 44 families with genetically-confirmed HLRCC identified cutaneous leiomyomas in 68% of 151 affected members; uterine leiomyomas in 82% of 93 female affected members; and renal tumors in 18% of 151 affected members."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000089"}},{"Reference":{"value":"/coll/reference_model/doc/RF000088"}}]}}}}]}}}},{"Penetrance":{"value":"ACPE472","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"5"},"Notes":{"value":"Renal cancer has low penetrance in HLRCC syndrome, with an estimated incidence from 2%-6% to 15%, and possibly as high as 32% of germline mutation affected families, depending upon selection bias and imaging utilized."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Renal cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000090"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR195","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information on relative risk was not available."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN213","properties":{"Key Text":{"value":"Affected individuals may have multiple cutaneous leiomyomas, a single skin leiomyoma, or no cutaneous lesion; a single renal tumor or no renal tumors; and/or uterine fibroids. 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The actual prevalence may be higher because of under diagnosis. A study of the Finnish population found that prevalence may be as high as 1/6,250."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000321"}},{"Reference":{"value":"/coll/reference_model/doc/RF000322"}},{"Reference":{"value":"/coll/reference_model/doc/RF000094"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"HNPP is characterized by episodic focal motor and sensory peripheral neuropathies in the hands and feet. These attacks are typically painless. The nerve palsies often recur over a period of many years, but some individuals have a single episode and others with a pathogenic variant remain asymptomatic. In many cases these symptoms are triggered by mechanical stresses to the nerve, such as compression, repetitive movement and/or stretching of the affected limbs. Common clinical manifestations include carpal tunnel syndrome and peroneal palsy with foot drop. In 50% of cases, recovery from the acute neuropathy is complete within a few days to months. Incomplete recovery is common, though the resulting disability rarely severe. Chronic motor deficits after nerve palsies are noted in 10-15%. In rare cases, strenuous activities can lead to severe and prolonged limb paralysis. \n\nAtypical presentations of HNPP are common and can include: recurrent positional short-term sensory symptoms, progressive mononeuropathy, Charcot-Marie-Tooth like polyneuropathy, chronic sensory polyneuropathy, and chronic inflammatory demyelinating polyneuropathy-like disorder."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000321"}},{"Reference":{"value":"/coll/reference_model/doc/RF000322"}},{"Reference":{"value":"/coll/reference_model/doc/RF000094"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Most individuals with HNPP typically experience their first episode in the second or third decade at a mean age of 37 years, but with a large range from birth through the eighth decade. The most common presenting symptom is acute onset of a focal neuropathy of a single nerve (mononeuropathy). Males and females are equally affected. Occasional episodes have been reported during pregnancy, likely related to physiological changes. Older patients often develop a symmetric sensory motor polyneuropathy. HNPP is not life threatening, and patients have a normal life expectancy."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000321"}},{"Reference":{"value":"/coll/reference_model/doc/RF000322"}},{"Reference":{"value":"/coll/reference_model/doc/RF000094"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1217","properties":{"Key Text":{"value":"Baseline evaluation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease following diagnosis the following evaluations are recommended: \n• History of focal nerve symptoms\n• Family history\n• Neurologic examination\n• Electromyography/nerve conduction velocity \n• Clinical genetics consultation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000321"}}]}}}},{"Patient Management":{"value":"ACPM1216","properties":{"Key Text":{"value":"Protective pads"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Protective pads at the elbows or knees may prevent pressure and trauma to local nerves."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000321"}},{"Reference":{"value":"/coll/reference_model/doc/RF000322"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU645","properties":{"Key Text":{"value":"No information in patient surveillance was available."},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":""},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]},"Family Managements":{"value":null,"items":[]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA540","properties":{"Key Text":{"value":"Physical movements"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Patients are advised to avoid prolonged sitting with legs crossed, prolonged leaning on the elbows, occupations requiring repetitive movements of the wrist, and rapid weight loss as these have been reported in case reports as being associated with the onset of HNPP symptoms."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000321"}},{"Reference":{"value":"/coll/reference_model/doc/RF000094"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA541","properties":{"Key Text":{"value":"Vincristine"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Vincristine, used in chemotherapy, has been reported to exacerbate HNPP. A single case report related to this exposure was identified. No studies were identified reporting the rate of developing HNPP symptoms following vincristine exposure"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000321"}},{"Reference":{"value":"/coll/reference_model/doc/RF000094"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC056","properties":{"Recommendation":{"value":"An overview of case reports addressing Charcot Marie Tooth (CMT) and toxic medication effects identified 22 reports (30 patients) addressing vincristine toxicity; however it is unclear whether this evidence may apply to HNPP. 18 of 30 patients developed marked sensory symptoms or new onset weakness, with some developing dysarthria and dysphagia. Nearly all reports describe eventual improvement, but frequently not to baseline levels. These cases occurred in both adults (15) and children (15). Most individuals having a reaction were previously unsuspected or undiagnosed with CMT (26 of 30) and were only recognized following administration of vincristine; however, 10 cases, in retrospect, had overt clinical signs or a close relative with known CMT."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000732"}}]}}}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Tier":{"value":"4"},"Notes":{"value":"The prevalence of pathogenic variants in PMP22 associated with HNPP was unavailable. However, PMP22 accounts for an estimated 100% of HNPP cases and thus the prevalence of pathogenic variants in PMP22 is expected to be similar to the prevalence of HNPP, or between 1/50,000 and 1/20,000."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000321"}},{"Reference":{"value":"/coll/reference_model/doc/RF000322"}},{"Reference":{"value":"/coll/reference_model/doc/RF000094"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE633","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Studies screening relatives of index patients have identified that 6-23% of family members may be asymptomatic. These rates are not reported within the context of the exposure to potential triggers."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000094"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR257","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information regarding relative risk was unavailable."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN288","properties":{"Key Text":{"value":"Large intrafamilial clinical variability has been noted."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000321"}},{"Reference":{"value":"/coll/reference_model/doc/RF000094"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI292","properties":{"Key Text":{"value":"The interventions identified in this report include wearing protective pads and avoidance of potential triggers including vincristine."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC287","properties":{"Key Text":{"value":"Individuals with HNPP are typically identified after their first episode and diagnosed via genetic testing and/or electrophysiological studies. Thus, patients are likely to escape detection prior to their first episode. Given pain is often a presenting symptom, individuals with HNPP are often clinically misdiagnosed with fibromyalgia upon presentation."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000321"}},{"Reference":{"value":"/coll/reference_model/doc/RF000094"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2018-06-04"},"Scorers 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Of Intervention":{"value":"3","properties":{"Notes":{"value":"I think it would be quite rare for there to be circumstances in which there were not reasonable alternatives to vincristine."}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuropathy","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoidance of triggers","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"It seems that avoiding physical triggers could be effective, but no data on how effective are presented."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"Could consider dropping to 2 for the cases in which vincristine is the indicated treatment and avoiding it would be problematic. But, that would be a small minority of cases."}}}}}}]}}}}]}}}},{"Scorer":{"value":"alexanderkatz","properties":{"First Name":{"value":"Alexander"},"Last Name":{"value":"Katz"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuropathy","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoidance of triggers","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuropathy","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":"GeneReviews states penetrance is unknown. Didn't find penetrance rate for HNPP in citation listed (just for CMT1A). 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{"ActionabilityDocID":{"value":"AC065","properties":{"Status":{"value":"Released"},"Genes":{"value":3,"items":[{"Gene":{"value":"LDLR","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:6547"},"GeneOMIM":{"value":"606945"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"143890"}}]}}}},{"Gene":{"value":"APOB","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:603"},"GeneOMIM":{"value":"107730"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"144010"}}]}}}},{"Gene":{"value":"PCSK9","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:20001"},"GeneOMIM":{"value":"607786"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"603776"}}]}}}}]},"Syndrome":{"value":"Homozygous Familial Hypercholesterolemia","properties":{"OmimIDs":{"value":3,"items":[{"OmimID":{"value":"143890"}},{"OmimID":{"value":"603776"}},{"OmimID":{"value":"144010"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":""},"Acronyms":{"value":2,"items":[{"Acronym":{"value":"Familial Hypercholesterolemia"}},{"Acronym":{"value":"Autosomal Dominant Hypercholesterolemia 3"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"\"Hyperlipoproteinemia Type II\"[Mesh]","properties":{"NumberOfHits":{"value":60},"Date":{"value":"2015-04-14"}}}},{"SearchString":{"value":"((((\"low density lipoprotein receptor, human\" [Supplementary Concept]) OR \"Apolipoproteins B\"[Mesh]) OR \"PCSK9 protein, human\" [Supplementary Concept])) AND \"Hypercholesterolemia\"[Mesh]","properties":{"NumberOfHits":{"value":7},"Date":{"value":"2015-04-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":5,"items":[{"SearchString":{"value":"Familial hypercholesterolemia","properties":{"NumberOfHits":{"value":24},"Date":{"value":"2015-04-14"}}}},{"SearchString":{"value":"Autosomal dominant hypercholesterolemia","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-04-14"}}}},{"SearchString":{"value":"LDLR","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-04-14"}}}},{"SearchString":{"value":"APOB","properties":{"NumberOfHits":{"value":14},"Date":{"value":"2015-04-14"}}}},{"SearchString":{"value":"PCSK9","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-04-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-04-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":3},"Date":{"value":"2018-05-08"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-04-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-04-14"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular events","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Hypercholesterolemia treatment to FH appropriate goal"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"The frequency of homozygous familial hypercholesterolemia (HoFH) has historically been estimated to be 1/1,000,000. However, recent estimates are 1/160,000 to 1/300,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000782"}},{"Reference":{"value":"/coll/reference_model/doc/RF000095"}},{"Reference":{"value":"/coll/reference_model/doc/RF000783"}},{"Reference":{"value":"/coll/reference_model/doc/RF000300"}},{"Reference":{"value":"/coll/reference_model/doc/RF000797"}},{"Reference":{"value":"/coll/reference_model/doc/RF000785"}},{"Reference":{"value":"/coll/reference_model/doc/RF000075"}},{"Reference":{"value":"/coll/reference_model/doc/RF000096"}},{"Reference":{"value":"/coll/reference_model/doc/RF000787"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"The clinical features of HoFH are characterized by extensive xanthomas, premature and progressive cardiovascular disease (CVD), and total cholesterol >500 mg/dL. The major clinical manifestations of FH result from prolonged exposure to high levels of LDL-C leading to the development of atherosclerotic lesions in the heart, brain, and peripheral arteries. This leads to an increased risk of cardiovascular disease (CVD), most commonly coronary artery disease (CAD). Symptoms of ischemia may occur due the restriction of blood flow; however, acute complications such as myocardial infarction (MI) and sudden cardiac death can occur as the first manifestations of CVD. Severe aortic stenosis is common. Xanthomas around the tendons and interdigital folds may occur leading to tendinitis and joint pain."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000782"}},{"Reference":{"value":"/coll/reference_model/doc/RF000095"}},{"Reference":{"value":"/coll/reference_model/doc/RF000300"}},{"Reference":{"value":"/coll/reference_model/doc/RF000075"}},{"Reference":{"value":"/coll/reference_model/doc/RF000786"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Untreated, most individuals with HoFH develop severe coronary artery disease (CAD) and aortic stenosis before age 20 and die before age 30. HoFH patients who are LDLR-defective (2-25% residual enzyme activity) have a better prognosis than those who are receptor negative (<2% enzyme activity). Individuals may be initially asymptomatic, presenting only with cutaneous and tendinous xanthomas and possibly a cardiac murmur. Most individuals with HoFH experience their first coronary event as children or adolescents with angina pectoris, MI, and death being reported in early childhood."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000782"}},{"Reference":{"value":"/coll/reference_model/doc/RF000095"}},{"Reference":{"value":"/coll/reference_model/doc/RF000783"}},{"Reference":{"value":"/coll/reference_model/doc/RF000300"}},{"Reference":{"value":"/coll/reference_model/doc/RF000797"}},{"Reference":{"value":"/coll/reference_model/doc/RF000788"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM929","properties":{"Key Text":{"value":"Specialist care"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Treatment for HoFH should be undertaken within a specialist center."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000797"}},{"Reference":{"value":"/coll/reference_model/doc/RF000785"}},{"Reference":{"value":"/coll/reference_model/doc/RF000798"}}]}}}},{"Patient Management":{"value":"ACPM922","properties":{"Key Text":{"value":"Statin"},"Tier":{"value":"1"},"Recommendation Text":{"value":"The initial treatment for individuals with FH, irrespective of their calculated cardiovascular risk, should be a high intensity statin with an aim of a reduction of at least 50% in LDL-C concentration from baseline. Statin treatment is lifelong. No studies have examined the use of statins vs placebo in adults with FH. However, high and moderate quality RCTs from populations without FH have found that high-intensity statins reduce non-fatal MI (RR: 0.46, 95% CI: 0.37-0.59). Statins have also been shown to have a small (but non-clinically important) effect on reducing 5-year all cause (RR: 0.90, 95% CI: 0.80-1.00), CV mortality (RR: 0.73, 95% CI: 0.61-0.88), and stroke (RR: 0.80, 95% CI: 0.70-0.91)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000798"}},{"Reference":{"value":"/coll/reference_model/doc/RF000799"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC209","properties":{"Recommendation":{"value":"Based on a meta-analysis of 4 observational studies, individuals with HeFH in the pre-statin era exhibited a higher risk for stroke compared with the general population (OR: 7.66, 95% CI: 6.06-9.68, p<0.01) but a lower odds for stroke following the generalization of statin therapy (OR: 0.25, 95% CI: 0.18-0.36, p<0.01)."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000781"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM932","properties":{"Key Text":{"value":"Ezetimibe"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Ezetimibe monotherapy is recommended as an option for treating primary HeFH in adults in whom initial statin therapy is contraindicated. No trials of ezetimibe in individuals with FH have been published. An RCT (IMPROVE-IT trial) of ezetimibe plus simvastatin vs simvastatin alone in 18,144 patients with stabilized acute coronary syndrome found a 6.4% relative risk reduction at 6 years a composite of cardiovascular death, major coronary event, or non-fatal stroke compared with simvastatin alone (HR: 0.94, 95% CI: 0.89-0.99)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000798"}},{"Reference":{"value":"/coll/reference_model/doc/RF000799"}},{"Reference":{"value":"/coll/reference_model/doc/RF000800"}}]}}}},{"Patient Management":{"value":"ACPM934","properties":{"Key Text":{"value":"Bile acid sequestrants and fibrates"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Adults with FH and contraindications to statin or ezetimibe should be offered a referral to a specialist with expertise in FH for consideration for treatment with either a bile acid sequestrant (resin) or a fibrate. RCTs have found that bile acid sequestrants (2 RCTs, N= 248 with FH) and fibrates (2 RCTs, N= 208 with FH) can results in similar reductions in LDL-C and total cholesterol compared to placebo as treatment with statins."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000798"}}]}}}},{"Patient Management":{"value":"ACPM931","properties":{"Key Text":{"value":"PCSK9 inhibitors"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Evolocumab (a PCSK9 inhibitor) can be considered with background therapy in HoFH. Homozygotes, compound heterozygotes, or double heterozygotes with a gain of function PSCK9 allele are likely to respond well to PCSK9 inhibition."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000797"}},{"Reference":{"value":"/coll/reference_model/doc/RF000801"}},{"Reference":{"value":"/coll/reference_model/doc/RF000794"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC208","properties":{"Recommendation":{"value":"One RCT (N=50) of individuals with HoFH found that Evolocumab lowered LDL-C 32% versus placebo in individuals already on a high-dose statin and ezetimibe in 12 weeks."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000793"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM924","properties":{"Key Text":{"value":"Lomitapide and mipomersen"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Lomitapide and mipomersen might be considered as adjunctive treatment in patients with HoFH, particularly if apheresis is not available. In an open label trial of 29 HoFH patients, lomitapide in addition to apheresis was found to reduce LDL-C by 50%. Mipomersen resulted in reduction of 25% in LDL-C over placebo in a trial of 51 HoFH patients."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000095"}},{"Reference":{"value":"/coll/reference_model/doc/RF000788"}},{"Reference":{"value":"/coll/reference_model/doc/RF000801"}},{"Reference":{"value":"/coll/reference_model/doc/RF000795"}}]}}}},{"Patient Management":{"value":"ACPM923","properties":{"Key Text":{"value":"Apheresis"},"Tier":{"value":"1"},"Recommendation Text":{"value":"LDL-C apheresis should be offered for treatment of HoFH with initiation and based on the response to lipid-modifying drug therapy and the presence of CHD."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000798"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC210","properties":{"Recommendation":{"value":"A Systematic review of 7 pre-post observational studies of HoFH (N= 61) found mean reductions in LDL-C levels from 57-76%. Two of these studies (n=39) reported that after extended follow up, the mean reduction was around 34-36%. Data from 34 adults with FH receiving apheresis for an average of 2.5 years found that after apheresis individuals had a 3.2-fold decrease in CV events and over a 20-fold decrease in cardiovascular interventions.  Subjectively individuals reported decreased episodes of angina symptoms and improved quality of life."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000787"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM930","properties":{"Key Text":{"value":"Aspirin"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Daily oral aspirin should be considered to prevent atherothrombosis. No studies of aspirin in FH were identified. In patients with HoFH who have not had a cardiovascular event, a net benefit of aspirin is a reasonable assumption because atheromatous disease is inevitable."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000797"}},{"Reference":{"value":"/coll/reference_model/doc/RF000075"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC207","properties":{"Recommendation":{"value":"A meta-analysis of 6 primary prevention trials found aspirin, compared to placebo, reduced serious vascular events (RR: 0.88, 95% CI: 0.82-0.94), due mainly to a reduction in non-fatal MI (RR: 0.77, 95% CI: 0·67–0·89); the effect on stroke and mortality were not significant. Analysis of 16 secondary prevention trial found aspirin yielded a greater absolute reduction in serious vascular events (RR: 0.81, 95% CI: 0.75-0.87), stroke (RR: 0.81, 95% CI: 0.71-0.92), major coronary events (RR: 0.80, 95% CI: 0.73-0.88), and total mortality (RR: 0.90, 95% CI: 0.82-0.99)."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000802"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM928","properties":{"Key Text":{"value":"Lifestyle advice"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Lifestyle advice should be provided as a component of medical management, and not a substitute for lipid-modifying drug therapy, including: individualized nutritional advice and physical activity advice, limiting alcohol consumption, stress reduction, and support for weight loss in line with national guidance for the general population. The aim of these interventions is not to lower LDL-C, but to confer a cardioprotective effect. However, there is no evidence that these interventions improve clinical outcomes in adults with FH."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000095"}},{"Reference":{"value":"/coll/reference_model/doc/RF000797"}},{"Reference":{"value":"/coll/reference_model/doc/RF000785"}},{"Reference":{"value":"/coll/reference_model/doc/RF000075"}},{"Reference":{"value":"/coll/reference_model/doc/RF000096"}},{"Reference":{"value":"/coll/reference_model/doc/RF000786"}},{"Reference":{"value":"/coll/reference_model/doc/RF000798"}},{"Reference":{"value":"/coll/reference_model/doc/RF000795"}},{"Reference":{"value":"/coll/reference_model/doc/RF000803"}}]}}}},{"Patient Management":{"value":"ACPM933","properties":{"Key Text":{"value":"CVD symptoms"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should be taught “red flag” symptoms of CVD and acute coronary events."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000797"}}]}}}},{"Patient Management":{"value":"ACPM925","properties":{"Key Text":{"value":"Psychological support"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Psychological support (including family support) should be part of routine care."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000095"}}]}}}},{"Patient Management":{"value":"ACPM920","properties":{"Key Text":{"value":"Alert card"},"Tier":{"value":"2"},"Recommendation Text":{"value":"The lipid team should be involved if patients hospitalized. An alert card with contact details should be issued."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000797"}}]}}}},{"Patient Management":{"value":"ACPM921","properties":{"Key Text":{"value":"Non-hormonal contraceptive"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Non-hormonal contraceptive techniques are recommended. Hormonal contraception is generally contraindicated for women with HoFH due to the risk of thrombosis."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000095"}},{"Reference":{"value":"/coll/reference_model/doc/RF000797"}}]}}}},{"Patient Management":{"value":"ACPM927","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Women should be advised that pregnancy in HoFH is hazardous due to the aggravation of hypercholesterolemia due to discontinuation of pharmacotherapy coupled with the effects of high levels of estrogen and progesterone on lipoprotein metabolism. Pre-conception, women should be referred to a cardiologist for a detailed cardiovascular assessment, including the aortic valve and root."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000095"}},{"Reference":{"value":"/coll/reference_model/doc/RF000797"}},{"Reference":{"value":"/coll/reference_model/doc/RF000785"}},{"Reference":{"value":"/coll/reference_model/doc/RF000798"}}]}}}},{"Patient Management":{"value":"ACPM926","properties":{"Key Text":{"value":"HRT"},"Tier":{"value":"2"},"Recommendation Text":{"value":"If HRT is provided for relief of postmenopausal symptoms, it should be taken in the lowest form of parenteral preparations, which have the lowest thrombotic risk."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000797"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU497","properties":{"Key Text":{"value":"Annual review"},"Tier":{"value":"2"},"Recommendation Text":{"value":"All people with FH should be offered a regularly structured review that is carried out at least annual including an update of family pedigree, changes in CHD status of relatives, assessment of any symptoms of CHD, smoking status, fasting lipid profile, discussion about concordance with medication, possible side effects of treatment, and changes in lifestyle or lipid-modifying drug therapy that may be required."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000798"}}]}}}},{"Surveillance":{"value":"ACSU498","properties":{"Key Text":{"value":"Cardiologist review"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Given the extremely high risk of early onset and rapid progression of CVD in HoFH, patients should be referred to a cardiologist and undergo comprehensive CV evaluation at diagnosis and repeated every 6 months with subsequent Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years or more frequently if needed."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000095"}},{"Reference":{"value":"/coll/reference_model/doc/RF000797"}},{"Reference":{"value":"/coll/reference_model/doc/RF000798"}}]}}}}]},"Family Managements":{"value":null,"items":[]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA404","properties":{"Key Text":{"value":"Smoking"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals with FH should be strongly discouraged from smoking or advised to stop smoking given the greatly increased risk for CHD."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000075"}},{"Reference":{"value":"/coll/reference_model/doc/RF000786"}},{"Reference":{"value":"/coll/reference_model/doc/RF000798"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Codominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Tier":{"value":"5"},"Notes":{"value":"Population screening of 50,762 individuals in a US health care system identified pathogenic variants associated with FH in 1:256 in unselected individuals; however, this may be an overestimate as it was based on screening within a single health care delivery system."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000796"}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE474","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Most individuals with HoFH experience severe CAD by their mid-20s."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000798"}}]}}}},{"Penetrance":{"value":"ACPE475","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"5"},"Notes":{"value":"An analysis of individuals identified from cascade screening in the identified 49 individuals with HoFH (20 were true homozygotes, 25 were compound heterozygotes). Within this population, 50% of the patients met the clinical criteria for HoFH (LDL-C .13.0 mmol/L) and 29% had a recorded history of a CVD event."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinical cardiovascular events"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000085"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR197","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information related to relative risk was identified related HoFH."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN215","properties":{"Key Text":{"value":"Despite this high risk of CVD compared with unaffected individuals, the clinical course of atherosclerotic cardiovascular disease in FH subjects is variable."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000788"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI220","properties":{"Key Text":{"value":"Interventions for HoFH included: surveillance (biochemical and cardiac imaging), medication use, and apheresis. Statins have possible adverse events of elevated liver enzymes, myopathy, and potential fetal teratogenicity.  Apheresis is a procedure in which either the plasma is separated from red blood cells before the physical removal of LDL-C or the LDL-C is directly removed from whole blood.  Apheresis typically needs to be undertaken approximately every two weeks (though frequency can vary) and requires specialist administration and monitoring with the duration of the procedure ranging from 2 to >3 hours. Serious adverse events are rare, with the most common reactions being light-headedness, nausea/vomiting, hypotension, and chest pain.  Adverse reactions with ezetimibe monotherapy are generally gastrointestinal and usually mild, when taken with a statin adverse events may include: elevated liver enzymes, headache, and myalgia. Trials of PCSK9 inhibitors indicate that there is no significant difference in the frequency of adverse events compared to those on placebo. The most frequently observed adverse events during use of lomitapide were gastrointestinal symptoms and liver fat accumulation. For mipomersen, the most frequently reported events were injection site reactions and increased liver fat accumulation. Aspirin can, in rare cases, lead to gastrointestinal and extracranial bleeds."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000095"}},{"Reference":{"value":"/coll/reference_model/doc/RF000787"}},{"Reference":{"value":"/coll/reference_model/doc/RF000798"}},{"Reference":{"value":"/coll/reference_model/doc/RF000800"}},{"Reference":{"value":"/coll/reference_model/doc/RF000793"}},{"Reference":{"value":"/coll/reference_model/doc/RF000802"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC213","properties":{"Key Text":{"value":"HoFH is typically diagnosed when considerable CAD has already developed."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000095"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final 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Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":10,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular events","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Hypercholesterolemia treatment to FH appropriate goal","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular events","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not 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worse...I'd consider bumping my score for hets up or my score for this entity down... On the other hand, \"moderately effective\" covers a lot of ground so maybe they both deserve that designation? Should be an interesting discussion."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"I could be talked up to a \"3\", but since apheresis is rather intrusive I went with a 2 for now..."}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular events","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Hypercholesterolemia treatment to FH appropriate goal","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":"Not sure if moderate or highly effective"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"alexanderkatz","properties":{"First Name":{"value":"Alexander"},"Last Name":{"value":"Katz"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular events","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Hypercholesterolemia treatment to FH appropriate goal","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":"all interventions scored together?"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"LDL apaheresis included so more intense"}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular events","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"Also considered Natural History data on most individuals dying by 30s."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Hypercholesterolemia treatment to FH appropriate goal","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"We're extrapolating here - sometimes from HeFH data and sometimes from general statin use data - and have more data on LDL-C than CV events."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular events","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Hypercholesterolemia treatment to FH appropriate goal","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular events","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Hypercholesterolemia treatment to FH appropriate goal","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular events","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Hypercholesterolemia treatment to FH appropriate goal","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular events","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Hypercholesterolemia treatment to FH appropriate goal","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular events","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Hypercholesterolemia treatment to FH appropriate goal","properties":{"Effectiveness":{"value":"Not Scored","properties":{"Notes":{"value":"How effect if started at 18?  it reduces chol, but does it prevent death from CVD in HoFH?"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"How often do HoFH pts require apheresis?"}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinical cardiovascular events","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3B","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Hypercholesterolemia treatment to FH appropriate goal","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"RefMetadata":{"value":0,"items":[]},"Release":{"value":"2.0.1","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36056},"ReasonCode":{"value":"Q4","properties":{"Reason":{"value":"Scoring pairs updated <strong>with</strong> major updates in the report"}}},"Date":{"value":"2018-05-21"},"ReleasedBy":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"}}}}}}}},
{"ActionabilityDocID":{"value":"AC066","properties":{"Status":{"value":"Released"},"Genes":{"value":2,"items":[{"Gene":{"value":"SMAD4","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:6770"},"GeneOMIM":{"value":"600993"},"SyndromeOMIMs":{"value":2,"items":[{"OMIM":{"value":"174900"}},{"OMIM":{"value":"175050"}}]}}}},{"Gene":{"value":"BMPR1A","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:1076"},"GeneOMIM":{"value":"601299"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"174900"}}]}}}}]},"Syndrome":{"value":"Juvenile polyposis syndrome","properties":{"OmimIDs":{"value":2,"items":[{"OmimID":{"value":"174900"}},{"OmimID":{"value":"175050"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Juvenile polyposis syndrome is an autosomal dominant condition that predisposes gene carriers to various types of tumors. The diagnosis is based on the occurrence of hamartomatous gastrointestinal polyps that turn into malignant lesions in some cases."},"Acronyms":{"value":2,"items":[{"Acronym":{"value":"JUVENILE POLYPOSIS SYNDROME"}},{"Acronym":{"value":"JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME; JPHT"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":3,"items":[{"SearchString":{"value":"((\"Juvenile polyposis syndrome\" [Supplementary Concept]) OR ( \"Smad4 Protein\"[Mesh] OR \"SMAD4 protein, human\" [Supplementary Concept] )) OR \"BMPR1A protein, human\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":3},"Date":{"value":"2015-12-18"}}}},{"SearchString":{"value":"Juvenile polyposis syndrome (text search)","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-12-18"}}}},{"SearchString":{"value":"(\"Neoplastic Syndromes, Hereditary\"[Mesh]) AND \"Intestinal Polyposis\"[Mesh]","properties":{"NumberOfHits":{"value":60},"Date":{"value":"2015-12-18"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Juvenile polyposis syndrome OR smad4 OR madh4 OR bmpr1a","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-12-18"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-12-18"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-12-18"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-12-18"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"smad4 OR madh4 OR bmpr1a OR Juvenile polyposis syndrome","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-12-18"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Gastrointestinal cancer","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Endoscopic surveillance"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Notes":{"value":"Robust prevalence estimates for Juvenile polyposis syndrome (JPS) are not available because of its rarity, the lack of comprehensive clinical phenotype ascertainment and the fact that there are no population-based molecular studies. However, estimates of the population prevalence suggest the frequency of JPS may be similar to that of Peutz-Jeghers syndrome suggesting a frequency of around 1:50,000, although it may be as low as 1:120,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000023"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"JPS is characterized by predisposition to hamartomatous polyps in the gastrointestinal tract, specifically in the stomach, small intestine, colon, and rectum. Histological differences and topographical distribution within the gastrointestinal tract serve to distinguish between JPS and Peutz-Jeghers Syndrome.   The number of polyps in individuals with JPS varies, with dozens to many hundreds of polyps present in the fully developed syndrome. \n\nA combined syndrome of JPS and hereditary hemorrhagic telangiectasia (HHT) (termed JPS/HHT) is present in most individuals with an SMAD4 pathogenic variant. [Hereditary hemorrhagic telangiectasia is addressed in a separate report]"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000323"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"The term 'juvenile' refers to the polyp type rather than to the age of onset, although most individuals with JPS have some polyps by 20 years of age. JPS usually manifests during childhood with polyps beginning to appear in the first decade of life. The average age at diagnosis is 18.5 years, but may be later, with rectal bleeding with anemia as the most common presenting symptom.  \n \n \nMost juvenile polyps are benign; however, malignant transformation can occur. In those who develop cancer, the mean age of colon cancer is 34 years, with a range of 15 to 68 years and the median age of upper GI cancer is 58 years with a range of 21 to 73 years."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000323"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM936","properties":{"Key Text":{"value":"Baseline evaluation"},"Tier":{"value":"3"},"Recommendation Text":{"value":"To determine the extent of disease, a baseline evaluation of patients should include a clinical history, complete blood count, colonoscopy, and upper endoscopy."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000323"}}]}}}},{"Patient Management":{"value":"ACPM935","properties":{"Key Text":{"value":"Colectomy/proctocolectomy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Colectomy and ileorectal anastomosis or proctocolectomy and ileal pouch-anal anastomosis is indicated for polyp-related symptoms, or when the polyps cannot be managed endoscopically. One case series reported on long-term outcomes of colonic surgery in 13 patients presenting with symptomatic colon polyps (median age at diagnosis=10 years, range=1-50 years). Eight patients had their rectum removed during the study period; 5 had an ileal pouch-anal anastomosis, one had a Koch pouch as a restorative surgery, and 2 had an end ileostomy. No relation was observed between the number of colonic and rectal polyps and the type of surgery or the need for proctectomy. Patients were followed up a median of 3 years (range=2-24 years) after their ultimate operations. During this period, one patient (20%) who underwent restorative proctectomy and 4 patients (80%) whose rectums were preserved required multiple endoscopic polypectomies for recurrent polyps in the pouch (first patient) or their rectums (the other 4 patients). The patient who underwent the Koch procedure required surgery for recurrent polyps in her pouch."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU499","properties":{"Key Text":{"value":"Colonoscopy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Colonoscopy is recommended in patients with JPS. Recommended starting age ranges across guidelines from 12-18, while frequency ranges from annually to every 3 years. The frequency of screening may be determined by the findings of the previous endoscopy, and may be extended to longer intervals after age 35. There are no comparative studies to demonstrate the potential benefit of screening; however, there is substantial risk of CRC in JPS patients. The life-time risk of CRC death in JPS patients not undergoing surveillance is estimated to be as high as 1 in 6. One retrospective review of a registry of 44 patients with JPS undergoing routine surveillance (380 patient-years follow up) of the upper and lower GI tract has reported surveillance results.  Screening detected 767 polyps and 20 adenomatous polyps. Five patients were identified requiring colorectal surgery. Two patients developed colorectal cancer while undergoing surveillance. However, given the lack of a control group it is unclear how many of these patients would have been detected clinically without undergoing surveillance."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000228"}},{"Reference":{"value":"/coll/reference_model/doc/RF000198"}}]}}}},{"Surveillance":{"value":"ACSU501","properties":{"Key Text":{"value":"Upper endoscopy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Upper endoscopy is also recommended in patients with JPS. Recommended starting age ranges across guidelines from 12-25 years, while frequency ranges from annually to every 3 years. The frequency of screening is determined by the findings of the previous endoscopy, and may be extended to longer intervals after age 35. The risk of gastric and duodenal cancer in JPS is around 15-21%.  Among the retrospective registry of JPS patients, gastrodueodenal polyps were found in 37% of patients and two patients were identified with adenomatous polyps of the stomach. Two patients were identified requiring gastrectomy. One patient developed cancer while undergoing surveillance.  However, given the lack of a control group it is unclear how many of these patients would have been detected clinically without undergoing surveillance."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000228"}},{"Reference":{"value":"/coll/reference_model/doc/RF000198"}}]}}}},{"Surveillance":{"value":"ACSU500","properties":{"Key Text":{"value":"Enteroscopy/capsule endoscopy/CT enterography"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Periodic enteroscopy, capsule endoscopy and/or CT enterography may be used for surveillance of the small intestine."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000228"}}]}}}},{"Surveillance":{"value":"ACSU502","properties":{"Key Text":{"value":"Enteroscopy/capsule endoscopy/CT enterography"},"Tier":{"value":"5"},"Recommendation Text":{"value":"A case series of small-bowel capsule endoscopy of ten adults (median age 39.2 years) with documented JPS identified 2 patients that had small-bowel polyps beyond the range of standard gastroscopy identified at capsule endoscopy. Duodenal polyps were detected in a third patient at capsule endoscopy not previously detected by standard gastroscopy. However, given the lack of a control group it is unclear how many of these patients would have been detected clinically without undergoing surveillance."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000229"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM331","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Genetic testing should be performed on at-risk family members in the first to second decade of life to identify those who will benefit from early surveillance intervention."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000323"}}]}}}},{"Family Management":{"value":"ACFM332","properties":{"Key Text":{"value":"Family surveillance"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Relatives of individuals with an identified SMAD4 or BMPR1A pathologic variant who have not undergone molecular genetic testing or whose tests results were uninformative should undergo monitoring for stool change. In addition these patients should receive a complete blood count, colonoscopy and upper endoscopy starting in the mid-teens or at time of symptoms. The frequency of subsequent screening depends on the number of polyps identified on endoscopic screening."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000323"}}]}}}},{"Family Management":{"value":"ACFM330","properties":{"Key Text":{"value":"Family surveillance"},"Tier":{"value":"3"},"Recommendation Text":{"value":"For relatives not found to have a family specific genetic variant, CBC and lower initial endoscopy should be performed at age 15 years as a baseline screen, and if negative, repeated every ten years until age 45 after which time standard CRC screening recommendations may be followed."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000323"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA405","properties":{"Key Text":{"value":""},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"None identified."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"No estimates were identified for the prevalence of SMAD4 or BMPR1A mutations.  Up to 60% of individuals with a clinically defined JPS are found to exhibit mutations of the SMAD4 or BMPR1A genes."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE476","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"No studies have examined the proportion of individuals with known germline pathogenic variants for JPS who develop polyps. It is expected to be higher than 90%."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Gastrointestinal cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000323"}}]}}}},{"Penetrance":{"value":"ACPE477","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Estimates for the risk of colorectal cancer range from 10-68%, though a more recent synthesis estimates a range of 38-68%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000323"}}]}}}},{"Penetrance":{"value":"ACPE478","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"An estimated 21% of patients with JPS will develop upper gastrointestinal cancer."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR198","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"The relative risk of developing colorectal cancer was found to be 34.0 (14.4 to 65.7)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000323"}}]},"Tier":{"value":"3"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN216","properties":{"Key Text":{"value":"The number of polyps in individuals with JPS varies. Some individuals may have only four or five polyps over their lifetime; others in the same family may have more than 100."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000323"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI221","properties":{"Key Text":{"value":"Identified interventions include upper and lower gastrointestinal surveillance."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC214","properties":{"Key Text":{"value":"The average age at diagnosis is 18.5 years, but may be later, with rectal bleeding with anemia as the most common presenting 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{"ActionabilityDocID":{"value":"AC067","properties":{"Status":{"value":"Released"},"Genes":{"value":5,"items":[{"Gene":{"value":"SMAD3","properties":{"GeneFunction":{"value":"SMAD family member 3"},"HGNCId":{"value":"HGNC:6769"},"GeneOMIM":{"value":"603109"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"613795"}}]}}}},{"Gene":{"value":"TGFB2","properties":{"GeneFunction":{"value":"transforming growth factor beta 2"},"HGNCId":{"value":"HGNC:11768"},"GeneOMIM":{"value":"190220"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"614816"}}]}}}},{"Gene":{"value":"TGFB3","properties":{"GeneFunction":{"value":"transforming growth factor beta 3"},"HGNCId":{"value":"HGNC:11769"},"GeneOMIM":{"value":"190230"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"615582"}}]}}}},{"Gene":{"value":"TGFBR1","properties":{"GeneFunction":{"value":"transforming growth factor beta receptor 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3"}},{"Acronym":{"value":"Loeys-Dietz syndrome 4"}},{"Acronym":{"value":"Loeys-Dietz syndrome 5"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"(((\"Loeys-Dietz Syndrome\"[Mesh]) OR \"TGF-beta type I receptor\" [Supplementary Concept]) OR \"transforming growth factor-beta type II receptor\" [Supplementary Concept]) OR \"SMAD3 protein, human\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":10},"Date":{"value":"2015-03-20"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":4,"items":[{"SearchString":{"value":"Loeys 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LDS is mainly characterized by vascular (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections; arterial tortuousity) and skeletal (pectus deformity, scoliosis, joint laxity, arachnodactyly, club foot) manifestations. Patients may also display craniofacial (widely spaced eyes, bifid uvula, cleft palate, and craniosynostosis) and cutaneous (translucent skin, easy bruising, dystrophic scars) manifestations.\n\nPathogenic variants in TGFBR1 and TGFBR2 are associated with 2 types of LDS that are clinically indistinguishable: Type I (LDS1; ~70% of cases) with vascular, skeletal, cutaneous, and craniofacial manifestations and Type II (LDS2; ~20% of cases) with the systemic manifestations of LDS1 but minimal or absent craniofacial manifestations. SMAD3 pathogenic variants are associated with Type III (LDS3; ~5% of cases), which overlaps with Types I and II, but is characterized by an increased risk of osteoarthritis. TGFB2 is associated with Type IV (LDS4; ~1% of cases), which has classic LDS features but milder phenotype, with club feet and mitral valve disease as the most recurrent features. TGFB3 is associated with Type V (LDS5), which has the typical LDS features of aortic aneurysms and other systemic features, but no striking aortic or arterial tortuosity and no strong evidence for early aortic dissection."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000100"}},{"Reference":{"value":"/coll/reference_model/doc/RF000324"}},{"Reference":{"value":"/coll/reference_model/doc/RF000047"}},{"Reference":{"value":"/coll/reference_model/doc/RF000049"}},{"Reference":{"value":"/coll/reference_model/doc/RF000045"}},{"Reference":{"value":"/coll/reference_model/doc/RF000698"}},{"Reference":{"value":"/coll/reference_model/doc/RF000699"}},{"Reference":{"value":"/coll/reference_model/doc/RF000700"}},{"Reference":{"value":"/coll/reference_model/doc/RF000701"}},{"Reference":{"value":"/coll/reference_model/doc/RF000702"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"The vascular disease in LDS is aggressive, with a mean age of death of 26 years. However, recent studies indicate a higher survival rate (80% at age 60) and later age of onset (31 years for LDS1 and 46 years for LDS2) than previous reported. A study of 45 LDS3 patients indicated an age of onset range of 18 to 61 years for joint complaints and 20 to 66 years for cardiovascular abnormalities. A study of 2 LDS4 families reported a median age of aortic disease of 35 years. A study of 12 individuals with LDS5 indicated that 7 presented with aneurysms and dissections between the ages of 40 and 68. There is a high incidence of pregnancy-related complications, including aortic dissection/rupture and uterine rupture during pregnancy or delivery and aortic dissection/rupture in the immediate postpartum period. No ethnic/racial or gender difference has been reported, though there is evidence that males have a greater risk of aortic events and an earlier age of onset of vascular disease than females."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000100"}},{"Reference":{"value":"/coll/reference_model/doc/RF000324"}},{"Reference":{"value":"/coll/reference_model/doc/RF000047"}},{"Reference":{"value":"/coll/reference_model/doc/RF000698"}},{"Reference":{"value":"/coll/reference_model/doc/RF000699"}},{"Reference":{"value":"/coll/reference_model/doc/RF000700"}},{"Reference":{"value":"/coll/reference_model/doc/RF000701"}},{"Reference":{"value":"/coll/reference_model/doc/RF000702"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM940","properties":{"Key Text":{"value":"Risk Reducing Surgery"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Prophylactic surgical repair is typically recommended at an aortic diameter of > 4.2 cm, but this threshold can vary depending on rate of expansion. Timely repair of aortic aneurysms prolongs survival and approaches that of age-matched controls in patients with Marfan syndrome; however, evidence on effectiveness was not provided for patients with LDS."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000047"}},{"Reference":{"value":"/coll/reference_model/doc/RF000049"}},{"Reference":{"value":"/coll/reference_model/doc/RF000050"}},{"Reference":{"value":"/coll/reference_model/doc/RF000045"}}]}}}},{"Patient Management":{"value":"ACPM937","properties":{"Key Text":{"value":"Pharmacotherapy"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Beta-blockers or other medications can be used to reduce hemodynamic stress."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000100"}},{"Reference":{"value":"/coll/reference_model/doc/RF000324"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC211","properties":{"Recommendation":{"value":"Specifically, the use of an angiotensin II receptor blocker (ARB; e.g., losartan) in addition to beta-blockers has been proposed for Marfan syndrome (MFS), a recommendation that may also apply to LDS. However, data on the effectiveness of beta blockers and ARBs is not available for LDS.  A systematic review of beta blocker, angiotensin-converting enzyme inhibitor, and ARB use in MFS concluded that these medications slowed the progression of aortic dilation. Three of the included studies showed that the treatment group’s aortic dilation progressed by roughly 1mm/year less than the non-treatment group, though no information was provided on how this impacted clinical outcomes."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000486"}}]}}}},{"RecommendationID":{"value":"REC212","properties":{"Recommendation":{"value":"In addition, two randomized trials in patients with MFS reported reductions in aortic root dilation rate with ARB added to beta blockers at three-year follow-up, indicating that treatment with beta blockers and ARB may be more effective than beta blockers alone. In contrast, a double-blind randomized trial found no significant difference between ARB and placebo on aortic root dilation rate at median 3.5-year follow-up, with most patients in both treatment groups also on beta blockers (86%)."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000703"}},{"Reference":{"value":"/coll/reference_model/doc/RF000704"}},{"Reference":{"value":"/coll/reference_model/doc/RF000705"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM943","properties":{"Key Text":{"value":"Patient Awareness"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals with either a TGFBR1 or TGFBR2 mutation should be taught the signs and symptoms of aortic dissection and should consider wearing a medical alert bracelet."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000049"}}]}}}},{"Patient Management":{"value":"ACPM944","properties":{"Key Text":{"value":"Dental management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Prophylactic antibiotics for any invasive procedure including dentistry are recommended."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000050"}}]}}}},{"Patient Management":{"value":"ACPM942","properties":{"Key Text":{"value":"Spinal Fusion"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Because of a high risk of cervical spine instability, an x-ray of the cervical spine should be performed prior to intubation or any other procedure involving manipulation of the neck. Surgical fixation of the cervical spine may be necessary to prevent damage to the spinal cord."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000100"}},{"Reference":{"value":"/coll/reference_model/doc/RF000324"}}]}}}},{"Patient Management":{"value":"ACPM939","properties":{"Key Text":{"value":"Orthopedics"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Patients should undergo radiographs to detect skeletal manifestations, such as scoliosis, that may require attention by an orthopedist"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000324"}}]}}}},{"Patient Management":{"value":"ACPM938","properties":{"Key Text":{"value":"Ophthalmology"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Patients should undergo an eye examination by an ophthalmologist with expertise in connective tissue disorders to assess for retinal detachment and blue sclerae."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000324"}}]}}}},{"Patient Management":{"value":"ACPM941","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"During pregnancy there is a high incidence of pregnancy-related complications including uterine rupture, hemorrhage, and death. 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I scored a D based on the conflicting clinical trial evidence for beta-blocker + ARB and no evidence specific to LDS."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Clinically Significant Aortic Aneurysm","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Clinically Significant Aortic Aneurysm","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"?timely surgery prolongs survival"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"? no specific efficacy given"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Clinically Significant Aortic Aneurysm","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"will defer to group knowledge on side effects"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"will defer to group knowledge on side effects"}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Clinically Significant Aortic Aneurysm","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Do you mean echo prior to treatment? Should evidence level be dropped?"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Clinically Significant Aortic Aneurysm","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Clinically Significant Aortic Aneurysm","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"2.0.2","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36060},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-10"},"ReleasedBy":{"value":"hunterj","properties":{"First Name":{"value":"Jessica"},"Last Name":{"value":"Hunter"}}}}}}}},
{"ActionabilityDocID":{"value":"AC068","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"TP53","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:11998"},"GeneOMIM":{"value":"191170"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"151623"}}]}}}}]},"Syndrome":{"value":"Li-Fraumeni Syndrome","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"151623"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Classic tumors: soft tissue sarcoma, osteosarcoma, breast cancer, brain tumors, adrenocortical carcinoma, leukemiasTumor onset is typically during childhood or young-adulthood."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Li Fraumeni Syndrome"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"\"Li-Fraumeni Syndrome\"[Mesh] AND ( Guideline[Publication Type] OR Meta-Analysis[Publication Type] OR Systematic Review[Publication Type] )","properties":{"NumberOfHits":{"value":4},"Date":{"value":"2016-11-01"},"Notes":{"value":""},"searchURL":{"value":"https://www.ncbi.nlm.nih.gov/pubmed/?term=%22Li-Fraumeni+Syndrome%22%5BMesh%5D+AND+(+Guideline%5BPublication+Type%5D+OR+Meta-Analysis%5BPublication+Type%5D+OR+Systematic+Review%5BPublication+Type%5D+)"},"Label":{"value":"PubMed1"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":0,"items":[]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2014-01-07"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2014-01-07"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2014-01-07"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2014-01-07"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Li Fraumeni syndrome-associated cancers","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Cancer surveillance"}},{"Intervention":{"value":"Avoidance of radiotherapy"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"LFS is a rare cancer syndrome, with an estimated prevalence of 1-9 in 100,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000739"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"LFS is a cancer predisposition syndrome associated with early onset of neoplasms and multiple primary neoplasms within an individual. The most common cancers are soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, brain tumors, and adrenocortical carcinoma, which account for about 70% of LFS-related cancers. Other cancers include colon cancer, gastric cancer, and leukemia. To date, male breast cancer has rarely been reported in families with LFS."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000258"}},{"Reference":{"value":"/coll/reference_model/doc/RF000104"}},{"Reference":{"value":"/coll/reference_model/doc/RF000739"}},{"Reference":{"value":"/coll/reference_model/doc/RF000740"}},{"Reference":{"value":"/coll/reference_model/doc/RF000741"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"LFS-related cancers often occur in childhood or young adulthood. Women have a higher risk of developing cancer and a younger average age of onset (29 years) compared to men (40 years). Roughly 50% of tumors develop by age 30 and 90% by age 60. Individuals with LFS often develop additional malignancies, with an estimated 57% developing a second cancer, and 38% developing a third. The probability of additional cancers is inversely correlated with younger age at diagnosis of first malignancy. Besides an earlier age of onset, the characteristics of LFS-associated tumors compared to non-LFS are unclear, though there is some evidence that breast cancers in LFS are more likely to be HER2-positive compared to other cases. They are also predominantly estrogen and/or progesterone hormone receptor-positive. The overall prognosis is unknown for LFS and depends on the type and severity of cancers developed."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000258"}},{"Reference":{"value":"/coll/reference_model/doc/RF000104"}},{"Reference":{"value":"/coll/reference_model/doc/RF000739"}},{"Reference":{"value":"/coll/reference_model/doc/RF000740"}},{"Reference":{"value":"/coll/reference_model/doc/RF000741"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM947","properties":{"Key Text":{"value":"Breast Aware"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Women should be ‘breast aware’, in line with Department of Health advice for all women, and promptly report any changes to their healthcare provider. Guidelines are conflicting for recommendations for clinical breast exams. One guideline recommends that women should undergo clinical breast exams every 6-12 months starting at age 20. However, another guideline notes that there is a lack of evidence for a high-risk population that either clinical breast examination or self-examination is useful as the sole surveillance modality."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000022"}},{"Reference":{"value":"/coll/reference_model/doc/RF000740"}}]}}}},{"Patient Management":{"value":"ACPM948","properties":{"Key Text":{"value":"Chemoprevention"},"Tier":{"value":"1"},"Recommendation Text":{"value":"For chemoprevention, tamoxifen should be offered for 5 years to premenopausal women (unless they have a past history of or may be at increased risk for thromboembolic disease or endometrial cancer) and anastrozole should be offered for 5 years to postmenopausal women. Tamoxifen and raloxifene could be considered in postmenopausal women who have severe osteoporosis or do not wish to take anastrozole. No direct evidence for the effectiveness of chemoprevention specific to women with TP53 pathogenic variants was identified. Data are available among high-risk populations (defined by family history of breast, ovarian or related cancer or genetic predisposition). Four studies (3 RCTs and one prospective cohort study) compared tamoxifen with placebo (n=488 to 13,207) in women aged 30 to 70. Treatment duration ranged from 5 to 8 years. Low quality evidence from a meta-analysis of the 3 RCTs (n=19,687) indicated tamoxifen is associated with a lower incidence of invasive breast cancer when compared to placebo (RR=0.70, 95% CI: 0.61-0.80). Moderate quality evidence from a meta-analysis of the 3 RCTs indicated tamoxifen was associated with a lower incidence of ductal carcinoma in situ compared to placebo (RR=0.59, 95% CI: 0.44-0.78). A long-term follow-up from one of these trials has subsequently been published which found that over a median of 16 years, there was a significant reduction in the occurrence of all breast cancers in the tamoxifen group (HR=0.71; 95% CI: 0.60 to 0.83). However, no significant difference was found in breast-cancer specific mortality (OR=1.19; 95% CI: 0.68-2.10). One randomized trial of moderate quality reported a reduction in incidence of invasive breast cancer for anastrozole versus placebo (RR=0.51; 95% CI: 0.33-0.77). Evidence from a single randomized trial of low quality suggests the incidence of breast cancer is lower in patients given exemestane compared with those given a placebo (HR=0.35, 95% CI: 0.18-0.70)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000022"}}]}}}},{"Patient Management":{"value":"ACPM946","properties":{"Key Text":{"value":"Prophylactic Surgery"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Prophylactic bilateral mastectomy and oophorectomy should be offered as a risk-reducing strategy. No direct evidence for the effectiveness of risk-reducing surgery among women with TP53 pathogenic variants was identified. Risk reduction for breast cancer after bilateral mastectomy and oophorectomy is roughly 90% and 50-75%, respectively, among populations considered high-risk due to a family history or BRCA1/2 variants. One observational study found that risk-reducing mastectomy was associated with an 81-94% reduction in breast cancer mortality in women identified as high-risk."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000022"}}]}}}},{"Patient Management":{"value":"ACPM950","properties":{"Key Text":{"value":"Health Awareness"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should be educated regarding the signs and symptoms of cancer."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000740"}}]}}}},{"Patient Management":{"value":"ACPM949","properties":{"Key Text":{"value":"Health Awareness"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Patients should contact their physician for any lingering symptoms and illnesses, such as headaches, bone pain, or abdominal discomfort."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000258"}}]}}}},{"Patient Management":{"value":"ACPM945","properties":{"Key Text":{"value":"Health Awareness"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Pregnant women should bring any potential symptoms of cancer to the attention of their physicians."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000258"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU506","properties":{"Key Text":{"value":"Management Centers"},"Tier":{"value":"4"},"Recommendation Text":{"value":"The screening and management of LFS is complex. It is preferred that individuals with LFS be followed at centers with expertise in the management of this syndrome."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000740"}}]}}}},{"Surveillance":{"value":"ACSU505","properties":{"Key Text":{"value":"Breast Surveillance"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Annual surveillance with breast MRI should be offered to women aged 20-49 years, and should be considered for women aged 50-69. Ultrasound and mammogram breast surveillance should not be offered, unless MRI is not suitable or when results of MRI are difficult to interpret. Evidence on the effectiveness of MRI breast surveillance in TP53 carriers is not available. However, one study reported that women aged less than 50 years with a family history who were diagnosed with breast cancer during mammographic surveillance were less likely to die from breast cancer compared to a control group of unscreened women of similar age who developed breast cancer (HR=0.24; 95% CI: 0.09-0.66). A second study reported that women with a BRCA1/2 variant aged 28 to 77 years diagnosed with breast cancer during an intensive mammographic surveillance program were less likely to die from any cause compared to a control group diagnosed outside this program (HR=0.44 (95% CI: 0.25-0.77). Although MRI has been shown to be more sensitivity at early detection of breast cancer in women at high-risk, there is no evidence that this modality confers a survival benefit."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000022"}}]}}}},{"Surveillance":{"value":"ACSU507","properties":{"Key Text":{"value":"Surveillance protocol"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Many of the other cancers associated with germline mutations in TP53 do not lend themselves to early detection. Thus, additional recommendations are general and include: comprehensive physical exams including neurological examination every 6-12 months with a high index for suspicion for rare cancers and second malignancies, colonoscopy and upper endoscopy every 2-5 years starting at age 25 or 5 years before the earliest known colon cancer in the family, annual dermatological examination starting at age 18, annual full blood count, annual whole body MRI, and annual brain MRI. Additional surveillance may be recommended based on family history. One 11-year prospective observational study reported outcomes among 40 TP53 carriers who chose to undergo a surveillance protocol and 49 who declined surveillance (19 crossed over to the surveillance group for a total of 59 undergoing surveillance). Surveillance included biochemical methods and imaging techniques, such as annual mammography, annual brain MRI, annual rapid total-body MRI, ultrasound of the abdomen and pelvis, and colonoscopy. Over a median period of 32 months (IQR: 12-87), surveillance identified 40 asymptomatic neoplasms in 19 of 59 (32%) patients, including both malignant tumors and low-grade or premalignant lesions. Among the 49 individuals who initially declined surveillance, 61 symptomatic tumors were diagnosed in 43 (88%). Of the patients who chose surveillance and were diagnosed with cancer, 84% (16 out of 19) were alive at follow-up (median 38 months, IQR: 12-86) compared to 49% (21 out of 43; median follow-up of 46 months, IQR: 22-72) patients diagnosed with cancer who had not chosen surveillance (p=0.012). All patients who died in the non-surveillance group died of cancer. The 5-year overall survival was greater for the surveillance group (88.8%) compared to the non-surveillance group (59.6%) (p=0.0132). A separate meta-analysis evaluated whole-body MRI among 578 individuals across 13 prospective cohorts where a whole-body MRI was administered as part of a baseline assessment with all participants asymptomatic at the time of the baseline scan and not required to be newly diagnosed. Cancer was identified in 7% of the sample, with 83% of cancers being localized and able to treat with curative intent."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000740"}},{"Reference":{"value":"/coll/reference_model/doc/RF000741"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM335","properties":{"Key Text":{"value":"Genetic Testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Relatives of an individual with a TP53 pathogenic variant should be referred to a specialist genetics clinic to discuss their genetic risk, risk assessment, and management options."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000022"}},{"Reference":{"value":"/coll/reference_model/doc/RF000740"}}]}}}},{"Family Management":{"value":"ACFM336","properties":{"Key Text":{"value":"Surveillance"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Women who have a first degree relative with a TP53 mutation, but have not undergone genetic testing themselves, should be offered the same recommendations for breast cancer patient management and surveillance as carriers. However, once this ungenotyped relative reaches 50 years of age without developing breast cancer or any other TP53-related malignancy, her carrier probability is considered lower than 30%, and she should be offered mammography in lieu of MRI surveillance unless a dense breast pattern is identified via mammography."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000022"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA408","properties":{"Key Text":{"value":"Radiotherapy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Therapeutic radiotherapy for cancer treatment should be avoided when possible and diagnostic radiation should be minimized to the extent feasible without sacrificing accuracy. Radiation-induced malignancies have been reported among individuals with TP53 pathogenic variants, including 12 case studies of individuals who developed subsequent malignancies in the radiation field following treatment."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000740"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA407","properties":{"Key Text":{"value":"Carcinogen Exposure"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Carriers of TP53 pathogenic variants are counseled to avoid sun exposure, tobacco use, and other known or suspected carcinogens. TP53 mutation carriers who smoke have been found to have a 3.16-fold (95% confidence interval =1.48-6.78) higher risk for lung cancer than the mutation carriers who do not smoke."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000258"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 5000"},"Tier":{"value":"3"},"Notes":{"value":"Germline mutations in the TP53 gene have been observed in 50-80% of families with features of LFS."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000258"}},{"Reference":{"value":"/coll/reference_model/doc/RF000740"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC051","properties":{"Recommendation":{"value":"The frequency of germline TP53 pathogenic variants in the general population is estimated between 1/5000 and 1/20,000 in the US and 1/10,000 and 1/25,000 in the UK."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000258"}},{"Reference":{"value":"/coll/reference_model/doc/RF000739"}},{"Reference":{"value":"/coll/reference_model/doc/RF000740"}}]}}}}]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE481","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"LFS is highly penetrance with a high lifetime risk for cancer. An analysis from the National Cancer Institute’s LFS study (N=286) showed a cumulative lifetime cancer incidence of nearly 100%. This study also estimated cumulative incidence rates by 70 years:\nWomen:  breast cancer=54%, soft tissue sarcoma=15%, brain cancer=6%, and osteosarcoma=5%\nMen: soft tissue sarcoma=22%, brain cancer=19%, osteosarcoma=11%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000740"}}]}}}},{"Penetrance":{"value":"ACPE482","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Pathogenic variants in TP53 are associated with estimated cancer risks of approximately 60% by age 45 and 95% by age 70."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000740"}}]}}}},{"Penetrance":{"value":"ACPE480","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"For lifetime risk of developing cancer, women have a nearly 100% risk while men have a 73% risk."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000258"}},{"Reference":{"value":"/coll/reference_model/doc/RF000739"}},{"Reference":{"value":"/coll/reference_model/doc/RF000741"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR200","properties":{"Key Text":{"value":">3"},"Notes":{"value":"The relative risk of overall tumor development was not found, however tumor-specific relative risks and 95% confidence intervals are available: bone: 107 (49-203), connective tissue: 61 (33-102), brain: 35 (19-60), pancreas: 7.3 (2-19), breast: 6.4 (4.3-9.3), colon: 2.8 (1-6), liver: 18 (2.1-64)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000258"}},{"Reference":{"value":"/coll/reference_model/doc/RF000741"}}]},"Tier":{"value":"3"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN218","properties":{"Key Text":{"value":"LFS patients display high variability in age at onset, tumor locations, and number of types of tumors."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000258"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI223","properties":{"Key Text":{"value":"Interventions identified in this report include prophylactic surgery to remove target organs, intense surveillance, and medications with potential side effects. Adverse events reported with chemoprevention drugs include headache, hot flushes, vaginal discharge, hypertension, musculoskeletal and vasomotor symptoms, cataracts, endometrial cancer, and thrombotic events."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC216","properties":{"Key Text":{"value":"Patients should undergo intensive surveillance protocols not typical of routine clinical monitoring or annual exams."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000740"}}]},"Tier":{"value":"2"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2018-02-19"},"Scorers Present":{"value":6,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"srego"}},{"Scorer":{"value":"odanielj"}}]},"Notes":{"value":"It was touch for the AWG to score avoidance of radiotherapy given the lack of clear evidence and the fact that it is optimal cancer care so there are implications for avoiding it. 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MUTYH-associated polyposis is caused by biallelic pathogenic variants. MAP is estimated to account for <1% of population-based CRC cases, and up to 2% of familial or early-onset CRC cohorts. Assuming a CRC frequency of 5% in the general European population, the overall prevalence is assumed to be around 1 in 5000. In one study, MAP was found in 2 out of 444 (0.5%) of unselected CRCs; another population study found a prevalence of 0.4% in 1042 population-based CRC cases. In a large (2,239 cases and 1,845 controls) population-based case–control study from Scotland, 0.8% of CRC cases <55 years old and 0.54% of all cases had MAP."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000239"}},{"Reference":{"value":"/coll/reference_model/doc/RF000326"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000772"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"MAP predisposes individuals to an attenuated polyposis phenotype and an increased risk of CRC. Most individuals with MAP have 10 to a few hundred polyps in the colon, although some might have over 1,000.  The predominant polyp type is adenomatous, though hyperplastic, sessile serrated, traditional serrated or mixed types can occur. Duodenal polyps are found in 17-25% and duodenal cancer is estimated at 4-5%. Other extraintestinal manifestations have been reported including ovarian cancer, bladder cancer, breast cancer, endometrial cancer, skin tumors, and thyroid cancer, although it is still not clear if the lifetime risk of these malignancies is increased. Although rare, other findings seen in patients with MAP have included sebaceous gland adenomas, carcinomas and epitheliomas, lipomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, desmoid tumors, epidermoid cysts, and pilomatrixomas."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000326"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000228"}},{"Reference":{"value":"/coll/reference_model/doc/RF000183"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Colorectal adenomatous polyps present, on average, at age 50. In the absence of timely surveillance, the lifetime risk for CRC ranges from 40% to almost 100%. The risk of CRC by age 50 years is 19% and by age 60 years is 43%, with an average age of CRC onset of 48 years (median age of presentation 45 – 59 years). CRC has presented in some individuals with MAP in the absence of polyposis. Duodenal polyps are found in 4-25% of individuals with MAP; the lifetime risk for duodenal cancer in individuals with MAP is 4-5% with the average age of diagnosis of 61 years. Stomach cancer occurs in 1% of individuals with MAP at an average age of diagnosis of 38 years. Most major ethnic groups seem to have mutations in the MUTYH gene. There appear to be a number of founder mutations common to specific ethnic groups."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000326"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000228"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}},{"Reference":{"value":"/coll/reference_model/doc/RF000773"}},{"Reference":{"value":"/coll/reference_model/doc/RF000198"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM954","properties":{"Key Text":{"value":"Baseline evaluation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs of an individual diagnosed with MAP, the following evaluations are recommended:\n• Review of personal medical history with emphasis on those features related to MAP (or colorectal cancer): colon polyps with the majority being adenomas, colon cancer, rectal bleeding, abdominal pain and discomfort, bloating, diarrhea\n• Colonoscopy and review of pathology\n• Upper endoscopy and review of pathology\n• Baseline thyroid ultrasound examination \n• Consultation with a clinical geneticist and/or genetic counselor"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000326"}}]}}}},{"Patient Management":{"value":"ACPM956","properties":{"Key Text":{"value":"Specialist management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"It is recommended that patients be managed by physicians or centers with expertise in MAP and that management be individualized to account for genotype, phenotype, and personal considerations."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000228"}}]}}}},{"Patient Management":{"value":"ACPM955","properties":{"Key Text":{"value":"Colectomy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Surgical evaluation and counseling is recommended, if appropriate, for individuals with a low polyp burden. (Procto)Colectomy with IRA or IPAA is recommended for patients with significant polyposis not manageable by polypectomy."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000228"}},{"Reference":{"value":"/coll/reference_model/doc/RF000183"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}},{"Reference":{"value":"/coll/reference_model/doc/RF000198"}},{"Reference":{"value":"/coll/reference_model/doc/RF000774"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC214","properties":{"Recommendation":{"value":"A retrospective observational study of 14 patients with MAP reported that of the 11 cases that underwent total colectomy with IRA and yearly proctoscopic surveillance, none developed rectal cancer during surveillance (median duration was 5 years)."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]}}}},{"RecommendationID":{"value":"REC213","properties":{"Recommendation":{"value":"After colectomy with IRA in a large series of patients with attenuated familial adenomatous polyposis (AFAP), an average of 3.4 recurrent polyps (range, 0–29) and only one cancer was found in the postcolectomy rectal remnant over a mean follow-up of 7.8 years (range, 1–34 years)."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]}}}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU515","properties":{"Key Text":{"value":"Colonoscopy and polypectomy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Colonoscopy and polypectomy are recommended starting in early adulthood (age and frequency varies by guideline and polyp burden). Although indirect evidence suggests colonoscopic surveillance and polypectomy may be effective in CRC control, this has yet to be definitively determined for MAP. There is no literature to date of any control subjects with bi-allelic MUTYH mutations who have reached the age of 55 years without developing CRC or polyposis."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000228"}},{"Reference":{"value":"/coll/reference_model/doc/RF000183"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}},{"Reference":{"value":"/coll/reference_model/doc/RF000198"}},{"Reference":{"value":"/coll/reference_model/doc/RF000774"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC035","properties":{"Recommendation":{"value":"Though evidence was not identified for the effectiveness of screening programs in patients with MAP, evidence indicates that screening in Lynch Syndrome patients at 1-3 year intervals decreases the risk of CRC. Five out of six studies found a significantly reduced incidence rate of CRC with surveillance (OR estimates ranged from 0.11 to 0.35), while the sixth study reporting an OR of 0.93 was not significant. Two out of four studies have shown a significant reduction in CRC-related mortality with surveillance (OR estimates range from 0.04 to 0.17), while three of the four studies reported no mortality in the study arm with surveillance."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000114"}}]}}}}]}}}},{"Surveillance":{"value":"ACSU513","properties":{"Key Text":{"value":"Upper endoscopy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Upper endoscopy, including duodenoscopy, is recommended for screening for gastric and proximal small bowel tumors, though frequency and age to begin surveillance varies by guideline. Upper endoscopy should be supplemented with a side-viewing duodenoscopy, and examination of the stomach should include random sampling of fundic gland polyps. Upper gastrointestinal screening has not been demonstrated to improve prognosis but is nonetheless recommended in view of the cancer risk and expectation that mortality can be improved."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Upper GI (stomach or duodenum) cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000228"}},{"Reference":{"value":"/coll/reference_model/doc/RF000183"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}},{"Reference":{"value":"/coll/reference_model/doc/RF000198"}},{"Reference":{"value":"/coll/reference_model/doc/RF000774"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC036","properties":{"Recommendation":{"value":"Duodenal surveillance appears to be of benefit in familial adenomatous polyposis (FAP), with the median survival after a screen detected cancer was 8 years (95% CI, 5.9 - not estimated), versus 0.8 years (95% CI, 0.03-1.7) after symptomatic cancer (p < 0.0001)"},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000775"}}]}}}}]}}}},{"Surveillance":{"value":"ACSU514","properties":{"Key Text":{"value":"Thyroid screening"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Annual thyroid screening by ultrasound should be recommended to individuals affected with familial colon polyposis syndromes including MAP. This recommendation is made on the basis of data for FAP. An increased risk for thyroid cancer to individuals with MAP has not been demonstrated."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000107"}},{"Reference":{"value":"/coll/reference_model/doc/RF000774"}}]}}}},{"Surveillance":{"value":"ACSU512","properties":{"Key Text":{"value":"Physical exam"},"Tier":{"value":"2"},"Recommendation Text":{"value":"An annual physical exam is recommended."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000228"}}]}}}}]},"Family Managements":{"value":null,"items":[]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA410","properties":{"Key Text":{"value":""},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"No recommendations were identified."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Tier":{"value":"3"},"Notes":{"value":"It is estimated that 1-2% of the general northern European population is heterozygous for a MUTYH mutation. The prevalence of biallelic carriers of MUTYH mutations can be derived as 1:40,000-1:10,000."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000239"}},{"Reference":{"value":"/coll/reference_model/doc/RF000326"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}}]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE485","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"The penetrance of colorectal polyposis is unknown, with up to 1/3 of MAP patients developing CRC in the absence of polyposis, suggesting incomplete penetrance."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000326"}}]}}}},{"Penetrance":{"value":"ACPE486","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Penetrance of CRC in MAP has been estimated from 43 to 100%."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000239"}},{"Reference":{"value":"/coll/reference_model/doc/RF000326"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}}]}}}},{"Penetrance":{"value":"ACPE484","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"For the lifetime risk of extracolonic tumors in MAP, in a study of 276 MAP patients, 17% had extracolonic lesions, with an estimated 38% lifetime risk of extracolonic malignancy that is approximately double the risk in the general population. The lifetime risk of duodenal cancer in MAP has been estimated to be 4-5%. Gastroduodenal polyposis is reported in over 20% of cases. Although gastric lesions have been found in up to 11% of patients with MAP and an estimated 1% develop stomach cancer, data are currently lacking to support an increased risk of gastric cancer."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Upper GI (stomach or duodenum) cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000183"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR202","properties":{"Key Text":{"value":">3"},"Notes":{"value":"In a study of 20,565 CRC cases and 15,524 controls, patients with MAP demonstrated a 28-fold increase in risk for CRC (OR=28.3, 95% confidence interval (CI): 6.95–115). A pooled meta-analysis of all published and unpublished datasets showed an increased risk for MAP (OR: 10.8, 95% CI: 5.02–23.2)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000776"}}]},"Tier":{"value":"1"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN220","properties":{"Key Text":{"value":"Development of colorectal adenomas is variable."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000228"}},{"Reference":{"value":"/coll/reference_model/doc/RF000183"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI225","properties":{"Key Text":{"value":"There is a small but appreciable risk of complications from colonoscopy including perforation, bleeding, and death."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000023"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC218","properties":{"Key Text":{"value":"Surveillance recommendations for MAP begin at an earlier age than the general population screening recommendations."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000228"}},{"Reference":{"value":"/coll/reference_model/doc/RF000183"}},{"Reference":{"value":"/coll/reference_model/doc/RF000198"}}]},"Tier":{"value":"2"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2018-05-07"},"Scorers Present":{"value":9,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"weaverm"}},{"Scorer":{"value":"srego"}},{"Scorer":{"value":"odanielj"}}]},"Notes":{"value":""}}},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Colorectal cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Overall Score":{"value":"10CC"},"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"Evidence for effectiveness extrapolated from Lynch syndrome"}}},"Nature Of 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with polypectomy","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Colorectal cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Upper GI (stomach or duodenum) cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Upper Endoscopy with polypectomy","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}}]}}},"Scorers":{"value":9,"items":[{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Colorectal cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"I gave it a \"2\" instead of a \"3\" since you can get into situations where the polyp burden is high enough that you just can't manage surveillance via periodic endoscopy.\nI knocked the evidence down by one rung since it is extrapolated."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"I know some might consider frequent colonoscopy more burdensome than a three..."}}}}}}]}}}},{"Outcome":{"value":"Upper GI (stomach or duodenum) cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"1N","properties":{"Notes":{"value":"I wasn't sure how to judge the evidence level. I gave it an \"E\" but all the referenes listed are guidelines so maybe this needs to be bumped up? We can discuss on the call..."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Upper Endoscopy with polypectomy","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Same reasoning with regard to evidence level as above for CRC"}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Colorectal cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"extrapolated from Lynch syndrome (3B)"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Upper GI (stomach or duodenum) cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Upper Endoscopy with polypectomy","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Colorectal cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"I don't think there is any consensus to do baseline ultrasound of thyroid. The Syngal article merged FAP and MAP and says is \"conditional\" NOS.  NCCN does not say to do US.  data in Nielsen cites only Cleveland clinic data pointing to this being reasonable. \nbalmana says \"The suggested surveillance protocol for MAP patients is similar to that for patients with AFAP. \"  but the context is not clear if she is referring to colonic/duodenal aspects or everything.  Stoffel says \"• Thyroid cancer: Annual cervical ultrasonography may be considered starting at age 25 to 30 years. for AFAP and that MAP might be similar.   So this is not a should be recommended statement."}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":"ultimately, this leads to colectomy, and duodenal surveillance with papillotomy  biopsy is risk for pancreatitis.  The proximal interventions would be a 2 but prophylactic surgery a 1."}}}}}}]}}}},{"Outcome":{"value":"Upper GI (stomach or duodenum) cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Upper Endoscopy with polypectomy","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Colorectal cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"3D","properties":{"Notes":{"value":"Not sure how to extrapolate down from a Tier 5 level of evidence (as was reported for Lynch data)."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Could be convinced to go 3, though seems to fit as invasive screening test + has perforation risk."}}}}}}]}}}},{"Outcome":{"value":"Upper GI (stomach or duodenum) cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Upper Endoscopy with polypectomy","properties":{"Effectiveness":{"value":"3D","properties":{"Notes":{"value":"Extrapolating from FAP, with the same caveat about extrapolating from a Tier 5 source."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last 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cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Upper Endoscopy with polypectomy","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"1 because of statement: \"expectation that mortality can be improved\""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Colorectal cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with 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2018 update of MAP from the original report (curated in 2014). It includes new evidence synthesis, new scoring pairs, and new scores, as well as an update to topic name (from MYH-Associated Polyposis to MUTYH-Associated Polyposis).\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36066},"ReasonCode":{"value":"Q4","properties":{"Reason":{"value":"Scoring pairs updated <strong>with</strong> major updates in the report"}}},"Date":{"value":"2018-05-08"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC075","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"HNF1A","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:11621"},"GeneOMIM":{"value":"142410"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"600496"}}]}}}}]},"Syndrome":{"value":"Maturity Onset Diabetes of the Young Type III","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"600496"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"MODY is a form of familial noninsulin-dependent diabetes mellitus characterized by an early age of onset (childhood, adolescence, or young adulthood under 25 years) and autosomal dominant inheritance.  Mutations in the HNF1A gene are the most common cause of MODY. Patients with MODY3 may have the full spectrum of complications of diabetes."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Maturity-onset diabetes of the young, type 3"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"MODY3 OR (\"maturity onset\" AND \"type 3\" AND diabetes) OR (monogenic AND diabetes)","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-08-26"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":3,"items":[{"SearchString":{"value":"MODY3","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-08-26"}}}},{"SearchString":{"value":"'diabetes' AND  'monogenic'","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-08-26"}}}},{"SearchString":{"value":"'diabetes' AND 'MODY'","properties":{"NumberOfHits":{"value":47},"Date":{"value":"2015-08-26"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-08-26"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-08-26"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-08-26"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"HuGE review AND each of these terms:  MODY3, HNF1, diabetes","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-08-26"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Suboptimal glycemic control","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Sulfonylureas/ optimal diabetic control"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Notes":{"value":"The prevalence of mature onset diabetes of the young (MODY) has been well characterized in European and North American populations but not in African and Asian populations.  The minimum population prevalence of MODY in the United Kingdom (UK) is estimated at 108 cases per million. Studies of population-based childhood diabetes registries estimated the minimum prevalence of monogenic diabetes as 3.1/100,000 in Norwegian children, 4.2-4.6/100,000 in Polish children, 2.39/100,000 in German children, and 2.1/100,000 in American children. The frequency of the different genetic subtypes, including MODY3, is variable and greatly depends on the clinical recruitment (either pediatric or adult)."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000136"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"MODY is a form of familial diabetes characterized by an early age of onset and by impaired insulin secretion with little or no defects in insulin action. Cases of MODY3 can be misdiagnosed as familial type 1 or type 2 diabetes because the clinical features are similar. Patients with MODY3 have decreased renal absorption of glucose (i.e., a low renal threshold for glucose) and glycosuria.  Lacking are features typical of type 1 diabetes (islet autoantibodies, insulin requirements 5 years after diagnosis) or early-onset type 2 diabetes (high BMI, hypertension, dyslipidemia, acanthosis nigricans).  In addition, patients are at risk for familial liver adenomatosis and hemorrhage."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000136"}},{"Reference":{"value":"/coll/reference_model/doc/RF000137"}},{"Reference":{"value":"/coll/reference_model/doc/RF000138"}},{"Reference":{"value":"/coll/reference_model/doc/RF000139"}},{"Reference":{"value":"/coll/reference_model/doc/RF000140"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"The MODY3 subtype (associated with mutations in the HNF1A gene) is the most common in undiagnosed adults. Glucose intolerance becomes evident during adolescence or early adulthood, with an age of onset generally before 40 years. In the early stages of disease, fasting blood glucose may be normal but patients tend to show a large increment in blood glucose after meals or during an oral glucose tolerance test. Over time, fasting hyperglycemia and osmotic symptoms become evident but typically without ketosis. The disease is progressive and patients have a similar risk of microvascular complications (e.g., retinopathy, neuropathy, or nephropathy) as patients with type 1 and type 2 diabetes. Similarly, patients are also at an increased risk of cardiovascular disease. Exposure to maternal diabetes in utero (if the mutation is maternally inherited) lowers the age of onset."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000136"}},{"Reference":{"value":"/coll/reference_model/doc/RF000138"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM957","properties":{"Key Text":{"value":"Treatment with diet, sulfonylureas"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Persons who are positive for an HNF1A mutation and who develop clinical symptoms can initially be treated with diet.  With progressive deterioration in glycemic control, low-dose sulfonylureas are recommended as the first-line treatment, which differs from treatment recommendations for other forms of diabetes. In a series of 43 misclassified diabetic patients initially treated with insulin, 34 changed from insulin to a sulfonylurea after detection of an HNF1A mutation and 24 remained off insulin for 39 months with no deterioration in glycemic control. Successful transfer from insulin to sulfonylurea was correlated with a shorter duration of diabetes prior to changing treatment and emphasizes the need for early genetic diagnosis."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000136"}},{"Reference":{"value":"/coll/reference_model/doc/RF000138"}}]}}}},{"Patient Management":{"value":"ACPM958","properties":{"Key Text":{"value":"Statin therapy"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Patients with MODY3 are at risk of vascular complications and cardiovascular disease. Thus statin therapy is recommended by age 40, regardless of lipid status. In one study of 39 families (mutation carriers [n=153] vs. non-carriers [n=241], no correction for multiple family members, no information on statin treatment), the hazard ratio for cardiovascular death was 2.6 (95% CI, 1.5-4.4, p=0.001)."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000136"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU516","properties":{"Key Text":{"value":"Screening asymptomatic mutation carriers"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Annual screening for diabetes in asymptomatic mutation carriers is recommended from the age of 10."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000136"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM340","properties":{"Key Text":{"value":"First-degree relatives"},"Tier":{"value":"4"},"Recommendation Text":{"value":"First-degree relatives will be at 50% risk of inheriting the mutation and asymptomatic individuals may be offered predictive genetic testing (after appropriate genetic counseling) in order to provide reassurance (for those shown not to carry the mutation) or regular blood glucose monitoring with early diagnosis and appropriate treatment (for mutation carriers and those at risk who refuse genetic testing)."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000136"}},{"Reference":{"value":"/coll/reference_model/doc/RF000139"}}]}}}},{"Family Management":{"value":"ACFM341","properties":{"Key Text":{"value":"First degree diabetic relatives"},"Tier":{"value":"4"},"Recommendation Text":{"value":"First degree diabetic relatives of patients with HNF1A mutations should be offered genetic testing. This allows for the correct diagnosis in affected relatives who may be misclassified and not adequately treated. Genetic confirmation of MODY and assessment of endogenous insulin production in insulin-treated patients is essential before undertaking a change in treatment."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000136"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA411","properties":{"Key Text":{"value":"None found"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"Information on circumstances to avoid was not available."},"Outcomes":{"value":null},"References":{"value":null}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Tier":{"value":"3"},"Notes":{"value":"Approximately 52% of confirmed UK MODY families have HNF1A mutations. Based on a U.S. MODY condition prevalence of 2.1/100,000, HNF1A mutation prevalence is estimated at 1.1 per 100,000."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000136"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE487","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"The penetrance of HNF1A mutations for diabetes increases with age; it is approximately 63% by age 25 years, 79% before age 35 and 96% before 55 years."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Suboptimal glycemic control"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000136"}},{"Reference":{"value":"/coll/reference_model/doc/RF000138"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR203","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was found."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN221","properties":{"Key Text":{"value":"The clinical expression of MODY3 varies widely, partly due to environmental and genetic factors, including the characteristics of the HNF1A mutation itself."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000141"}}]},"Tier":{"value":"5"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI226","properties":{"Key Text":{"value":"Surveillance involves routine blood tests. Treatment with an oral sulfonylurea is associated with possible side effects of weight gain and hypoglycemia."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC219","properties":{"Key Text":{"value":"Without a correct genetic diagnosis, persons at risk and their family members may be incorrectly diagnosed with type 1 or type 2 diabetes, leading to suboptimal treatment, delays in obtaining a correct diagnosis, potential progression of disease sequelae, and delays in diagnosing other family members."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000140"}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers 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{"ActionabilityDocID":{"value":"AC077","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"MEN1","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:7010"},"GeneOMIM":{"value":"613733"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"131100"}}]}}}}]},"Syndrome":{"value":"Multiple Endocrine Neoplasia Type I","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"131100"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"- AD disorder characterized by varying combos of endocrine and non-endocrine tumors\r- Most common tumors occur in the parathyroids, pancreatic islets, duodenal endocrine cells, and anterior pituitary\r- Less common tumors are foregut carcinoids, lipomas, angiofibromas, thyroid adenomas, adrenocortical adenomas, angiomyolipomas, and spinal cord ependymomas\r- Except for gastrinomas, most of the tumors are nonmetastasizing, but many can create striking clinical effects because of the secretion of endocrine substances such as gastrin, insulin, parathyroid hormone, prolactin, growth hormone, glucagon, or adrenocorticotropic hormone.\r- 90% have onset between ages 20-25\r- 94% penetrance by age 50"},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"MEN1: Multiple endocrine neoplasia type 1"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"(\"Multiple Endocrine Neoplasia Type 1\"[Mesh]) OR \"MEN1 protein, human\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":11},"Date":{"value":"2015-06-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":0,"items":[]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-06-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-06-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-06-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Multiple endocrine neoplasia 1","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-06-04"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from parathyroid adenoma","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Biochemical surveillance"}}]}}}},{"Outcome":{"value":"Morbidity from other neuroendocrine tumors","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Biochemical surveillance"}},{"Intervention":{"value":"Imaging surveillance"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 10000"},"Notes":{"value":"Multiple Endocrine Neoplasia type 1 (MEN1) has an estimated prevalence of 1/10,000 to 1/30,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000344"}},{"Reference":{"value":"/coll/reference_model/doc/RF000332"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"MEN1 syndrome includes varying combinations of more than 20 endocrine and non-endocrine tumors.  Associated endocrine tumors including parathyroid tumors, anterior pituitary tumors, well-differentiated endocrine tumors of the gastro-entero-pancreatic tract, carcinoid tumors, and adrenocortical tumors. Parathyroid tumors, resulting in primary hyperparathyroidism, are the most common feature of MEN1. Clinical features are related to the sites of the tumors and their products of secretion. Non-endocrine tumors include facial angiofibromas, collegenomas, lipomas, meningiomas, edendymomas, and leiomyomas."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000344"}},{"Reference":{"value":"/coll/reference_model/doc/RF000332"}},{"Reference":{"value":"/coll/reference_model/doc/RF000121"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Parathyroid tumors, resulting in primary hyperparathyroidism, are the most common feature and the first clinical manifestation in 90% of individuals with MEN1 with onset typically between ages 20 and 25 years.  However MEN1 affects all age groups, with a reported age range of 5 to 81 years. Untreated patients with MEN1 have a decreased life expectancy with a 50% probability of death by age 50. The cause of death in 50-70% of cases due to a malignant tumor process or sequelae of the disease.  MEN1-associated tumors are more difficult to treat surgically, are more associated with occult metastatic disease, and may be larger, more aggressive, and more resistant to treatment than non-MEN1 associated tumors. MEN1 affects both sexes equally."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000344"}},{"Reference":{"value":"/coll/reference_model/doc/RF000121"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM961","properties":{"Key Text":{"value":"Prophylactic thymectomy"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Prophylactic thymectomy should be considered at the time of neck surgery for primary hyperparathyroidism in males with MEN1 syndrome, particularly those who are smokers or have relatives with thymic carcinoid."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000332"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU517","properties":{"Key Text":{"value":"Biochemical and imagining screening"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with MEN1 should undergo a program of combined clinical, biochemical, and radiological screening for MEN1-associated tumors. Patients are recommended to undergo screening for parathyroid tumors with an annual assessment of plasma calcium and parathyroid hormone to screen for primary hyperparathyroidism beginning at age 8. Patients are also suggested to undergo additional screening for pancreatic NET, pituitary tumors, thymic NET, bronchopulmonary NET, gastric NET, and adrenal tumors. The nature and timing of the screening will depend on local resources, clinical judgment, and patient preferences. The prognosis for MEN1 patients might be improved by presymptomatic tumor detection as earlier diagnosis and treatment of these tumors may help reduce morbidity and mortality."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000121"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM344","properties":{"Key Text":{"value":"Genetic couseling and testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"First degree relatives should be offered genetic counseling and MEN1 germline testing at the earliest opportunity given MEN1 manifestations may occur by the age of 5. In addition, genetic testing in relatives is recommended before biochemical and radiological screening tests for detection of MEN1 tumors to avoid the burden of multiple tests and reduce financial costs."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000121"}}]}}}},{"Family Management":{"value":"ACFM345","properties":{"Key Text":{"value":"Surveillance"},"Tier":{"value":"4"},"Recommendation Text":{"value":"When molecular genetic testing for MEN1 is not possible or is not informative, first degree relatives of an individual with MEN1 should undergo the routine surveillance recommended for MEN1 patents."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000332"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA416","properties":{"Key Text":{"value":""},"Tier":{"value":"Not provided"},"Recommendation 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(8%)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000332"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR205","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information on relative risk of MEN1 tumors was not available."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN223","properties":{"Key Text":{"value":"Combinations of affected glands and their respective pathological features may differ in members of the same family and even between identical twins."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000332"}},{"Reference":{"value":"/coll/reference_model/doc/RF000121"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of 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{"ActionabilityDocID":{"value":"AC080","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"RET","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:9967"},"GeneOMIM":{"value":"164761"},"SyndromeOMIMs":{"value":2,"items":[{"OMIM":{"value":"171400"}},{"OMIM":{"value":"155240"}}]}}}}]},"Syndrome":{"value":"Multiple Endocrine Neoplasia IIA, Familial Medullary Thyroid Cancer","properties":{"OmimIDs":{"value":2,"items":[{"OmimID":{"value":"171400"}},{"OmimID":{"value":"155240"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"There are 3 subtypes: MEN2A accounts for 70-80% for cases, familial medullary thyroid carcinoma (FMTC - not in this report), accounts for 10-20% of cases and MEN2B accounts for 5% of cases.MEN2A disease symptoms appear in adulthood. It is characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid adenomas."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Multiple Endocrine Neoplasia, Type IIA"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"(\"Multiple Endocrine Neoplasia Type 2a\"[Mesh]) OR \"Multiple Endocrine Neoplasia Type 2b\"[Mesh]","properties":{"NumberOfHits":{"value":16},"Date":{"value":"2015-06-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":4,"items":[{"SearchString":{"value":"multiple endocrine neoplasia 2","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-06-04"}}}},{"SearchString":{"value":"men 2a","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-06-04"}}}},{"SearchString":{"value":"men 2b","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-06-04"}}}},{"SearchString":{"value":"multiple endocrine neoplasia type 3","properties":{"NumberOfHits":{"value":9},"Date":{"value":"2015-06-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-06-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-06-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":3},"Date":{"value":"2015-06-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-06-04"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Medullary thyroid cancer","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Thyroidectomy"}}]}}}},{"Outcome":{"value":"Pheochromocytoma","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Biochemical surveillance"}}]}}}},{"Outcome":{"value":"Hyperparathyroidism","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Biochemical screening"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Notes":{"value":"Altogether multiple endocrine neoplasia type 2 (MEN2) subtypes (MEN2A, MEN2B, and familial medullary thyroid cancer or FMTC) affect 1/30,000 to 1/35,000 individuals.  Within MEN2, MEN2A accounts for roughly 70-80% of cases, and FMTC accounts for roughly 10-20% of cases. Overall, MEN2A has an estimated prevalence of 1/40,000, while the prevalence of FMTC is unknown."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000343"}},{"Reference":{"value":"/coll/reference_model/doc/RF000123"}},{"Reference":{"value":"/coll/reference_model/doc/RF000124"}},{"Reference":{"value":"/coll/reference_model/doc/RF000332"}},{"Reference":{"value":"/coll/reference_model/doc/RF000125"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"MEN2A is associated with an increased risk for medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), and primary hyperparathyroidism (PHPT). Some patients with MEN2A also develop cutaneous lichen amyloidosis (CLA) and disturbances in gut transit that resemble those seen in Hirschprung disease.\\n\\nFMTC is considered to be a clinical subtype of MEN2A with the presentation of MTC in the absence of PHEO and PHPT due to decreased penetrance. Criteria for FMTC versus MEN2A are not standardized, but include the diagnosis of MTC only in multiple family members either across generations or within a generation. It can be clinically very difficult to determine that a family has FMTC rather than MEN2A since the former diagnosis depends upon the absecnce of PHEO and  PHPT. Thus limited family history and young patient age make distinguishing between MEN2A and FMTC difficult."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000343"}},{"Reference":{"value":"/coll/reference_model/doc/RF000123"}},{"Reference":{"value":"/coll/reference_model/doc/RF000124"}},{"Reference":{"value":"/coll/reference_model/doc/RF000332"}},{"Reference":{"value":"/coll/reference_model/doc/RF000126"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"MTC in individuals with MEN2 typically presents at a younger age than sporadic MTC and is more often associated with C-cell hyperplasia as well as multifocality or bilaterality.  In FMTC, MTC typically occurs in middle age. Onset of MEN2A is typically prior to age 35, usually between ages 5 and 25.  MTC is generally the first manifestation in MEN2A with probands presenting with a neck mass or neck pain. All individuals with MEN2A who have not had a thyroidectomy will demonstrate biochemical evidence of MTC by age 35.  PHEOs usually present after MTC or concomitantly, but are the first manifestation in 13-27% of individuals. PHEOs are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors, with malignant transformation occurring in about 4% of cases. PHPT is typically mild, with most individuals with PHPT having no symptoms, and may range from a single adenoma to marked hyperplasia. PHPT usually presents many years after the diagnosis of MTC, with an average age of onset of 38 years."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000343"}},{"Reference":{"value":"/coll/reference_model/doc/RF000123"}},{"Reference":{"value":"/coll/reference_model/doc/RF000124"}},{"Reference":{"value":"/coll/reference_model/doc/RF000332"}},{"Reference":{"value":"/coll/reference_model/doc/RF000126"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM962","properties":{"Key Text":{"value":"Prophylactic thyroidectomy"},"Tier":{"value":"1"},"Recommendation Text":{"value":"All patients with MEN2 or FMTC should undergo prophylactic thyroidectomy. The recommended timing of surgery is based on a classification system of RET mutations and other indicators of risk for aggressive MTC. RET mutations associated with MEN2A span the categories of \"high risk\" (thyroidectomy recommended by age 5 or earlier based on calcitonin levels) and \"moderate risk\" (thyroidectomy considered after age 5 or later based on calcitonin levels).  RET mutations associated with FMTC are classified as \"moderate risk\". The goal of early prophylactic thyroidectomy is to intervene before metastasis, which is associated with a low cure rate. In 2 follow-up studies of MEN2 patients who had undergone thyroidectomy, there were no signs of MTC in 41/46 MEN2A/FMTC patients after an average period of 7 years and in 44/50 MEN2A patients after 10 years, showing that detection and intervention of MTC can significantly alter associated morbidity."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000123"}},{"Reference":{"value":"/coll/reference_model/doc/RF000127"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU521","properties":{"Key Text":{"value":"Biochemical and imaging surveillance"},"Tier":{"value":"1"},"Recommendation Text":{"value":"In MEN2A \"moderate risk\" cases and FMTC cases where prophylactic thyroidectomy has been delayed, patients should undergo annual basal serum calcitonin testing and cervical neck ultrasound starting at age 5."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000123"}},{"Reference":{"value":"/coll/reference_model/doc/RF000127"}}]}}}},{"Surveillance":{"value":"ACSU519","properties":{"Key Text":{"value":"Biochemical surveillance"},"Tier":{"value":"2"},"Recommendation Text":{"value":"PHEO surveillance should include annual plasma free metanephrines and normetanephrines or 24-hour urine collection for metanephrines and normetanephrines. Based on typical age of PHEO onset, surveillance is recommended to begin at age 11 for MEN2A \"high risk\" cases and age 16 for MEN2A \"moderate risk\" and FMTC cases. Surveillance is recommended for FMTC cases because of the inherent uncertainty in definitively assigning this diagnosis."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000123"}},{"Reference":{"value":"/coll/reference_model/doc/RF000127"}}]}}}},{"Surveillance":{"value":"ACSU520","properties":{"Key Text":{"value":"Pregnancy planning and management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Because of the high risk to the fetus and mother, the presence of a PHEO must be excluded in women with a RET mutation associated with MEN2 who are planning a pregnancy or are pregnant."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000123"}},{"Reference":{"value":"/coll/reference_model/doc/RF000127"}}]}}}},{"Surveillance":{"value":"ACSU518","properties":{"Key Text":{"value":"Biochemical surveillance"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Surveillance for PHPT should happen at the same time as surveillance for PHEO and should include include annual albumin-corrected calcium or ionized serum calcium measurements (with or without serum intact-parathyroid hormone [PTH]) beginning at age 11 for MEN2A \"high risk\" cases and at age 16 years for MEN2A \"moderate risk\" and FMTC cases. Age to start surveillance is based on the typical age of onset for PHPT."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000123"}},{"Reference":{"value":"/coll/reference_model/doc/RF000127"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM346","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Individuals with a family history of MEN2 or FMTC should undergo RET testing. For MEN2A and FMTC, this should be done by age 5."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000123"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA417","properties":{"Key Text":{"value":"Medications to avoid"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Use of liraglutide or similar drugs for diabetes is contraindicated in patients with MEN2. Testing in animal studies has been associated with the development of thyroid C-cell tumors, although the relevance in humans is unknown."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000128"}},{"Reference":{"value":"/coll/reference_model/doc/RF000129"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"RET mutations are identified in at least 98% cases of MEN2A and in at least 95% of families with FMTC."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000332"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC054","properties":{"Recommendation":{"value":"Given MEN2A has an estimated prevalence of 1/40,000, RET mutations that lead to MEN2A are likely to have a similar prevalence. However, the estimated prevalence of FMTC is uknown and information on the frequency of RET mutations associated with FMTC was not available."},"Tier":{"value":"Not provided"},"References":{"value":null,"items":[]}}}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE491","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"For MEN2A, the frequencies of associated outcomes are: 90-98% MTC, 50-57% PHEO, 15-30% PHPT, and 10-15% CLA.\\n\\nIn FMTC, the frequency estimates for MTC range from 80% to 95%."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Medullary thyroid cancer"}},{"Outcome":{"value":"Pheochromocytoma"}},{"Outcome":{"value":"Hyperparathyroidism"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000332"}},{"Reference":{"value":"/coll/reference_model/doc/RF000123"}},{"Reference":{"value":"/coll/reference_model/doc/RF000124"}},{"Reference":{"value":"/coll/reference_model/doc/RF000125"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR206","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information regarding relative risk was not available."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN224","properties":{"Key Text":{"value":"Patients carrying the same mutation may show a heterogenic progression of disease. Even within the same family, the natural course of disease may vary."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000124"}}]},"Tier":{"value":"2"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI229","properties":{"Key Text":{"value":"The recommendations included in this report include prophylactic thyroidectomy, an invasive surgery associated with potential risk, as well as regular biochemical screening which could be burdensome."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC222","properties":{"Key Text":{"value":"MTC in individuals with MEN2A and FMTC is typically more aggressive and presents at an earlier age than sporadic MTC and would be highly likely to escape 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Individuals with MEN2B who do not undergo thyroidectomy prior to age 1 will develop metastatic MTC at an early age. Without thyroidectomy, the average age of death for those with MEN2B is age 21. PHEOs occur in only 50% of individuals, but 50% of those are multiple and often bilateral. 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In 2 follow-up studies of MEN2 patients who had undergone thyroidectomy, there were no signs of MTC in 41/46 MEN2A/FMTC patients after an average period of 7 years and in 44/50 MEN2A patients after 10 years, showing that detection and intervention of MTC can significantly alter associated morbidity."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000123"}},{"Reference":{"value":"/coll/reference_model/doc/RF000127"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU523","properties":{"Key Text":{"value":"Biochemical surveillance"},"Tier":{"value":"2"},"Recommendation Text":{"value":"PHEO surveillance should include annual plasma free metanephrines and normetanephrines or 24-hour urine collection for metanephrines and normetanephrines. 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Individuals within families may develop either or both types of cancer. PCMS is classically characterized by cutaneous findings of a high total body nevi count (usually more than 50 and often into the hundreds; including some atypical nevi which may resemble early melanoma) and a family history of melanoma. Controversy surrounds the pathologic significance of atypical nevi seen in PCMS syndrome; atypical nevi often regress and melanomas often develop on normal skin.  The clinical and histopathologic characteristics of melanoma in PCMS are not different from those seen in sporadic cases. Evidence is also mixed regarding whether there is a difference in location of melanomas between CDKN2A kindreds versus population-based controls. Pancreatic cancer is the second most frequent cancer diagnosed in PCMS kindreds."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000360"}},{"Reference":{"value":"/coll/reference_model/doc/RF000377"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"An earlier age of onset of melanoma is present in PCMS kindreds compared with the general population. A median age of melanoma diagnosis has been observed between 33 and 45 years old; however, there are several documented cases of melanoma occurring as early as the early teens and twenties.  Controversy exists as to whether or not pancreatic cancer is diagnosed at an earlier age in PCMS kindreds compared to sporadic cases."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000360"}},{"Reference":{"value":"/coll/reference_model/doc/RF000377"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM964","properties":{"Key Text":{"value":"Low Fat Diet"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Low fat diet should be recommended for the prevention of pancreatic cancer."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC215","properties":{"Recommendation":{"value":"Fat consumption has been hypothesized to influence pancreatic cancer risk; however a recent meta-analysis of epidemiologic studies found no statistically significant association between fat intake and pancreatic cancer risk."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000378"}}]}}}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU525","properties":{"Key Text":{"value":"Melanoma screening"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Screening recommendations for melanoma in PCMS kindreds are based on the PCMS clinical phenotype rather than the presence of a CDKN2A pathogenic variant. Screening should begin at age 10 with a baseline total body skin examination including scalp, oral mucosa, genital area, and nail, as family members may develop melanoma in their early teens. Patients should be examined every 6 months initially to ensure nevi stability. Once stability is established these visits can be conducted annually or as needed if the patient detects an abnormality on self-exam. Self-examination should be performed by the patient with assistance from a friend or family member every month. Nevi may become more unstable during puberty and pregnancy and may warrant increased frequency of physician examinations during these periods."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Melanoma morbidity and/or mortality"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000377"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC037","properties":{"Recommendation":{"value":"A retrospective case-control study compared the melanomas of 32 unscreened index patients with a CDKN2A pathogenic variant with those diagnosed in 92 relatives after entering an annual screening program. The surveillance detected melanomas were found to be thinner than those of the index patients indicating that they were detected in an earlier stage, except among patients who were not compliant with the surveillance protocol. However, the majority of screen-detected melanomas were diagnosed in patients that were under intensified surveillance because of a previous melanoma."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000379"}}]}}}},{"RecommendationID":{"value":"REC039","properties":{"Recommendation":{"value":"A systematic review addressing visual screening for skin cancer identified no trials addressing the effectiveness of skin cancer screening on morbidity and mortality in average-risk individuals. One ecological study found that after the implementation of a population based skin cancer screening program the population age- and sex-adjusted melanoma mortality decreased by 48% with an absolute mortality difference of 0.8 melanoma deaths per 100,000 persons. Eight observational studies examined the association between lesion thickness or stage at diagnosis and mortality. All studies demonstrated a consistent linear increase in the risk of melanoma mortality with increasing tumor thickness. Tumor thickness >4.0mm was associated with a hazard ratio of 3.1-32.6 in multivariate models, indicating increased risk of melanoma mortality compared with thinner lesions."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000383"}}]}}}}]}}}},{"Surveillance":{"value":"ACSU524","properties":{"Key Text":{"value":"Pancreatic screening"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Consensus guidelines state that due to increased risk of pancreatic cancer, surveillance  should be performed with endoscopic ultrasound and/or MRI of the pancreas. Guidelines differ regarding the frequency and age to start and stop surveillance. Due to variable penetrance, guidelines also differ on whether all individuals with a pathogenic variant in CDKN2A should be screened, or only those with a first degree relative with pancreatic cancer. Guidelines state that there is no proven effective screening tool to reduce pancreatic cancer mortality and that these screening recommendations are primarily based on evidence on increased risk, rather than a proven efficacy of screening. Therefore, surveillance is recommended to be performed in experienced centers utilizing a multidisciplinary approach and under research conditions.  The most common findings in surveillance studies are cystic lesions in the pancreas. Management of these cysts is unclear as, similar to cysts in a nonhereditary setting, most are benign or just have low-grade dysplasia."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Pancreatic cancer morbidity and/or mortality"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000380"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC038","properties":{"Recommendation":{"value":"178 patients with a pathogenic variant in CDKN2A were included in a screening program with annual MRI with or without ultrasound. Mean age at the start of the program was 56 years (range: 37-75 years) and mean follow up time was 53 months (range: 0-169 months). A total of 866 MRI and 106 ultrasounds were performed. Pancreatic ductal adenocarcinoma (PDAC) was detected in 13 (7.3%) patients. The mean age at diagnosis was 58 years. The cumulative incidence was 14% by age 70. The results showed increased rates in the identification of tumors in stages that allowed for treatment with resection. The resection rate of screen detected cancer (75%) was much higher than reported for sporadic cancer patients (15-20%) and compared to historical controls of with CDKN2A pathogenic variants with symptomatic PDAC (15%). The 5-year survival rate was substantially higher (24%) than the survival rate reported for patients with symptomatic sporadic cancer (4-7%)."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000381"}}]}}}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM348","properties":{"Key Text":{"value":"Melanoma screening"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Screening for melanoma should also be offered to all first- and some second-degree relatives regardless of mutation status.  Given the lack of convincing and concordant data regarding CDKN2A mutation status and cancer risk, CDKN2A mutation status should not be used for risk stratification or determination of followup program at this time."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000377"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA419","properties":{"Key Text":{"value":"Smoking"},"Tier":{"value":"2"},"Recommendation Text":{"value":"As smoking has been shown to be an independent risk factor for pancreatic cancer in families with familial pancreatic cancer (based on family history) (OR=3.7, 95% CI: 1.8-7.6) with smokers developing cancer one decade earlier than nonsmokers (59.6 vs. 69.1 years; p=0.01) , all high-risk individuals should be counseled against smoking."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Pancreatic cancer morbidity and/or mortality"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"No information on the prevalence of CDKN2A pathogenic variants in the general population were identified."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE495","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"The penetrance for melanoma in kindreds with CDKN2A pathogenic variants is estimated at 58% to 92% by 80 years of age and varies with geography."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Melanoma morbidity and/or mortality"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000377"}}]}}}},{"Penetrance":{"value":"ACPE496","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"A study of 19 families with known CDKN2A pathogenic variants estimated penetrance for pancreatic cancer to be 17% in individuals with CDKN2A pathogenic variants by 75 years of age."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Pancreatic cancer morbidity and/or mortality"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000360"}},{"Reference":{"value":"/coll/reference_model/doc/RF000377"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR208","properties":{"Key Text":{"value":">3"},"Notes":{"value":"The risk for developing pancreatic cancer in PCMS families with a known pathogenic variant in CDKN2A is increased 13- to 22- fold with some sources reporting a risk as high as 39 fold."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000380"}},{"Reference":{"value":"/coll/reference_model/doc/RF000377"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]},"Tier":{"value":"3"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN226","properties":{"Key Text":{"value":"PCMS has a highly variable phenotype both between and within kindreds. There is significant heterogeneity in the cutaneous phenotype, some family members will display only part of the phenotype or will show no cutaneous characteristics but may later develop melanoma or pancreatic cancer."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000377"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI231","properties":{"Key Text":{"value":"Interventions include the use of full body skin exams and imaging to screen for pancreatic cancer. Incorrect diagnosis of lesions identified during surveillance for pancreatic cancer is a significant concern. Some cysts are found at resection to be benign or low grade pancreatic intraepithelial neoplasia. These results highlight the risk of overtreatment using surveillance. The risk of overtreatment for pancreatic screening is magnified by the risks of morbidity and mortality (∼1–2%) of pancreatic surgery."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000380"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC224","properties":{"Key Text":{"value":"Some family members will display only part of the phenotype or will show no cutaneous characteristics but may later develop melanoma or pancreatic cancer."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000377"}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2016-12-12"},"Scorers 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Evidence level reflects this. I'm also torn between 1 and 2, because I don't know how much of the survival advantage is attributable to lead time bias."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"2 reflects the guideline recommendation for endoscopic US. MRI would be a 3."}}}}}},{"Intervention":{"value":"Smoking cessation and/or avoidance","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"No specific data on the synergy of smoking and CDKN2A variant status."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"We've argued this one before."}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Melanoma morbidity and/or mortality","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"1N","properties":{"Notes":{"value":"much inferred that earlier detection leads to decreased risk for death"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Pancreatic cancer morbidity and/or mortality","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Periodic pancreatic imaging","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"secondary to overtreatment of benign cysts"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"secondary to overtreatment of benign cysts"}}}}}},{"Intervention":{"value":"Smoking cessation and/or avoidance","properties":{"Effectiveness":{"value":"1D","properties":{"Notes":{"value":"is there evidence of efficacy?"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"avoidance"}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"Gene-disease pair updated.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36078},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-10"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC087","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"PTCH1","properties":{"HGNCId":{"value":"HGNC:9585"},"GeneOMIM":{"value":"601309"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"109400"}}]}}}}]},"Syndrome":{"value":"Basal Cell Nevus Syndrome (BCNS)","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"109400"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"377"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Title","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-09-28"},"Label":{"value":"Label"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance"}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance"}},{"Intervention":{"value":"Sun avoidance"}},{"Intervention":{"value":"Minimization of radiation"}}]}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Notes":{"value":"Few studies have assessed the prevalence of basal cell nevus syndrome (BCNS; also known as Gorlin syndrome). The most quoted prevalence is 1/57,000, an estimate based on study of a UK population. This figure has been since updated to 1/30,827, though the true figure is likely higher as individuals with milder features may not be recognized."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}},{"Reference":{"value":"/coll/reference_model/doc/RF000374"}},{"Reference":{"value":"/coll/reference_model/doc/RF000375"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"BCNS is characterized by developmental anomalies and a predisposition of neoplasms. Multiple basal cell carcinomas (BCCs) are common and mostly occur on the face, back, and chest and may range in number from a few to several thousand. Other common clinical manifestations include multiple ondontogenic keratocysts (OKCs) of the jaws, palmar-plantar pits, skeletal anomalies (e.g., bifid ribs, wedgeshaped vertebrae), and ectopic calcification of the central nervous system (particularly in the falx cerebri). Head and facial features may also be present and include macrocephaly, frontal bossing, coarse facial features, eye abnormalities, and facial milia. Other features may include medulloblastoma (now often called primitive neuroectodermal tumor or PNET) and cardiac and ovarian fibromas."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000376"}},{"Reference":{"value":"/coll/reference_model/doc/RF000373"}},{"Reference":{"value":"/coll/reference_model/doc/RF000374"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Some features that present shortly after birth or during childhood include macrocephaly, facial features, and skeletal features.  There is often some delay in motor milestones; however, most individuals catch up by about age five. The peak incidence of medulloblastoma is age 1-2 years, earlier compared to 7 years for the sporadic form. Medulloblastoma typically has a favorable prognosis and is more common in males. OKCs typically develop during the teenage years, though they can occur as early as 5 years, and rarely occur after age 30 years.  Patients have, on average, 5 OKCs, but the number can range from 1 to 30. Ectopic calcification is present in most individuals by age 20 and usually does not result in clinical manifestations.  Most individuals also develop BCCs with increasing frequency with age. These may occur in childhood, but in general do not present until the late teens or early adulthood with an average age of onset of 25 years. There is a relationship between skin pigmentation and BCCs, with fewer African American patients (40%) developing BCCs compared to Caucasians (90%). Individuals with type 1 skin (white skin that burns but never tans) and individuals with excessive ultraviolet light exposure seem especially prone to developing large numbers of BCCs. Evidence of metastatization of BCCs has been rarely reported. Life expectancy for BCNS is not significantly different from average. The major problem is with the cosmetic effect of treatment of multiple skin tumors and usually, to a lesser extent, treatment of OKCs. A poor cosmetic outcome can lead to social difficulties, including difficulty maintaining employment."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}},{"Reference":{"value":"/coll/reference_model/doc/RF000374"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM965","properties":{"Key Text":{"value":"Initial evaluations"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with BCNS, the following baseline evaluations are recommended:"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC216","properties":{"Recommendation":{"value":"• MRI of brain with contrast and epilepsy protocol for comparison of symptoms develop in the future\n• Pelvic ultrasound"},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000376"}}]}}}},{"RecommendationID":{"value":"REC217","properties":{"Recommendation":{"value":"• X-rays to evaluate for rib and vertebral anomalies and falx calcification\n• Ophthalmologic evaluation for evidence of strabismus, cataract, orbital cyst, microphthalmia, and pigmentary changes of the retinal epithelium\n• Evaluation by a dentist or orthodontist familiar with NCBS; jaw x-ray (orthopantogram) in individuals age eight years or older to evaluate for OKCs and other anomalies\n• Skin examination by a dermatologist familiar with NCBS\n• Clinical genetics consultation."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM967","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Since individuals with NCBS have a large head circumference, a woman who is carrying an affected fetus should be assessed for the need for either early induction of labor or cesarean section delivery due to cephalopelvic disproportion."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}}]}}}},{"Patient Management":{"value":"ACPM966","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"During pregnancy an assessment of the fetus should be performed for cardiac fibromas, hydrocephalus, and macrocephaly."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000376"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU527","properties":{"Key Text":{"value":"Surveillance protocol"},"Tier":{"value":"2"},"Recommendation Text":{"value":"The recommended management protocol for surveillance of adults with BCNS includes:\n\n• Full skin examination by a dermatologist every 4 months\n• Digital panorex of jaw annually\n• Medical/clinical genetics evaluation annually\n• Psychological evaluation as needed for support and counseling\n• Neurology evaluation annually if prior medulloblastoma\n• Obstetrics–gynecology evaluation annually for female patients\n• Nutritional assessment to include Vitamin A, B, C, and D levels on an annual basis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000376"}}]}}}},{"Surveillance":{"value":"ACSU526","properties":{"Key Text":{"value":"Skin exams"},"Tier":{"value":"5"},"Recommendation Text":{"value":"There is little evidence on effectiveness of skin exams in individuals with BCNS. In a recent US Preventative Services Task Force report, only limited evidence was identified for skin cancer screening in populations at general risk for skin cancer. However, this evidence was specific to melanoma mortality. The only evidence found related to non-melanoma skin cancer was related to the cosmetic appearance of shave biopsy."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000383"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM349","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Due to the need for surveillance for complications of NCBS and the need to avoid sun exposure and x-rays, clarification of the genetic status of at-risk relatives, including children, is appropriate."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}}]}}}},{"Family Management":{"value":"ACFM350","properties":{"Key Text":{"value":"Clinical exam"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Clinical examination and x-rays of the skull for calcification may be performed if the pathogenic variant in the family is not known."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA422","properties":{"Key Text":{"value":"Radiation exposure"},"Tier":{"value":"2"},"Recommendation Text":{"value":"It is prudent to limit the amount of any type of radiation for these patients. It is advised that radiographs, including skull film or chest X-ray, to assess for major or minor criteria not be performed unless the diagnosis is in question or it is clinically indicated for management of the patient for valid medical issues.  If necessary, modalities utilizing non-ionizing radiation, such as MRI, ultrasound, or digital technology, are preferred."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000376"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA420","properties":{"Key Text":{"value":"Radiotherapy"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Use of radiotherapy can lead to the development of thousands of BCCs in the radiation field and therefore should be avoided if there are alternative treatments. Among children with medulloblastoma treated with radiotherapy, an increase of BCC’s in areas that correspond to treatment zones have manifested at an earlier age at onset and in a distribution unlike that of other family members with BCNS. In addition, these BCCs occur with 6 months to 3 years of radiotherapy while the median latent period for radiogenic BCCs in general is 21 years."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}},{"Reference":{"value":"/coll/reference_model/doc/RF000375"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA421","properties":{"Key Text":{"value":"Excessive sun exposure"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Excessive sun exposure increases the likelihood of developing BCCs, which are most likely to appear in sun-exposed parts of the body, such as the face, back, and chest. Individuals should avoid direct sun exposure as much as possible, use complete sun block, and cover exposed skin with long sleeves, high collars, and hats."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}},{"Reference":{"value":"/coll/reference_model/doc/RF000375"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC044","properties":{"Recommendation":{"value":"There is little evidence on the effectiveness of avoidance of sun exposure on the development of BCCs in BCNS. One study of 55 individuals with BCNS did not detect a significant association between self-report history of sun exposure and number of BCCs."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000384"}}]}}}},{"RecommendationID":{"value":"REC045","properties":{"Recommendation":{"value":"In addition, a recent Cochrane review concluded that there is a lack of evidence regarding effectiveness of sun protection on the development of keratinocyte cancer, including BCCs, in the general population. Only one study was identified, which reported a lack of association between development of BCCs and daily application of sunscreen (n = 1621; RR=1.03, 95% CI: 0.74 to 1.43). No studies were identified that evaluated other sun protection measures, such as the use of sun-protective clothing, sunglasses, or hats, or seeking the shade when outdoors."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000385"}}]}}}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Tier":{"value":"Not provided"},"Notes":{"value":"The prevalence of pathogenic variants associated with BCNS in the general population was not available."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC056","properties":{"Recommendation":{"value":"However, pathogenic variants have high penetrance."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}},{"Reference":{"value":"/coll/reference_model/doc/RF000374"}},{"Reference":{"value":"/coll/reference_model/doc/RF000375"}}]}}}},{"RecommendationID":{"value":"REC055","properties":{"Recommendation":{"value":"Thus, the prevalence of pathogenic variance should be similar to prevalence estimates of BCNS, estimated as roughly 1/31,000."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}}]}}}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE497","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Experience clinically and from molecular testing is compatible with complete penetrance for BCNS."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}},{"Reference":{"value":"/coll/reference_model/doc/RF000374"}},{"Reference":{"value":"/coll/reference_model/doc/RF000375"}}]}}}},{"Penetrance":{"value":"ACPE498","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"Not provided"},"Notes":{"value":"Reported prevalence of certain clinical features in individuals diagnosed with BCNS include:"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC061","properties":{"Recommendation":{"value":"• OKC = 90%\n• Ectopic calcification = >90%\n• Palmar-plantar pits = 85%\n• Ovarian cysts and fibromas = 20-50%\n• Cardiac fibromas = 2%\n• Medulloblastoma = 5%"},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}},{"Reference":{"value":"/coll/reference_model/doc/RF000374"}}]}}}},{"RecommendationID":{"value":"REC062","properties":{"Recommendation":{"value":"• BCC = 90%\n• Facial features = 60%."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}}]}}}}]}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN227","properties":{"Key Text":{"value":"Clinical features of BCNS are variable within and among families with BCNS."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000373"}},{"Reference":{"value":"/coll/reference_model/doc/RF000374"}},{"Reference":{"value":"/coll/reference_model/doc/RF000375"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI232","properties":{"Key Text":{"value":"Interventions identified for BCNS include regular surveillance with multiple specialists and avoidance of sun exposure, x-rays, and radiotherapy which may be burdensome to the patient."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC225","properties":{"Key Text":{"value":"Though many patients have had one or more early clinical signs suggestive of BCNS, some have not been diagnosed until adulthood."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000376"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2016-11-28"},"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"williamsm"}},{"Scorer":{"value":"weaverm"}}]}}},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Overall Score":{"value":"7CD"},"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Overall Score":{"value":"10CN"},"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Sun 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surveillance","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"0B"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"1D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"0B"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}}]}}},"Scorers":{"value":8,"items":[{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"0N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":"Theoretically this should help, but there's no information regarding effectiveness here."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"It's in a Tier 2 recommendation, but not with any data on effectiveness."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"Same as with the panorex - limited data on effectiveness, even though it's recommended in a Tier 2 recommendation."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Could be convinced to go with a 3C if the focus is on avoiding radiotherapy, given the # of BCCs in the radiation field and rapidity with which they appear."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"Not Scored","properties":{"Notes":{"value":"wouldn't we say the intervention is excision of keratocysts? the panorex is a diagnostic modality (and brand name-- panographic radiograph would be preferable).\nSome of the initial evaluation is just to help make the diagnosis, not to manage a patient (like the falx calcification)."}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":"I am not understanding how we can score for imaging but not for the surgery that most people will need."}}}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"again, the surveillance is not the management which is early excision or cryotherapy or pharmacotherapy..per GeneTests: to preserve normal tissue to prevent disfigurement. Surgical excision is supplemented by a number of other possible treatments including cryotherapy and laser treatment for early lesions and photodynamic therapy...Treatment of individuals with severe BCC manifestations and/or advanced lesions with sonic hedgehog inhibitors such as vismodegib is now possible. for this syndrome the goal is preservation of normal skin and early removal of lesions does do that.   If we are trying to capture the idea of burden of the medical intervention, then just seems like its the surgery/treatment not the skin exam."}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":"same issue.  For BRCA, did you score for mammography or for mastectomy? Maybe I just need some educating."}}}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"This was really tough. I could have gone with a zero since there's so little evidence."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Given how important UV radiation is in the formation of such lesions I went with a moderately effective rating."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"I lumped radiation and radiotherapy."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"This was tricky since the downside to not getting radiation therapeutically is that what it's meant to treat isn't treated as effectively. So I think there's more of a downside here than with sun exposure, hence my lower rating."}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"Not sure, if in comparison with everything else, this should be scored as a 1"}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":"I didn't find any information that this was effective, although it is recommended"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"1N","properties":{"Notes":{"value":"As per surveillance for skin exams"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Not sure if this should be minimally or moderately effective."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"Surgery may be required"}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Very effective in identifying OKCs, although intervention is less so. There is a conflict in evidence level between the patient management section and teh surveillance section. I used the latter to score evidence."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"Rarely cause invasive disease"}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"There is a conflict in evidence level between the patient management section and teh surveillance section. I used the latter to score evidence."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"I scored a 2 because this requires a balance of the risk vs. efficacy of the radiation for diagnostic or therapeutic purposes."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"I scored a 2 because this requires a balance of the risk vs. efficacy of the radiation for diagnostic or therapeutic purposes."}}}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Morbidity from odontogenic keratocysts","properties":{"Severity":{"value":"0","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"Outcome is likelihood not morbidity, right?"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Panorex surveillance","properties":{"Effectiveness":{"value":"0B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity from basal cell carcinomas","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Skin surveillance","properties":{"Effectiveness":{"value":"0N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Sun avoidance","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Might not be possible b/c of profession or for other reasons"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Might not be possible b/c of profession or for other reasons"}}}}}},{"Intervention":{"value":"Minimization of radiation","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Might not be possible."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Might not be possible."}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.3","properties":{"Notes":{"value":"Two typos corrected while logged into ACI for another reason.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36080},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-02-15"},"ReleasedBy":{"value":"elizabeth.v.clarke@kpchr.org","properties":{"First Name":{"value":"Elizabeth"},"Last Name":{"value":"Clarke"}}}}}}}},
{"ActionabilityDocID":{"value":"AC089","properties":{"Status":{"value":"Released"},"Genes":{"value":2,"items":[{"Gene":{"value":"COL5A1","properties":{"GeneFunction":{"value":"collagen type V alpha 1"},"HGNCId":{"value":"HGNC:2209"},"GeneOMIM":{"value":"120215"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"130000"}}]}}}},{"Gene":{"value":"COL5A2","properties":{"GeneFunction":{"value":"collagen type V alpha 2"},"HGNCId":{"value":"HGNC:2210"},"GeneOMIM":{"value":"120190"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"130010"}}]}}}}]},"Syndrome":{"value":"Ehlers-Danlos syndrome, classic type","properties":{"OmimIDs":{"value":2,"items":[{"OmimID":{"value":"130000"}},{"OmimID":{"value":"130010"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"278"}}]},"Overview":{"value":""},"Acronyms":{"value":0,"items":[]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"COL5A1","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-10-11"},"Label":{"value":"COL5A1"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Physical/occupational therapy program"}}]}}}},{"Outcome":{"value":"Perinatal complications","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"High-risk pregnancy management"}}]}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Notes":{"value":"The prevalence of Ehlers-Danlos Syndrome (EDS) type I is estimated at 1 in 20,000. However, it is likely that some individuals with milder manifestations of the disease, previously classified as EDS type II, may go undetected."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000388"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Previously EDS types I and II were classified separately for different phenotypic severity, but are now recognized as a continuum of findings and termed classic EDS. Classic EDS is a connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility. Affected individuals skin is smooth/velvety, hyperelastic, and fragile. Areas over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin) are easily split following relatively minor trauma. These wounds have delayed healing and often have stretching of scars after apparently successful healing. Other dermatologic features may include molluscoid pseudotumors (fleshy, heaped-up lesions associated with scars over pressure points) and subcutaneous spheroids (small, cyst-like nodules over the bony prominences of the arms and legs caused by calcified fat deposits). Manifestations of generalized tissue extensibility and fragility are observed in multiple organs including: cervical insufficiency during pregnancy, inguinal/umbilical hernia, hiatal/incisional hernia, or recurrent rectal prolapse in early childhood. Other problems related to joint hypermobility and instability may include: sprain, dislocations/subluxations (usually resolve spontaneously or are easily managed), chronic pain, foot deformities, temporomandibular joint dysfunction, joint effusions, and osteoarthritis. Other features may include hypotonia with delayed motor development, fatigue and muscle cramps, and easy bruising. Structural cardiac malformations are less common in classic EDS than other forms of EDS. Mitral valve prolapse, and less frequently tricuspid valve prolapse, and aortic dilation may occur, but medical or surgical intervention is rarely necessary. Spontaneous rupture of large arteries, along with intracranial aneurysms and arteriovenous fistulae may occur in the rare individual with a severe form of classic EDS. \n\nClassic EDS bears risk for newborns and mothers including: premature rupture of membranes/prematurity when mother or baby are affected, breech presentation (when the baby is affected) leading to dislocation of the hips or shoulder of the newborn, tearing of the perineal skin by forceps and, after delivery, extension of episiotomy incisions and prolapse of the uterus and/or bladder may occur when mother is affected."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000388"}},{"Reference":{"value":"/coll/reference_model/doc/RF000389"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Onset of EDS class is typically during the neonatal, infancy, or childhood periods. However, some individuals may have a mild phenotype and may go undiagnosed. Muscle hypotonia, delayed gross motor development, and hip dislocations can be early presentations of the disorder.  Joint hypermobility depends on age, gender, family, and ethnic background. It is usually noted when a child starts to walk. Hyperflexibility of the skin is difficult to assess in young children due to abundant subcutaneous fat. When aortic dilation does occur, the dilations tend to be of little clinical consequence and the mitral valve prolapse is rarely severe. Medical or surgical intervention is rarely necessary for either. Overall mortality Is not significantly reduced in classic EDS, but has significant morbidity."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000388"}},{"Reference":{"value":"/coll/reference_model/doc/RF000390"}},{"Reference":{"value":"/coll/reference_model/doc/RF000389"}},{"Reference":{"value":"/coll/reference_model/doc/RF000391"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM970","properties":{"Key Text":{"value":"Baseline evaluation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease in an individual diagnosed with classic EDS the following evaluations are recommended: \n• Clinical examination of the skin with assessment of skin hyperextensibility, atrophic scars and bruises, and other manifestations of classic EDS\n• Evaluation of joint mobility with use of Beighton score\n• Evaluation of clotting factors if severe easy bruising is present\n• Baseline echocardiogram\n• Baseline ophthalmologic evaluation"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000388"}},{"Reference":{"value":"/coll/reference_model/doc/RF000389"}}]}}}},{"Patient Management":{"value":"ACPM973","properties":{"Key Text":{"value":"Physical/occupational therapy program"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"Supportive therapy of joints and musculature by isotonic training at home after physiotherapeutic instructions. Physical or occupational therapists can instruct on proper joint use within normal range of motion as well as gentle muscle strengthening. Non-weight-bearing exercise, such as swimming is useful to promote muscular development, strength, and coordination. Low-resistance activities and hydrotherapy may also be beneficial. (Tier 4) \n\nNo evidence related to the use of exercise/physical therapy in classic EDS was identified. A systematic review of therapeutic exercise in joint hypermobility syndrome (JHS) identified four studies (two randomized trials and 2 cohort studies) including 142 patients.  There was no consistent evidence that exercise was better than control or that joint-specific and generalized exercise differed in effectiveness. (Tier 1) \n\nA study of 12 women with EDS-HT and chronic pain were offered multidisciplinary management including two and a half weeks in a rehabilitation unit (consisting of testing, physical training, group discussions, and lectures) followed by individual home exercise for three months with weekly guidance from a physiotherapist. Participants had statistically significant improvements in perceived performance of daily activities, muscle strength and endurance, and a reduction in kinesiophobia. The participants also reported increased participation in daily life. (Tier 5)"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Musculoskeletal morbidity"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000394"}},{"Reference":{"value":"/coll/reference_model/doc/RF000388"}},{"Reference":{"value":"/coll/reference_model/doc/RF000392"}},{"Reference":{"value":"/coll/reference_model/doc/RF000393"}},{"Reference":{"value":"/coll/reference_model/doc/RF000389"}}]}}}},{"Patient Management":{"value":"ACPM969","properties":{"Key Text":{"value":"Emergency health card"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals should carry an emergency health card noting information about the diagnosis, possible complications, and therapeutic measures."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000392"}}]}}}},{"Patient Management":{"value":"ACPM977","properties":{"Key Text":{"value":"Management of skin tears"},"Tier":{"value":"4"},"Recommendation Text":{"value":"When skin tears occur, irregularly frayed wound margins should be excised and precisely adapted to allow rapid healing without dystrophic scarring which is especially important in the case of facial wounds; numerous fine, atraumatic stitches should be used and left in place for twice as long as usual."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000392"}}]}}}},{"Patient Management":{"value":"ACPM975","properties":{"Key Text":{"value":"Vitamin C"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Ascorbic acid (vitamin C) may reduce easy bruising but has no effect on the primary findings of skin hyperextensibility, atrophic scarring, and joint hypermobility. In general, a dose of two grams per day is recommended for adults."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000388"}},{"Reference":{"value":"/coll/reference_model/doc/RF000389"}}]}}}},{"Patient Management":{"value":"ACPM968","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Because of the increased risk of skin lacerations, postpartum hemorrhages, and prolapse of the uterus and/or bladder, monitoring of women throughout pregnancy and in the postpartum period is recommended. Monitoring for preterm labor is warranted during the third trimester when the risk of premature rupture of the membranes is increased. Cervical incompetence should be anticipated and sought at each prenatal visit, with consideration of imaging at 16-20 weeks gestation to determine cervical length."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Perinatal complications"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000388"}},{"Reference":{"value":"/coll/reference_model/doc/RF000389"}}]}}}},{"Patient Management":{"value":"ACPM971","properties":{"Key Text":{"value":"Surgical management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Particular considerations during surgery and use of  anesthesia include: particular care during placement of spinal anesthesia to avoid post-dural puncture headache; monitoring of neuromusucular blockade; interoperative patient positioning with optimal padding, reduction of shear forces, and protection of eyes; adhesive tapes should be easily removable and avoided when possible to avoid skin damage; careful preparation of airway/ventilation  to avoid pressure; careful transport and mobilization; and avoidance of tourniquets, central venous catheters, and arterial lines."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000391"}}]}}}},{"Patient Management":{"value":"ACPM976","properties":{"Key Text":{"value":"Post surgical wound care"},"Tier":{"value":"4"},"Recommendation Text":{"value":"After surgical interventions and other dermal wounds, wounds should be closed without tension, preferably in two layers; deep stitches should be applied generously and cutaneous sutures left in place for twice as long as usual. The borders of adjacent skin should be taped carefully to prevent stretching of the scar. Superficial wounds can be closed with butterfly bandages or dermal glue. Wounds should be closely monitored for dehiscence and inadequate scar formation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000388"}},{"Reference":{"value":"/coll/reference_model/doc/RF000392"}},{"Reference":{"value":"/coll/reference_model/doc/RF000389"}}]}}}},{"Patient Management":{"value":"ACPM974","properties":{"Key Text":{"value":"DEXA"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Bone mineral density scans (DEXA) should be considered in all adults with EDS."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000389"}}]}}}},{"Patient Management":{"value":"ACPM972","properties":{"Key Text":{"value":"Protective padding"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Supportive stockings can be worn in classic EDS to help protect the shins. Elbow and/or knee pads may also be of benefit to prevent significant bruising, fragility tears, and atrophic scarring."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000389"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU529","properties":{"Key Text":{"value":"Symptom monitoring"},"Tier":{"value":"4"},"Recommendation Text":{"value":"At routine physician visits, patients should be evaluated for gastrointestinal symptoms, sleep difficulties, pain and headache, and symptoms of depression and anxiety."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000389"}}]}}}},{"Surveillance":{"value":"ACSU528","properties":{"Key Text":{"value":"Echocardiogram"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"Guidelines are mixed with regard to monitoring aortic dilation with some recommending monitoring every 6-24 months and others stating echocardiogram is warranted only if an abnormality such as aortic dilation or mitral valve prolapse is present on baseline echocardiogram.(Tier 4)  \n\nA cohort of 27 individuals with classic and hypermobile EDS underwent an average of 6 echocardiograms in early childhood (≤14 years), as well in late childhood or adulthood (>14 years). Seven individuals were found to have dilated aortic roots before age 14 (including one patients with classic EDS), and only one individual (with hypermobile EDS) continued to show dilation after age 14. The patient whose aorta remained dilated was placed on a beta blocker and remained on it throughout the study period. None of the remaining individuals were prescribed medication because their aortas were just above the normal range. No patients had symptoms of their dilated aortic roots, and serial measurements did not indicate significant progression in these six patients. No patient with a normal aortic root in childhood had development of dilation in later childhood or adulthood.(Tier 5)"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Aortic dilation requiring surgical intervention"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000395"}},{"Reference":{"value":"/coll/reference_model/doc/RF000388"}},{"Reference":{"value":"/coll/reference_model/doc/RF000389"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM351","properties":{"Key Text":{"value":"Assessment of relatives"},"Tier":{"value":"4"},"Recommendation Text":{"value":"It is estimated that 50% of cases inherited a pathogenic variant from a parent while 50% have a de novo variant. Thus, parents of a proband with an apparent de novo pathogenic variant should be evaluated by physical exam of the skin with special attention to delayed wound healing, easy bruising, joint hypermobility or recurrent dislocations, and chronic articular pain. If a pathogenic variant has been identified in the proband, molecular genetic testing can be performed in the parents."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000388"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA426","properties":{"Key Text":{"value":"Contact sports"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals should avoid sports with heavy joint strain such as competitive and contact sport activities and activities that cause joints to overextend (e.g., pitching, gymnastics). When individuals do participate in sporting events, legs, arms, and face should be protected with athletes’ pads or bandages to avoid traumatic skin injuries leading which could lead to ugly scars."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000388"}},{"Reference":{"value":"/coll/reference_model/doc/RF000392"}},{"Reference":{"value":"/coll/reference_model/doc/RF000389"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA424","properties":{"Key Text":{"value":"Aspirin"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Aspirin should be avoided."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000388"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA423","properties":{"Key Text":{"value":"Sun exposure"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Excessive sun exposure should be avoided to prevent damage to the skin."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000389"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA425","properties":{"Key Text":{"value":"Scar revision products"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Scar revision (vanishing) products should also be avoided as the breakdown of the scar tissue can result in atrophic scarring."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000389"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"No information on the prevalence of classic EDS mutations was identified; however, mutations of COL5A1 and COL5A2 are estimated to make up 50% of classic EDS, which has a prevalence estimated around 1 in 20,000. However, this number may be an underestimate given no prospective studies of COL5A1 and COL5A2 have been performed in a clinically well-defined group."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000388"}},{"Reference":{"value":"/coll/reference_model/doc/RF000392"}}]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE500","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"4"},"Notes":{"value":"Mutations for EDS are considered fully penetrant."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000392"}}]}}}},{"Penetrance":{"value":"ACPE501","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"5"},"Notes":{"value":"Information on penetrance was only available from individuals clinically suspected of having classic EDS.\n\nClinical features were examined in a study of 40 patients with suspected classic EDS from 28 families (26 probands were identified to have a COL5A1 or COL5A2 mutation). The following clinical features were identified: hyperextensible skin (39/40), skin fragility with defective scarring (38/40), and joint hypermobility (32/40). A history of recurrent/sporadic dislocations/subdislocations was present in 60% of patients. Cardiovascular signs were present among some patients including valvular regurgitation (7/40) and mitral valve prolapse (6/40). Other identified features included chronic fatigue syndrome (8/40), gastroesophageal reflux (6/40), hypotonia at birth (5/40), hernias (4/40), and delayed motor development (2/40). Neither severe aneurysmatic dilation nor arterial rupture was present in any patient."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000390"}}]}}}},{"Penetrance":{"value":"ACPE499","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"A retrospective review of patients with EDS undergoing screening echocardiography showed that at a median age of 16 years, 3/50 (6%) patients with classic EDS had aortic dilation at their first echocardiogram. No individual had a rupture of their aorta or any other blood vessel or aortic root replacement."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Aortic dilation requiring surgical intervention"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000388"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR209","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN228","properties":{"Key Text":{"value":"Inter- and intra-familial variability in the severity of the phenotype can be great. (Tier 4) In some families with a null variant, an affected family member can have a very mild classic phenotype while other family members may have a severe phenotype. 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In infantile-onset GSD2, GAA enzyme activity is completely or nearly completely absent (<1% of normal activity), while some residual activity (~2-40% of normal activity) is present in the late-onset form.\n\nThe classic infantile-onset form is more severe and is characterized by cardiomegaly with respiratory distress, muscular hypotonia, and feeding difficulties. The non-classic variant of the infantile-onset form is typically less severe and presents with motor delays and/or muscle weakness. \n\nThe late-onset form is characterized by progressive proximal muscle weakness, particularly in the trunk and lower limbs, and respiratory insufficiency without clinically apparent cardiac involvement. However, some adults with late-onset disease have been found to have arteriopathy. Ectasia of the basilar and internal carotid arteries has been noted, and may be associated with clinical signs, such as transient ischemic attacks and 3rd nerve paralysis. In addition, dilation of the ascending thoracic aorta has been noted. Intracranial aneurysms may be present in some patients leading to subarachnoid hemorrhage. Other features may include exercise intolerance, exertional dyspnea, orthopnea, sleep apnea, hyperlordosis and/or scoliosis (childhood and juvenile onset),  hepatomegaly (childhood and juvenile onset), macroglossia (childhood onset), difficulty chewing and swallowing, weak cough, increased respiratory infections, decreased deep tendon reflexes, Gower sign, joint contractures, cardiac hypertrophy (childhood onset), and developmental delay in motor skills (childhood onset)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000400"}},{"Reference":{"value":"/coll/reference_model/doc/RF000401"}},{"Reference":{"value":"/coll/reference_model/doc/RF000398"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}},{"Reference":{"value":"/coll/reference_model/doc/RF000397"}},{"Reference":{"value":"/coll/reference_model/doc/RF000069"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"The classic infantile-onset form typically presents in the first 2 months of life. Without treatment by enzyme replacement therapy (ERT), it rapidly progresses and commonly results in death in the first year of life due to progressive left ventricular outflow obstruction. The non-classic variant of infantile-onset usually presents within the first year of life, has a slower progression, and typically results in death from ventilatory failure in early childhood. \n\nThe late-onset form can present at variable ages, from early childhood (after age one) into adulthood (as late at the 7th decade of life). The median age at diagnosis has been estimated as 38 years, though some affected adults often describe symptoms beginning in childhood. Progression of the disease is slower than the infantile-onset form and is often predicted by the age of onset and residual enzyme activity. The presenting symptom in 93% of patients is weakness of proximal extremities (generally preceded by myalgia and muscle cramps). Progression of skeletal muscle involvement eventually involves the diaphragm and accessory respiratory muscles. Roughly 60% of patients will have mild reduction in vital capacity and 30-40% will have moderate reduction. Affected individuals have a mean reduction in vital capacity of approximately 1.5% per year following diagnosis and the likelihood of needing either non-invasive or invasive ventilation increases by an average of 8% each year following diagnosis. Affected individuals often become wheelchair dependent because of lower limb weakness, with the probability of wheelchair use increasing, on average, 13% each year after diagnosis without treatment. Respiratory failure causes the major morbidity and mortality of this form of the disease. Male gender, severity of skeletal muscle weakness, and duration of disease are all risk factors for severe respiratory insufficiency. The median age at death in untreated adults has been estimated as 55 years (range 23-77 years)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000400"}},{"Reference":{"value":"/coll/reference_model/doc/RF000401"}},{"Reference":{"value":"/coll/reference_model/doc/RF000398"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}},{"Reference":{"value":"/coll/reference_model/doc/RF000397"}},{"Reference":{"value":"/coll/reference_model/doc/RF000402"}},{"Reference":{"value":"/coll/reference_model/doc/RF000069"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM979","properties":{"Key Text":{"value":"Initial Evaluations"},"Tier":{"value":"2"},"Recommendation Text":{"value":"The following evaluations should be performed at diagnosis:\n\n• Echocardiogram\n• 24-hour ambulatory ECG \n• Assessment of pulmonary function and gas exchange\n• Chest X-ray\n• Polysomnography and detailed sleep history for sleep respiratory function\n• Measure cardiorespiratory status and response to position and activity with pulse oximetry\n• Screen for osteopenia/osteoporosis with  dual-energy x-ray absorptiometry (DEXA)\n• Assessment of musculoskeletal impairment and muscle strength\n• Measures of function, disability, pain, and quality of life\n• Perform neurology assessments including nerve conduction studies, needle electromyography (EMG) to determine presence of denervation as evidence of anterior horn cell involvement, and hearing tests."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000399"}}]}}}},{"Patient Management":{"value":"ACPM987","properties":{"Key Text":{"value":"Multidisciplinary management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Management of patients should consist of a team including a physician with experience in managing GSD2 and specialists in the field of neurology, pulmonary, cardiology, orthopedics, metabolic dietician, general medicine, occupational therapists, and disease geneticists."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000400"}},{"Reference":{"value":"/coll/reference_model/doc/RF000401"}}]}}}},{"Patient Management":{"value":"ACPM983","properties":{"Key Text":{"value":"Therapeutic exercise"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Though there are no established guidelines for muscle strengthening or therapeutic exercise for individuals with late-onset GSD2, a physical or occupational therapist should develop an exercise program with a focus on submaximal aerobic exercise and/or muscle strengthening, following guidelines for other degenerative muscle diseases. Functional activities should also be incorporated and strategies to optimize biomechanical advantage and use of energy conservation techniques. Although evidence is minimal (few studies with small sample sizes) in patients with GSD2, some studies suggest that submaximal exercise may increase muscle strength and function through improved clearance of accumulated glycogen in muscle. However, there is insufficient evidence that resistance training improves strength."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000398"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC219","properties":{"Recommendation":{"value":"Little evidence is available for the effectiveness of muscle strengthening and therapeutic exercise in adult patients with GSD2. One study reported the results of a 12-week exercise intervention in adults mildly affected with GSD2 to improve aerobic fitness, muscle strength, and core stability. The study included 25 patients who had received ERT for at least one year and were not dependent on a ventilator and/or walking device. 23 patients completed the program and achieved decreased levels of fatigue and pain and improvements in endurance, muscle strength of the hip flexors and shoulder abductors, and core stability.  However, no significant differences were observed in self-reported motor function or patient activity."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000403"}},{"Reference":{"value":"/coll/reference_model/doc/RF000404"}}]}}}},{"RecommendationID":{"value":"REC218","properties":{"Recommendation":{"value":"A systematic review of physiotherapy among patients with non-GSD2 neuromuscular disorders (e.g., muscular dystrophy) found that aerobic exercise (with or without strengthening exercises) had a positive effect on body function and activities and participation. However, inconsistent and insufficient evidence was found for the use of strengthening exercises alone."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000405"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM980","properties":{"Key Text":{"value":"Secondary management of musculoskeletal impairments"},"Tier":{"value":"2"},"Recommendation Text":{"value":"No established guidelines exist for management of secondary musculoskeletal impairments, including contracture and deformity, in late-onset GSD2, though general principles established for the management of other neuromuscular disorders can be applied. These principles should be applied early and include limiting contracture and deformity by gentle daily stretching, correction of improper positioning, judicious and timely use of splints and orthotic interventions, and provision of adequate support in all positions, including sitting and supported standing. Prevention of contracture and deformity is critical to preserve function and limit other secondary complications, such as skin breakdown and chronic musculoskeletal pain."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000398"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC221","properties":{"Recommendation":{"value":"Little evidence is available for the effectiveness of measures that manage secondary musculoskeletal impairments in adult patients with GSD2. However, gentle stretching, splinting, and bracing are effective in patients with Duchenne muscular dystrophy in slowing the development of contractures, maintaining joint extension, and extending walking time."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000406"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM984","properties":{"Key Text":{"value":"Fall risk assessment"},"Tier":{"value":"2"},"Recommendation Text":{"value":"On the basis of a recent study showing a high prevalence of osteoporosis in patients with GSD2, all patients should undergo fall risk assessment."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000398"}}]}}}},{"Patient Management":{"value":"ACPM986","properties":{"Key Text":{"value":"Adequate nutrition"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Nutrition needs to be adequate in terms of intake of calcium, Vitamin D, and protein intake."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000400"}},{"Reference":{"value":"/coll/reference_model/doc/RF000398"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}}]}}}},{"Patient Management":{"value":"ACPM982","properties":{"Key Text":{"value":"Enzyme replacement therapy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"ERT with alglucosidase is the only specific treatment available for late-onset GSD2 in adults and children. However, it is not recommended for patients with no symptoms or objective signs (proximal muscle weakness or reduced FVC). ERT is recommended at the earliest onset of symptoms or objective signs. No clinical studies have yet been conducted to show whether the treatment of asymptomatic patients can delay the onset of symptoms of the disease. The Late-Onset Treatment Study (LOTS) is a randomized controlled trial for ERT that has been conducted in 90 patients aged 8 years and older.  The results of the study indicate that ERT has a positive effect on the disease process or processes that produce impaired ambulation and respiratory insufficiency in late-onset GDS2. At week 78, statistically significant findings were reported with improvements in the 6-minute walk test (this improvement occurred in the first 26 weeks of treatment and maintained for the next 52 weeks) and percent of predicted upright FVC results among those administered ERT compared to those on placebo. An open label extension study indicated that improvements in walking distance and stabilization of pulmonary function noted at week 78 were maintained at week 104. However, it is unclear how these study endpoints translate into functional improvements for patients. Quality-of-life measures collected in the same study found no associated improvements."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000400"}},{"Reference":{"value":"/coll/reference_model/doc/RF000398"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}},{"Reference":{"value":"/coll/reference_model/doc/RF000069"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC220","properties":{"Recommendation":{"value":"A systematic review of mostly uncontrolled clinical studies of symptomatic ERT treatment summarized outcomes of 368 patients with late-onset GSD2, including 251 adults (age ≥18). Creatine kinase levels decreased in 70% of patients, stabilized in 11%, and increased in 20%. Motor performances improved in 78% of patients, stabilized in 8%, and declined in 14%. Of patients with impaired ambulatory status 6% had improvements following ERT treatment. Respiratory dysfunction improved in 52% of patients, stabilized in 14% and declined in 35%. Following treatment, 8% of patients reported an improvement in quality of life outcomes."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000402"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM989","properties":{"Key Text":{"value":"Strict hygiene"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Given the increased risk of infections, strict hygiene and handwashing precautions should be implemented and medical attention should be sought for common symptoms such as a cough or fever."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000400"}},{"Reference":{"value":"/coll/reference_model/doc/RF000401"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}}]}}}},{"Patient Management":{"value":"ACPM988","properties":{"Key Text":{"value":"Vaccinations"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients and other household contacts should stay up to date on vaccinations (particularly pneumococcus and influenza)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000400"}},{"Reference":{"value":"/coll/reference_model/doc/RF000401"}},{"Reference":{"value":"/coll/reference_model/doc/RF000398"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}}]}}}},{"Patient Management":{"value":"ACPM978","properties":{"Key Text":{"value":"Aggressive treatment of infections"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Early and aggressive treatment of bacterial and viral infections (particularly pulmonary infections) given the high risk for pneumonia and other infections that may lead to respiratory failure, intubation with ventilator dependence, and even death. Antivirals should be used for the flu."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000400"}},{"Reference":{"value":"/coll/reference_model/doc/RF000401"}},{"Reference":{"value":"/coll/reference_model/doc/RF000398"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}}]}}}},{"Patient Management":{"value":"ACPM985","properties":{"Key Text":{"value":"Anesthesia management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"General anesthesia must be performed by someone familiar with anesthesia in patients with GDS2 due to the risk of fatality. Surgical procedures must be grouped for a single anesthetic where possible. Intubation during surgery should be avoided, if possible."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000401"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}}]}}}},{"Patient Management":{"value":"ACPM981","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Pregnant women should undergo careful respiratory and cardiac surveillance in consultation with a maternal fetal medicine specialist. A growing fetus may pose additional complications for women with myopathy and respiratory insufficiency."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000397"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU533","properties":{"Key Text":{"value":"Regular assessments"},"Tier":{"value":"2"},"Recommendation Text":{"value":"The following assessments should be performed at regular intervals: \n\n• Chest X-ray\n• Echocardiogram\n• 24-hour ambulatory ECG to assess for life-threatening arrhythmias\n• Monitor for arrhythmias\n• Laboratory tests: serum creatinine kinase, transaminases, lactate dehydrogenase, and urinary hex4\n• Assess respiratory status at each visit\n• Assess pulmonary function and gas exchange annually\n• Measurement of maximal clearance of airway secretions\n• Spirometry, pulse oximetry, capnography should routinely be performed\n• Detailed sleep history and assessment of symptoms associated with sleep-disordered breathing to assess for respiratory dysfunction during sleep\n• Other assessments, such as swallowing and neurological exams."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000398"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}},{"Reference":{"value":"/coll/reference_model/doc/RF000069"}}]}}}},{"Surveillance":{"value":"ACSU531","properties":{"Key Text":{"value":"Musculoskeletal assessments"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should be annually assessed for musculoskeletal impairments, functional deficits, levels of disability, and society participation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000399"}}]}}}},{"Surveillance":{"value":"ACSU532","properties":{"Key Text":{"value":"Regular muscle and pulmonary assessments"},"Tier":{"value":"2"},"Recommendation Text":{"value":"When a presymptomatic patient is confirmed to have GSD2 through newborn screening, sibling screening, or another screening program, it is recommended that such patients be examined every 6 months and that muscle strength and pulmonary function (including FVC in both upright and supine positions) be monitored at these visits for the onset of symptoms to guide initiation of ERT."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000398"}}]}}}},{"Surveillance":{"value":"ACSU530","properties":{"Key Text":{"value":"Regular DEXA screens"},"Tier":{"value":"2"},"Recommendation Text":{"value":"All patients with GSD2 should be screened, regardless of age and wheelchair use, with DEXA with follow-up considered on a yearly basis. Low bone mineral density (BMD) is a common feature in patients, and a recent study demonstrated that 67% of the patients tested had a BMD z-score of -1 and that the decrease in BMD was present in both the infantile- and late-onset forms of the disease."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000398"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM352","properties":{"Key Text":{"value":"Genetic counseling and testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Genetic counseling should be provided to all parents with an affected child with GSD2 and all adults with GSD2. DNA analysis is necessary for the identification of additional family members in the extended family who may be carriers."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000400"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA429","properties":{"Key Text":{"value":"Overwork of muscles and joints"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with GDS2 should avoid overwork weakness, excessive fatigue, disuse, strenuous exercises, and eccentric contractions. Excessively strenuous resistance exercises have been discouraged in muscle disorders due to the potential for exacerbating muscle degeneration. In GSD2, there is additional theoretical concern that excessive muscle contraction might lead to increased leakage of glycogen from lysosomes or cause lysosomal rupture, thereby hastening muscle damage."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000398"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA427","properties":{"Key Text":{"value":"Changes in fluid status"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Avoid drastic changes in fluid status, either through dehydration or fluid overload."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000399"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA428","properties":{"Key Text":{"value":"Medications"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should exercise caution when using some medications. Care should be taken with drugs that have a myorelaxant effect and central nervous system depressants. Some over the counter medications to treat cough, colds, and other symptoms often contain sympathomimetic agents which can be detrimental to the heart. The risk benefit ratio of use of medications such as steroids (risk of progressive muscle weakness and osteopenia) and loop diuretics (ototoxicity and calciuria) must be considered prior to administration."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000398"}},{"Reference":{"value":"/coll/reference_model/doc/RF000399"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Tier":{"value":"4"},"Notes":{"value":"The risk of being a heterozygous carrier of a mutation in the gene that causes GSD2 is approximately 1/100."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000400"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE502","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"Not provided"},"Notes":{"value":"Penetrance for individuals detected based on genotype was not identified. Information for patients detected clinically is listed below:"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC064","properties":{"Recommendation":{"value":"Common findings in cases of infantile GSD2:\n    Hypotonia/muscle weakness= 52%-96%\n    Cardiomegaly=92%-100%\n    Hepatomegaly=29%-90%\n    Left ventricular hypertrophy=83%-100%\n    Cardiomyopathy=88%\n    Respiratory distress=41%-78%\n    Murmur=46%-75%\n    Absent deep tendon reflexes=33%-35%."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000397"}}]}}}},{"RecommendationID":{"value":"REC063","properties":{"Recommendation":{"value":"Findings in late-onset GSD2:\n    Progressive proximal muscle weakness=93-95%\n    General fatigue and poor endurance=50-76%\n    Muscle pain and soreness=46%."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000398"}},{"Reference":{"value":"/coll/reference_model/doc/RF000397"}}]}}}}]}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN229","properties":{"Key Text":{"value":"Intergenerational phenotypic variation has been reported in several families with GSD2.The clinical phenotype of late-onset GSD2 varies."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000398"}},{"Reference":{"value":"/coll/reference_model/doc/RF000397"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI234","properties":{"Key Text":{"value":"Preventive stretching regimens are better tolerated and accepted if they are initiated before muscle tendon tightness and contractures develop, a point at which stretching often becomes painful. Aggressive stretching should be approached cautiously because, at least in severely affected children, a tendency for pathologic fracture has been observed.\n\nIn general, the use of ERT is safe. However, life-threatening anaphylactic reactions, severe allergic reactions, and immune-mediated reactions have been observed in some patients during ERT infusions. In the LOTS trial 5% of patients experienced an anaphylactic reaction. In an ERT trial, patients in the treatment and placebo groups had similar frequencies of adverse events, serious adverse events, and treatment-related adverse events. Most adverse events were mild to moderate and not considered to be related to the use of ERT. All ERT recipients tested negative for immunoglobulin G (IgG) anti-GAA antibodies at baseline, and all patients seroconverted by week 12. ERT is administered intravenously every 2 weeks; a device such as a ‘port-a-cath’ may be implanted to make access easier."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000400"}},{"Reference":{"value":"/coll/reference_model/doc/RF000398"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC227","properties":{"Key Text":{"value":"The diagnosis of the late-onset form is often difficult because it can clinically resemble a myriad of other neuromuscular disorders. It can take several years to get a correct diagnosis, with one review finding a diagnostic delay ranging from 5 to 30 years. A high level of clinical suspicion is necessary for a timely and accurate diagnosis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000400"}},{"Reference":{"value":"/coll/reference_model/doc/RF000398"}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2016-12-12"},"Scorers Present":{"value":6,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"bieseckerl"}}]}}},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Overall Score":{"value":"9CB"},"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Overall Score":{"value":"9CB"},"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Overall Score":{"value":"9CB"},"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Overall Score":{"value":"6DD"},"Effectiveness":{"value":"1D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]},"FinalScoreOfScorers":{"value":8,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"1D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"0B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"1A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"1A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"1D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"1N"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"1D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"1D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":8,"items":[{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"High likelihood of requiring a wheelchair qualifies it in my mind for a \"2\"."}}},"Likelihood":{"value":"3D","properties":{"Notes":{"value":"These are all tough ones to quantify given the poor evidence, hence my evidence level for all of them as \"D\"."}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"PT, excercise, etc. are difficult to comply with. At least for me :)\nSo I gave it a 2."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"PT, excercise, etc. are difficult to comply with. At least for me :)\nSo I gave it a 2."}}}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"The gains appear to be pretty modest in that: \"it is unclear how these study endpoints translate into functional improvements for patients. Quality-of-life measures collected in the same study found no associated improvements.\". Clearly the evidence for real gains is weak. Thus my score of minimal effectiveness and evidence."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Having to have an indwelling cath is not trivial given its own risks. And going to a facility for infusion every two weeks isn't completely trivial. So I went with a 2 instead of a 3."}}}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"30-40% with moderate reduction in vital capacity and a progressively increasing need for ventilation makes me go with a 2, although it certainly can be milder."}}},"Likelihood":{"value":"3D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"This seems a little more encouraging so I gave it a \"2\". However, I knocked hte evidence down a bit since the studies were not done in asymptomatic people."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Having to have an indwelling cath is not trivial given its own risks. And going to a facility for infusion every two weeks isn't completely trivial. So I went with a 2 instead of a 3."}}}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"I extrapolated from other disorders where infection is a risk, deciding that we do certainly know that things like vaccinations, antibiotics, hand washing, etc. work well. But I gave it a \"C\" for evidence since it is extrapolation."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"an every 2 week infusion (and costs) seems more than moderate as it affects a person's life alot"}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":"an every 2 week infusion (and costs) seems more than moderate as it affects a person's life alot"}}}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"no info on how often lifethreatening infections afflict this group as a whole nor how many can be averted  but prevention of infection is basic medical care for all medically  fragile people."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"There are some references to Tier 2 and Tier 5."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"Tier 1 and Tier 2 quoted."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"No data provided"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"Although various interventions are recommended, there is no data on whether they are effective."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Incomplete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"1N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"I went with a B evidence level as the controlled trial data seems more robust than the systematic review which mostly consisted of uncontrolled trials. Even that would technically be tier one, a systematic review of poor quality studies doesn't surpass the controlled trial--even though it was small."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"Same rationale"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"No information is provided about the prevalence of severe infection."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"0B","properties":{"Notes":{"value":"I think the effectiveness of this intervention in adults is unknown."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":"I'm swayed but only 8% of participants reporting an improvement in quality of life."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"We've previously scored ERT as a 2."}}}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"0B","properties":{"Notes":{"value":"no data on effectiveness"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"1N","properties":{"Notes":{"value":"Had a tough time with the one and ended up extrapolating from some of the non-GSD2 data."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":"Depends on whether on values measurements of muscle function or QoL more highly. If the latter, could go to a 1 since there were minimal reported improvements in QoL."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Downgraded from 3 because of IV every 2 weeks is somewhat burdensome and because of  risk for reactions."}}}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"Based on scoring late-onset GSD2 and lack of evidence on pulmonary function."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":"Same comment as ERT:musculoskeletal impairment."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"As above, based on scoring late-onset GSD2."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"No data on effectiveness presented, but stands to reason from regular clinical practice that these interventions would be effective, particularly vaccinations."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"1N","properties":{"Notes":{"value":"1.5?"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Risk higher in peds-onset.  Since we are scoring for adult-onset, this may be only a 1"}}}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"There is not much data about extent of impact/improvement"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"5% risk for anaphylaxis; impact on QOL"}}}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"Can this info be shown in left frame?"}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":"did not see a number for this"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":"There does not appear to data about efficacy of this"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Musculoskeletal morbidity","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"This is scored as C but no one in the real world will take this seriously."}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"Not clear exactly what we are scoring - improvement in resp fxn or prolonging life from resp death"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Impaired pulmonary function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Enzyme replacement therapy","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Severe or life-threatening infections","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"No information presented - but again this strains credulity."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Vaccination and aggressive prevention/treatment of infections","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36084},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-10"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC091","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"MET","properties":{"HGNCId":{"value":"HGNC:7029"},"GeneOMIM":{"value":"164860"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"605074"}}]}}}}]},"Syndrome":{"value":"Familial papillary renal cell carcinoma 1","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"605074"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"47044"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Title","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-10-17"},"Label":{"value":"Label"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging"}}]}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"The incidence of familial papillary renal cell carcinoma (FPRCC) is unknown. However, the annual incidence of all familial renal cell carcinoma (RCC) syndromes is less than 1 in 1,500,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000411"}},{"Reference":{"value":"/coll/reference_model/doc/RF000257"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"FPRCC is characterized by a predisposition for developing multiple bilateral papillary RCCs.  Patients may develop 1100-3400 microscopic tumors in a single kidney. The types of papillary tumors range from microscopic lesions to clinically symptomatic carcinomas. However, tumors are always type 1 papillary RCC with low nuclear grade.  However, some tumors do metastasize."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000411"}},{"Reference":{"value":"/coll/reference_model/doc/RF000412"}},{"Reference":{"value":"/coll/reference_model/doc/RF000257"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"FPRCC has late onset, typically between ages 50 and 70 years.  A study of 10 families with FPRCC reported that the average age of diagnosis of affected individuals in these families was 45, with an estimated mean survival of 7 years following diagnosis. Although 5-year survival rates for patients with RCC have improved in recent years, the outcome for patients with advanced stage disease remains poor."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000411"}},{"Reference":{"value":"/coll/reference_model/doc/RF000412"}},{"Reference":{"value":"/coll/reference_model/doc/RF000257"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM990","properties":{"Key Text":{"value":"Nephron Sparing Surgery"},"Tier":{"value":"5"},"Recommendation Text":{"value":"Treatment aims at controlling the risk of advanced disease, including metastasis, while at the same time preserving renal function due to the high likelihood of future de novo RCC. Sporadic and certain types of hereditary RCC usually acquire metastatic potential when their size reaches >3-7 cm. For some forms of hereditary RCC (such as FPRCC, von Hippel-Lindau syndrome, and Birt-Hogg Dube syndrome), the standard recommendation is the removal of all lesions in the same kidney once a single solid lesion or the largest solid is >3cm (the “3cm rule”), while other hereditary forms (such as hereditary leiomyomatosis and renal cell cancer and SDH-associated tumors) require more aggressive surgery due to a more aggressive nature with metastatic potential at smaller tumor size."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000413"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC222","properties":{"Recommendation":{"value":"Partial nephrectomy (PN), also known as nephron-sparing surgery is now the standard method of hereditary RCC treatment. Bilateral nephrectomy eliminates the risk of metastasis from RCC but requires renal replacement therapy, including dialysis and kidney transplantation. However, the significant morbidity, mortality, and effects on quality of life, associated with dialysis makes this form of renal replacement therapy a last resort. In addition, options for kidney transplantation in hereditary patients may be limited due to the presence of RCC or other co-morbidities. Evidence for effectiveness of PN compared to bilateral nephrectomy among patients with FPRCC specifically was not available. However, available evidence suggest promising overall survival outcome for the PN intervention in hereditary RCC cases. One study assessed a cohort of 58 patients with hereditary RCC treated with PN for solid tumors greater than 4cm. The cohort which included 41 (71%) patients with von Hippel-Lindau, 10 (17%) patients with Birt-Hogg-Dube, and 7 (11%) with FPRCC. The mean age was 43.7 (range 18–63) and the mean largest tumor size was 5.3 cm (range 4–13). The mean number of resected kidney tumors was 6.4 (range 1–44). Overall survival of the cohort was 93% and metastasis-free survival was 96.5% at the median follow up of 45 months (range 2–163), rates similar to those reported in the literature series for patients undergoing PN for tumors in the sporadic population."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000257"}}]}}}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU534","properties":{"Key Text":{"value":"CT Imaging"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Imaging is often difficult due to the small size of lesions and their hypovascularity. In this context, CT is the imaging modality of choice for FPRCC patient screening. Surveillance should be started at age 30-35 and/or 10 years before the earlier age or onset of an RCC in the family. The frequency of surveillance can range from every 3-6 months to every 2-3 years depending on the size of the lesions."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000257"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM353","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Once a specific gene anomaly has been demonstrated in a proband, genetic testing may be offered to at-risk relatives, and clinical follow-up has to be initiated for carriers of the familial germline mutation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000257"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":""},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE503","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"FPRCC is associated with high penetrance with a 90% likelihood of developing RCC by age 80."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000257"}}]}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI235","properties":{"Key Text":{"value":"Interventions identified in this report include surveillance with CT scans and treatment with nephron-sparing surgery. Surgical mortality of partial nephrectomy is less than 1% at experienced centers. A study of 50 patients with hereditary RCC who underwent 65 partial nephrectomies indicated the most common complications were pneumothorax (4.2%), renal atrophy (4.6%), prolonged urinal drainage (4.6%), and perinephric abscess (1.5%)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000414"}},{"Reference":{"value":"/coll/reference_model/doc/RF000415"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC228","properties":{"Key Text":{"value":"In a study of 10 families with FPRCC reported that RCC was often detected incidentally in asymptomatic individuals or during screening of asymptomatic members of RCC families."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000412"}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2017-02-13"},"Scorers Present":{"value":0,"items":[]}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Overall Score":{"value":"10CN"},"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]},"FinalScoreOfScorers":{"value":7,"items":[{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}}]}}},"Scorers":{"value":7,"items":[{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"Hard to assess the success of surveillance in the absence of surgery."}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":"The 1 includes surgery; if without surgery, I would score a 2."}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"This is a tough one. Of course the CT surveillance itself is not too onerous and could get a 3. However, most of these folks require surgery so I went with a \"2\". I'm thinking some might score it a 1.."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"This is a tough one. Of course the CT surveillance itself is not too onerous and could get a 3. However, most of these folks require surgery so I went with a \"2\". I'm thinking some might score it a 1.."}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3B","properties":{"Notes":{"value":"Evidence tier not provided. However this is taken from a systematic review so I think that's a B."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"3N","properties":{"Notes":{"value":"I chose E, as we have no evidence directly for FPRCC but are inferring from other hereditary RCC disorders. D would also potentially work, but I don't this C is appropriate since this is inferred evidence. Also, it's less about the CT scan, per se, but the identification of the tumor at a size that allows nephron sparing surgery."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Between 1 and 2 here."}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"1D","properties":{"Notes":{"value":"This is a tough one. I tried to combine the effects of CT surveillance identifying tumors that would derive benefit from nephron-sparing surgery, hence the D for evidence level. Was on the fence between 1 and 2 for effectiveness."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"If there's sufficient concern about radiation exposure with CTs, could go down to 2."}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":"No statistics on the effectiveness of CT imaging to detect lesions."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"Really unsure about the adjective here - I could be talked into moderately."}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity/mortality associated with papillary renal cell carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic surveillance via renal CT imaging","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"No data on early detection = better."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"?? how to consider CT radiation"}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"Paired gene-OMIM phenotype\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36086},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-10"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC093","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"SERPINA1","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:8941"},"GeneOMIM":{"value":"107400"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"613490"}}]}}}}]},"Syndrome":{"value":"Alpha-1 Antitrypsin Deficiency","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"613490"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":""},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Alpha-1 antitrypsin deficiency"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":3,"items":[{"SearchString":{"value":"\"alpha 1-Antitrypsin Deficiency\"[Mesh], limited (from Stage 1)","properties":{"NumberOfHits":{"value":3},"Date":{"value":"2016-03-21"}}}},{"SearchString":{"value":"\"alpha 1-Antitrypsin Deficiency\"[Mesh] OR \"alpha-1-Antitrypsin Deficiency, Autosomal Recessive\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":23},"Date":{"value":"2016-03-21"}}}},{"SearchString":{"value":"\"Pulmonary Disease, Chronic Obstructive\"[Mesh] LIMITED TO ONLY consensus development conferences or guidelines","properties":{"NumberOfHits":{"value":87},"Date":{"value":"2016-03-21"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"antitrypsin","properties":{"NumberOfHits":{"value":3},"Date":{"value":"2016-03-21"}}}},{"SearchString":{"value":"serpina1","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-03-21"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-03-21"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-03-21"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-03-21"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-03-21"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":3,"items":[{"Outcome":{"value":"COPD","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Smoking cessation"}}]}}}},{"Outcome":{"value":"Liver disease","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Limit alcohol consumption"}}]}}}},{"Outcome":{"value":"Emphysema","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"A1AT augmentation therapy"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 10000"},"Notes":{"value":"Alpha-1 Antitrypsin (A1AT) deficiency (defined by A1AT level) occurs in approximately 1 in 5000 to 7000 individuals in North America and in 1 in 1500 to 3000 in Scandinavia. Severe A1AT deficiency is most commonly found in Whites, followed by Hispanics and African Americans with the lowest prevalence among Mexican Americans and none among Asians. Less severe A1AT deficiency genotypes occur more frequently in Mexican American or Hispanic American populations but remain rare among African Americans and absent among Asian Americans."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000409"}},{"Reference":{"value":"/coll/reference_model/doc/RF000416"}},{"Reference":{"value":"/coll/reference_model/doc/RF000410"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"A1AT deficiency is characterized by an increased risk for chronic obstructive pulmonary disease (COPD; defined as emphysema, persistent airflow obstruction, and/or chronic bronchitis) in adults; liver disease in children and adults; panniculitis (inflammation of subcutaneous adipose tissue); and c-ANCA-positive vasculitis (microscopic polyangiitis, Churg-Strauss syndrome, or granulomatosis with polyangiitis). The frequency of A1AT-associated COPD cases is about 1-2% of overall COPD patients.\n\nA1AT deficiency in the lung results in reduced inhibition of neutrophil elastase (increased in smokers) and excessive destruction of alveolar wall elastin.  In hepatocytes, protein products of pathogenic alleles accumulate and polymerize causing liver disease."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000409"}},{"Reference":{"value":"/coll/reference_model/doc/RF000410"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Severity of disease depends on genotype as well as environmental factors (see section on Prevalence of Genetic Mutations for an overview of genotype designations for A1AT deficiency).\n\nLiver abnormalities develop in only a portion of children with AATD.  The overall risk that individuals of PI*ZZ genotype, the most common and severe deficiency genotype, will develop severe liver disease in childhood is low, about 2%. Up to 20% of adults of the same genotype develop liver disease (primarily cirrhosis and fibrosis) by age 50 years; risk may be higher for males and peak in the 6th decade. Prevalence of liver disease may be highest in individuals who have never smoked and do not have COPD (as high as 40% in older individuals, based on autopsy studies). The risk for hepatocellular carcinoma in PI*ZZ individuals is elevated compared to those with liver cirrhosis but no A1AT deficiency. Individuals of PI*SZ genotype, the next most severe, are not at high risk for liver disease.\n\nEmphysema is the dominant pulmonary lesion in A1AT deficiency and the most common manifestation of the disease.   Patients with severe (serum A1AT levels ≤ 11 uM or PI*ZZ) A1AT deficiency are at high risk and those with intermediate (A1AT levels 11-20 uM or PI*MZ, *SS, or *SZ) deficiency are mostly at low risk of lung disease.  However, the 20% of PI*SZ individuals with low A1AT levels are known to be at increased risk. A1AT deficiency-related emphysema changes are typically more pronounced in the bases of the lungs, in contrast to the usual pattern of upper lobe involvement. Lung function tests show decreased expiratory airflow, increased lung volumes, and decreased diffusing capacity. Active smoking is the most important additional risk factor for the development and course of lung function deficits and COPD.  Onset of respiratory disease is usually between ages 40 and 50 years in smokers.  Individuals with A1AT deficiency, who have never smoked, rarely develop respiratory symptoms before the 5th decade and detectable impairment by lung function tests does not occur before the 6th or 7th decade.  For non-smokers, some never develop COPD and may have a normal lifespan. Other environmental and genetic modifiers may also be independent risk factors.\n\nChronic bronchitis may occur in 20 to 34% of A1AT deficiency cases overall, but in up to 59% of those who smoke. Bronchial hyper-responsiveness is common among A1AT-deficient individuals, with asthma reported at a frequency of 4 to 34%.\n\nAmong patients enrolled in the NHLBI Alpha-1-Antitrypsin Deficiency Registry (severe A1AT deficiency, mean age 46 years) who had not been treated with A1AT augmentation therapy and had been followed for at least 6 months and up to 5 years, 5-year mortality was approximately 33% for those with FEV1<50% at enrollment (n=122) and 3% for those with FEV1≥50% at enrollment (n=204)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000409"}},{"Reference":{"value":"/coll/reference_model/doc/RF000418"}},{"Reference":{"value":"/coll/reference_model/doc/RF000419"}},{"Reference":{"value":"/coll/reference_model/doc/RF000417"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM992","properties":{"Key Text":{"value":"Initial evaluations"},"Tier":{"value":"3"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with A1AT deficiency, evaluations of lung (pulmonary function tests, chest CT), liver (including biopsy when clinically indicated), skin (assessment for panniculitis), and vasculature are recommended."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000409"}}]}}}},{"Patient Management":{"value":"ACPM993","properties":{"Key Text":{"value":"Specialist center for clinical management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients identified as having A1AT deficiency should be offered a referral to a specialist center for clinical management of this condition."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000444"}}]}}}},{"Patient Management":{"value":"ACPM991","properties":{"Key Text":{"value":"Augmentation therapy"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Recommendations on the use of A1AT augmentation therapy in patients with A1AT deficiency are conflicting. While guidelines based on evidence do not recommend augmentation therapy."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000444"}},{"Reference":{"value":"/coll/reference_model/doc/RF000420"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC224","properties":{"Recommendation":{"value":"Other guidelines that include expert consensus indicate that augmentation therapy may be considered."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000421"}},{"Reference":{"value":"/coll/reference_model/doc/RF000446"}},{"Reference":{"value":"/coll/reference_model/doc/RF000422"}},{"Reference":{"value":"/coll/reference_model/doc/RF000423"}}]}}}},{"RecommendationID":{"value":"REC223","properties":{"Recommendation":{"value":"Most of these latter recommendations provide specific criteria for treatment such as age (aged 18 or older), severity of A1AT deficiency (A1AT concentration ≤50 mg/dl), smoking status (ex- or former smokers), documented COPD due to emphysema (e.g., FEV1 25-80% of predicted value), and genotype (PI*ZZ or PI*null cases). Studies on the effectiveness of augmentation therapy are conflicting. Nonrandomized registry data studies have reported non-significant improvements in loss of lung density based on CT scans and decline in FEV1. One study of registry data indicated improved survival (relative risk = 0.64, 95% CI: 0.43-0.94). However, these studies may be biased, as subjects were not randomized and decisions about treatment were made by the clinician. Randomized controlled trials published to date are small and report no significant benefit of augmentation therapy. 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There is evidence that adolescents aware of AAT deficiency status are less likely to start smoking than their peers."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000447"}}]}}}}]}}}},{"Circumstance to Avoid":{"value":"ACCA430","properties":{"Key Text":{"value":"Environmental exposures"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Reduction of total personal exposure to occupational dusts, fumes, and gases and to indoor and outdoor air pollutants may be more difficult but should be attempted."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000409"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC047","properties":{"Recommendation":{"value":"The Lung Health Study, which was not specific for A1AT deficiency, evaluated the effects on symptoms of chronic cough, chronic phlegm production, wheezing and shortness of breath. The prevalence of each of the four symptoms in the two intervention groups was significantly less than in the usual care group (p<0.0001). Smokers with early COPD who were assigned to a smoking cessation intervention had fewer respiratory symptoms after 5 years of follow-up."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000444"}}]}}}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 5000"},"Tier":{"value":"4"},"Notes":{"value":"A1AT deficiency results from the presence of one or two deficiency alleles for the SERPINA1 gene.  The protein product of this gene, sometimes referred to as protease inhibitor (PI), can be characterized in the clinical laboratory to determine an individual's A1AT phenotype.  The PI*M phenotype is normal, while PI*Z is the most common deficiency phenotype followed by PI*S.  PI*ZZ reflects a genotype of 2 deficiency alleles and is associated with serum levels of A1AT at 10-20% of normal. PI*ZZ is the genotype of 95% of affected individuals with clinical manifestations of A1AT deficiency. The remaining are linked to PI*SZ and many other rare null (level of A1AT is 0) or other genotypes. Individuals of PI*MM, *MS, *MZ, and *SS genotypes are considered to be at background risk for disease manifestations."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000409"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC057","properties":{"Recommendation":{"value":"Estimated prevalence (1/x):\n               PI*ZZPI*SZPI*SS\nWorldwide:33,3005,0001,250\nAmericans:\nAsian        0         0\nBlack        153,000 17,500\nHispanic        12,000 1,100\nMexican         0         0\nWhite          4,500 1,100"},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000409"}},{"Reference":{"value":"/coll/reference_model/doc/RF000416"}}]}}}}]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE505","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Risk of emphysema:\nPI*ZZ: 80-100% \nPI*SZ: 20-50%\nPI*SS: Background\nNull-Null: 100%"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Identify those at risk to and institute interventions appropriate to severity"}},{"Outcome":{"value":"COPD"}},{"Outcome":{"value":"Liver disease"}},{"Outcome":{"value":"Emphysema"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000409"}}]}}}},{"Penetrance":{"value":"ACPE506","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"Risk of cirrhosis: \nPI*ZZ and age >50: 15-19% \nPI*SZ: Not found\nPI*SS: Not found\nNull-Null: 0%"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Liver disease"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000409"}},{"Reference":{"value":"/coll/reference_model/doc/RF000456"}}]}}}},{"Penetrance":{"value":"ACPE504","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Risk of hepatocellular carcinoma: \nPI*ZZ: 1.5%"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Emphysema"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000409"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR210","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No relative risk estimates were found."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN230","properties":{"Key Text":{"value":"Phenotypic expression varies within and between families. Smoking or occupational exposures can accelerate lung disease, but do not account for all variation in disease expression.  Genetic modifiers that remain poorly understood likely account for some variability."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000409"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI236","properties":{"Key Text":{"value":"Interventions consist of avoidance of smoking and environmental irritants, vaccines to prevent lung and liver infection, non-invasive lung function tests, imaging procedures, and invasive liver biopsy if clinically indicated."},"References":{"value":null}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC229","properties":{"Key Text":{"value":"A poll of 304 individuals diagnosed to have severe A1AT deficiency found an average delay of 7.2 years between the first onset of symptoms and the initial diagnosis of the condition; 43% of respondents reported seeing at least three physicians and 12% reported seeing 6-10 physicians before the correct diagnosis was made."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000419"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC023","properties":{"Recommendation":{"value":"A1AT deficiency is significantly underdiagnosed with as many as 90% of cases going undetected."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000447"}}]}}}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers 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Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Emphysema","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"A1AT augmentation therapy","properties":{"Effectiveness":{"value":"1D"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.3","properties":{"Notes":{"value":"Outcome/Intervention pair (Identify those at risk to and institute interventions appropriate to severity Serum A1AT measurement) is deleted based on request.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36088},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-05-02"},"ReleasedBy":{"value":"ronakypatel","properties":{"First 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{"ActionabilityDocID":{"value":"AC095","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"HMBS","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:4982"},"GeneOMIM":{"value":"609806"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"176000"}}]}}}}]},"Syndrome":{"value":"Acute Intermittent Porphyria","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"176000"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Porphyrias are inherited defects in the biosynthesis of heme. Acute intermittent porphyria, the most common form of porphyria, is an autosomal dominant disorder characterized by recurrent attacks of abdominal pain, gastrointestinal dysfunction, and neurologic disturbances."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Acute Intermittent Porphyria"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"((\"Porphyrias, Hepatic\"[Mesh]) OR \"Porphyria, Acute Intermittent\"[Mesh]) OR \"Hydroxymethylbilane Synthase\"[Mesh]","properties":{"NumberOfHits":{"value":12},"Date":{"value":"2016-09-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":3,"items":[{"SearchString":{"value":"\"acute intermittent porphyria\"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2016-09-14"}}}},{"SearchString":{"value":"Pbgd OR porphobilinogen","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2016-09-14"}}}},{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2016-09-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-09-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2016-09-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-09-14"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"HMBS","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-09-14"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Unknown"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"Yes","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Neurovisceral attacks","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Optimal clinical management to reduce risk of attacks (e.g., avoidance of harmful medications, dietary advice, treatment of infections, avoidance of smoking/alcohol)"}}]}}}},{"Outcome":{"value":"Hepatocellular carcinoma","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver US surveillance"}}]}}}},{"Outcome":{"value":"Morbidity of acute attacks","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Optimal treatment (Hemin) in the event of an attack"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"The prevalence estimates for acute intermittent porphyria (AIP) across all European countries (excluding Sweden) range from 5.4-5.9/1,000,000. In Sweden, the incidence and prevalence of AIP are about 4 times higher than in Europe due to a founder effect."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000451"}},{"Reference":{"value":"/coll/reference_model/doc/RF000425"}},{"Reference":{"value":"/coll/reference_model/doc/RF000426"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"AIP results from half normal activity of the enzyme hydroxymethylbilane synthase (HMBS) involved in the biosynthesis of heme. The condition is characterized by intermittent and sometimes life-threatening acute neurovisceral attacks of severe abdominal pain without peritoneal signs. These attacks may be accompanied by nausea, vomiting, distention, constipation, diarrhea, tachycardia, hypertension, and hyponatremia. Neurologic findings may also occur including mental changes (e.g., insomnia, paranoia), convulsions, hallucinations, peripheral neuropathy (that may progress to respiratory paralysis), pain in extremities, paresis, weakness, and altered consciousness (from somnolence to coma). Attacks may be provoked by certain drugs, crash dieting, alcoholic beverages, smoking, endocrine factors, calorie restriction, stress, and infections or surgery which can increase the demand for hepatic heme. Attacks are usually due to the additive effects of several triggers, including some that are unknown."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000426"}},{"Reference":{"value":"/coll/reference_model/doc/RF000427"}},{"Reference":{"value":"/coll/reference_model/doc/RF000428"}},{"Reference":{"value":"/coll/reference_model/doc/RF000429"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Attacks rarely occur before puberty, usually beginning in the third or fourth decade of life. Attacks are more common in women than men, with acute attacks in women usually related to the menstrual cycle. Most symptomatic individuals with AIP have one or a few attacks. Approximately 5% of patients (mainly women) have recurrent attacks (defined as >4 per year) that may persist for years. Affected individuals may recover from acute attacks within days, but severe attacks that are not promptly treated may take weeks or months. Long term complications can include chronic renal failure, hepatocellular carcinoma (HCC), and hypertension. Some patients experience chronic neuropathic pain, which may account for an increased risk for depression and suicide.  Pregnancy is usually well-tolerated, but it increases attacks in some women. While all individuals with a mutation in HMBS are predisposed to acute attacks, most never have symptoms and are said to have latent (or presymptomatic AIP).  The risk that an individual with latent AIP will later develop symptoms depends on age, sex, exposure to provoking agents, and other factors.  Mortality directly related to acute attacks is now very rare in most countries as a result of improved treatment.  However, sudden death, presumably from cardiac arrhythmia, may occur during an acute attack. Death may also occur as a complication of HCC or liver transplantation."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000426"}},{"Reference":{"value":"/coll/reference_model/doc/RF000427"}},{"Reference":{"value":"/coll/reference_model/doc/RF000428"}},{"Reference":{"value":"/coll/reference_model/doc/RF000429"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM999","properties":{"Key Text":{"value":"Evaluation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with acute AIP the\nfollowing evaluations are recommended:\n\n  • Full clinical history and examination, including neurologic evaluation if symptomatic\n\n  • Review of medications to assess risk versus benefit\n\n  • Quantitation of urine porphobilinogen excretion to establish a baseline for comparison with future measurements taken during symptoms suggestive of active porphyria\n\n  • Referral to a porphyria specialist for more detailed clinical advice on AIP\n\n  • Referral to clinical genetics for counseling"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000426"}}]}}}},{"Patient Management":{"value":"ACPM998","properties":{"Key Text":{"value":"Regular meals"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Regular meals and symptomatic treatment of nausea and loss of appetite are important to help ensure an adequate diet and avoid precipitation of an attack."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000427"}},{"Reference":{"value":"/coll/reference_model/doc/RF000430"}}]}}}},{"Patient Management":{"value":"ACPM995","properties":{"Key Text":{"value":"Medical alert"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should wear medical alert bracelets and carry wallet cards to notify emergency medical personnel and ensure that unsafe drugs are not given to patients in emergencies."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000427"}}]}}}},{"Patient Management":{"value":"ACPM996","properties":{"Key Text":{"value":"Treatment of illness"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals should seek timely treatment of systemic illness or infection."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000426"}}]}}}},{"Patient Management":{"value":"ACPM997","properties":{"Key Text":{"value":"Treatment of acute attacks"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Specific treatment is indicated only in patients with clinical features of an acute attack and increased excretion of porphobilinogen in the urine. In mild attacks (mild pain, no vomiting, no paralysis, no hyponatremia), elimination  of precipitating factors, a high carbohydrate diet, and supportive and symptomatic therapy may be used alone or can be given while awaiting delivery of hemin. Hemin therapy should be started early for most acute attacks, including patients with neuropathy. Many uncontrolled clinical studies suggest a favorable biochemical and clinical response to hemin. In general early initiation of intravenous hemin is associated with improved outcome, and hemin is more effective than glucose in reducing excretion of porphyrin precursors. The only placebo controlled trial of hemin involved 12 patients and found striking decreases in urinal porphobilinogen excretion and trends in clinical benefit (less pain, decreased need for pain medication, and shorter hospital stay); however, the study lacked statistical power to identify a significant difference. In a larger, uncontrolled study of 22 patients and 51 acute attacks treated with hemin, treatment was initiated within 24 hours of admission in 37 attacks (73%). All patients responded (including 2 patients with paresis), and hospitalization was less than 7 days in 90% of cases."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000427"}},{"Reference":{"value":"/coll/reference_model/doc/RF000430"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU537","properties":{"Key Text":{"value":"Liver ultrasound"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Periodic (annual) liver ultrasound should be considered for individuals aged >50 years with previous overt or asymptomatic disease who ask to be tested after careful discussion of the likely risks and benefits. A case-control study of HCC screening in DNA-diagnosed AIP carriers included 62 patients (57% with a history of acute attacks) with 15 years follow up. Patients were screened every 1-1.5 years and were compared with gene carriers who had never been screened, screened for the first time, screened at intervals of >2 years, or drop outs. Over the 15 years of follow up 22 patients developed HCC. Surgery was an option for 7/8 patients in the screened group compared to 4/14 patients in the control group (p=0.024). All individuals with HCC in the control group died during the study (all from HCC except for one prostate cancer) versus 2 patients from the screened group (1 from anaplastic pulmonary cancer and one from HCC). Those who underwent screening had significantly improved 3- and 5-year survival rates. An excess risk of hepatocellular cancer has been reported in Swedish patients with API. As Sweden has a relatively high prevalence of AIP due to a founder effect, it is uncertain to what extent the finding is generalizable to other populations and whether early intervention through screening can improve outcomes."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000431"}},{"Reference":{"value":"/coll/reference_model/doc/RF000432"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM355","properties":{"Key Text":{"value":"Family management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"If the HMBS pathogenic variant is known in a family, at-risk relatives can benefit from molecular genetic testing to clarify their genetic status, so that those at increased risk of developing acute attacks of AIP can be identified early and counseled about preventive measures (see Patient Management and Circumstances to Avoid).("},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000426"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA434","properties":{"Key Text":{"value":"Avoidance of triggers"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should avoid alcohol, smoking, medications, and illicit drugs that can induce exacerbations."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000427"}},{"Reference":{"value":"/coll/reference_model/doc/RF000430"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC049","properties":{"Recommendation":{"value":"A retrospective population based study in Sweden included 356 gene carriers. Among these patients clinical manifestations of AIP were identified in 42%. Self-reported smoking was associated with high attack frequency (>10 attacks) (OR 1.62, CI 1.07-11.46) compared with non-smokers adjusted for age and gender. In addition, other self-reported triggers included medication use (20%), fasting (19%), physical strain (12%), psychological strain (31%), alcohol (14%), work environment (8%), infections (15%), menstruation (32%), and pregnancy (9%)."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000433"}}]}}}},{"RecommendationID":{"value":"REC048","properties":{"Recommendation":{"value":"A study of 145 Finnish patients with AIP found that almost all of these patients had been exposed to prescription drugs or anesthetics included in the lists of unsafe drugs and use was never associated with an acute attack. Among 37 individuals reporting alcohol use only 3 reported an acute attack related to drinking; however, a majority reported some milder symptoms with heavy drinking being more risky."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000434"}}]}}}}]}}}},{"Circumstance to Avoid":{"value":"ACCA433","properties":{"Key Text":{"value":"Labor and Delivery"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Prolonged fasting should be avoided during labor and delivery, as should the use of unsafe drugs, for example, ergometrine. Stress should be minimized by providing good analgesia in the form of spinal or epidural anesthesia using bupivacaine (which has been safely used)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000426"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 10000"},"Tier":{"value":"Not provided"},"Notes":{"value":"The prevalence of the genetic mutation is estimated at 1-2 per 10,000 in Europe. Some countries, including Sweden have a higher prevalence due to founder effects in those populations."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000431"}}]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE507","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"2"},"Notes":{"value":"The penetrance for clinical manifestations of an HMBS pathogenic variant is not accurately known. \n\nApproximately 80% of carriers of a gene mutation remain asymptomatic and others may have only 1 or a few acute attacks throughout life."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurovisceral attacks"}},{"Outcome":{"value":"Hepatocellular carcinoma"}},{"Outcome":{"value":"Morbidity of acute attacks"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000427"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC065","properties":{"Recommendation":{"value":"In one study of Swiss patients, 52% of relatives ascertained through cascade screening were found to have \"typical\" clinical symptoms.  However, most reviews written by experienced porphyria specialists quote a penetrance, by which they imply an acute attack, leading to a hospital admission for medical management, of 10%-20%. Population surveys suggest a lower figure (e.g. a penetrance estimate of about 1% in France.)"},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000426"}}]}}}}]}}}},{"Penetrance":{"value":"ACPE508","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"One retrospective study of mortality in a US population of 136 patients with AIP over a 50-year period did not identify any cases of HCC, but follow-up data were not available in 22% of this cohort. An increased incidence of HCC has been reported for patients with AIP in a large prospective study in France with 5 cases of HCC developing among 430 patients over 7 years. In Switzerland, two cases of HCC occurred among 205 subjects with AIP during a 15-year period. The largest increase in risk for HCC appears to occur in Swedish patients with one 15 year prospective study identifying HCC among 22 of the 62 AIP gene carriers participating in regular screening. A recent prospective study identified a 63 - fold greater incidence per million inhabitants of this complication of AIP in Sweden than in the other countries (France, Netherlands, Switzerland, UK)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Hepatocellular carcinoma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000431"}}]}}}},{"Penetrance":{"value":"ACPE509","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":""},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Morbidity of acute attacks"}}]},"References":{"value":null,"items":[]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR211","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was identified."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN231","properties":{"Key Text":{"value":"Attacks are highly variable within and between individuals."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000426"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI237","properties":{"Key Text":{"value":"Recommended interventions include period liver ultrasound and avoidance of circumstances that may precipitate an attack. \n\n\nAdministration of hemin may cause a transient anticoagulant effect and often phlebitis at the site of infusion. Phlebitis can be severe and can compromise venous access with repeated administration. Other uncommon reported side effects of hemin include fever, aching, malaise, or hemolysis. Rare cases of circulatory collapse and renal failure have been reported."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000427"}}]},"Tier":{"value":"Not provided"}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC230","properties":{"Key Text":{"value":"Delayed diagnosis and treatment may contribute to the higher death rate among those with AIP. Attacks usually do not begin until the third or fourth decade of life."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000427"}},{"Reference":{"value":"/coll/reference_model/doc/RF000426"}}]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers Present":{"value":9,"items":[{"Scorer":{"value":"bieseckerl"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"williamsm"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"sobreiran"}}]},"Notes":{"value":"*Scores where the tier of evidence recommendation of the working group differs from the evidence level tier in the Summary Report."}}},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Neurovisceral attacks","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Optimal clinical management to reduce risk of attacks (e.g., avoidance of harmful medications, dietary advice, treatment of infections, avoidance of smoking/alcohol)","properties":{"Overall Score":{"value":"9CB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Hepatocellular carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver US surveillance","properties":{"Overall Score":{"value":"10CC"},"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"Scores where the tier of evidence recommendation of the working group differs from the evidence level tier in the Summary Report."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity of acute attacks","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Optimal treatment (Hemin) in the event of an attack","properties":{"Overall Score":{"value":"10CB"},"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":9,"items":[{"FinalScoreOfScorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Neurovisceral 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{"ActionabilityDocID":{"value":"AC097","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"CBS","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:1550"},"GeneOMIM":{"value":"613381"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"236200"}}]}}}}]},"Syndrome":{"value":"Homocystinuria due to Cystathionine Beta-Synthase Deficiency","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"236200"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":""},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"CBS Deficiency"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"\"Homocystinuria\"[Mesh]","properties":{"NumberOfHits":{"value":10},"Date":{"value":"2016-04-20"}}}},{"SearchString":{"value":"\"classic homocystinuria\" (CBS deficiency maps to homocystinuria MeSH 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Thromboembolism","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements)","properties":{"FullName":{"value":"Enter value here..."}}}},{"Intervention":{"value":"Prophylactic anti-coagulation in pregnancy"}}]}}}},{"Outcome":{"value":"Pyridoxine Responsive: Systemic manifestations (includes CNS disease, skeletal findings, and ocular findings)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements)","properties":{"FullName":{"value":"Enter value here..."}}}}]},"FullName":{"value":"Enter value here..."}}}},{"Outcome":{"value":"Pyridoxine Non-Responsive: Thromboembolism","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 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However, these estimates are based on newborn screening and clinical ascertainment and are likely underestimates due to undetected cases. A recent systematic review estimated of the prevalence as about 1/120,000 worldwide."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}},{"Reference":{"value":"/coll/reference_model/doc/RF000440"}},{"Reference":{"value":"/coll/reference_model/doc/RF000450"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Homocystinuria due to CBS deficiency is a disorder of methionine metabolism. There are two recognized phenotypic variants: B₆-responsive and B₆-non-responsive.  B₆-responsive is typically, but not always, milder with a later age of onset than B₆-non-responsive. In general, homocystinuria is characterized by involvement of four systems:\n\n•  Ocular system:  Ectopia lentis is a hallmark feature. Severe myopia may also be present either in the presence or absence of ectopia lentis. \n•  Skeletal system:  Patients may have skeletal abnormalities such as excessive height and limb length. Affected individuals are often tall and slender with a 'marfanoid' habitus, and are prone to osteoporosis. \n•  Vascular system:   The cardinal vascular sign is thromboembolism which can affect both small and large arteries and veins. \n•  Central nervous system (CNS):   Intellectual disability/developmental delay is the most common CNS manifestation. Though IQ can range widely from 10 to 138. Seizures, extrapyramidal signs (e.g., dystonia) and psychiatric problems (e.g, depression, obsessive-compulsive disorder) may also occur. \n\nSome patients have been reported to have a milder form of homocystinuria, which is characterized by an increased risk for thrombotic events in young adulthood, but without the other ocular, skeletal, or nervous system manifestations."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000441"}},{"Reference":{"value":"/coll/reference_model/doc/RF000439"}},{"Reference":{"value":"/coll/reference_model/doc/RF000450"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"In general, patients appear normal at birth but have a progressive disease course if untreated.  Clinical features typically manifest in the first or second decade of life. Intellectual disability may be the first recognizable sign and may present as developmental delay after the first to second year of life. Myopia typically occurs after age one with the majority of untreated individuals developing ectopia lentis by age 8. Roughly half of patients show signs of osteoporosis by their teens. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier.  Thromboembolism is the major cause of early death and morbidity. Among B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature. Pregnancy often increases the risk of thromboembolisms, especially in the post-partum period. However, most pregnancies are uncomplicated."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000441"}},{"Reference":{"value":"/coll/reference_model/doc/RF000439"}},{"Reference":{"value":"/coll/reference_model/doc/RF000450"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1003","properties":{"Key Text":{"value":"Procedures at initial diagnosis"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in all individuals diagnosed with homocystinuria caused by CBS deficiency, the following are recommended:\n\n•  Pyridoxine (vitamin B₆) challenge prior to treatment to determine B₆-responsiveness\n•  Medical genetics consultation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}},{"Reference":{"value":"/coll/reference_model/doc/RF000450"}}]}}}},{"Patient Management":{"value":"ACPM1002","properties":{"Key Text":{"value":"Pyridoxine"},"Tier":{"value":"4"},"Recommendation Text":{"value":"In B₆-responsive patients, treatment with pyridoxine should be given. Pyridoxine may also be included in treatment despite evidence of B₆-non-responsiveness. For those that are responsive to pyridoxine, it remains debatable as to whether pyridoxine alone or in combination with other measures provides the optimal biochemical control."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}},{"Reference":{"value":"/coll/reference_model/doc/RF000450"}}]}}}},{"Patient Management":{"value":"ACPM1000","properties":{"Key Text":{"value":"Dietary modifications"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Dietary modifications:\n\n•  B₆-non-responsive and most B₆-responsive patients require a methionine-restricted diet which should be continued indefinitely.  Dietary treatment reduces methionine intake by restricting natural protein intake. To prevent protein malnutrition, a methionine-free amino acid formula supplying the other amino acids including cysteine is provided. This diet is often not tolerated if begun in mid-childhood or later. This diet has been shown to normalize plasma homocysteine levels and prevent clinical manifestations when initiated neonatally. When initiated in late detected cases in whom clinical disease may already be present, no reversal of abnormalities present have been noted, but further progression of complications seems to be halted or ameliorated. In a study of 629 patients, B₆-nonresponsive patients identified neonatally who were administered a methionine-restricted diet had higher IQs and retarded rate of lens dislocation compared to late-detected B₆-nonresponsive patients who were not administered a methionine-restricted diet. Further, patients with both neonatal and late-detected patients had lower rates of thrombotic events then expected without treatment. In a second study, B₆-nonresposive patients diagnosed at birth and compliant with treatment had a full-scale IQ of 105.8 (range 84-120) while the poorly compliant group had a mean full-scale IQ of 80.8 (range 40-103)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}},{"Reference":{"value":"/coll/reference_model/doc/RF000450"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC228","properties":{"Recommendation":{"value":"•  Betaine, which converts homocysteine to methionine, may be added to the treatment regimen in individuals poorly compliant with dietary treatment or may become the major treatment modality in those intolerant of the diet.  Betaine supplementation has been shown to substantially reduce homocysteine concentrations when among 5 B₆-non-responsive individuals who could not attain metabolic control on diet."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}},{"Reference":{"value":"/coll/reference_model/doc/RF000450"}}]}}}},{"RecommendationID":{"value":"REC225","properties":{"Recommendation":{"value":"•  Supplementation with folate and vitamin B₁₂ is recommended to optimize the conversion of homocysteine to methionine by methionine synthase, thus helping to decrease homocysteine concentrations."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}}]}}}},{"RecommendationID":{"value":"REC227","properties":{"Recommendation":{"value":"•  In a study of 32 patients receiving treatment with pyridoxine, folic acid, and vitamin B₁₂: 17 B₆-reponsive patients maintained plasma total free homocysteine levels <20μmol/L over an average treatment period of 16.6 years, while 15 B₆-non-responsive (who also received betaine) maintained low plasma total free homocysteine levels over an average period of 11 years (mean = 33±17 μmol/L). There were 2 vascular events in B₆-reponsive group, compared to 11 expected based on rates among untreated patients. There were no vascular events in the B₆-non-responsive group, compared to 10 expected."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000442"}}]}}}},{"RecommendationID":{"value":"REC226","properties":{"Recommendation":{"value":"•  A study of 5 patients with good control of plasma homocysteine through pyridoxine, diet, betaine, and folic acid reported that all patients had bone mineral densities within the normal range with no significant change in skeletal morphology."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000443"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1001","properties":{"Key Text":{"value":"Prophylactic coagulation"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Because women with homocystinuria may be at greater than average risk for thromboembolism, especially post-partum, prophylactic anticoagulation during the third trimester of pregnancy and post-partum is recommended.  Maternal homocystinuria does not have a major teratogenic potential. However, treatment with pyridoxine and/or methionine-restricted diet should be continued during pregnancy. Betaine may also be continued. The exact the risk of a thromboembolism event during pregnancy and post-partum is unclear, as the evidence of fatal and near-fatal thromboembolic events in untreated women is limited to single case studies. The evidence for the effectiveness of anticoagulants is also limited.  The largest study to date reported 15 pregnancies in 11 women, where 2 of the 5 pyridoxine non-responsive and 3 of the 6 pyridoxine responsive cases were administered anticoagulants. Of the 15 pregnancies, there was only one thrombotic event (superficial thrombophlebitis of the leg) in a pyridoxine responsive case not administered anticoagulants. The remaining evidence includes case studies of women treated with dietary modification (including protein-restriction, pyridoxine, vitamin B12, and betaine) and anticoagulants during pregnancy reported good maternal and fetal outcomes  However, additional case studies report thrombotic events even after anticoagulant therapy."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU539","properties":{"Key Text":{"value":"Monitored for clinical complications"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Affected individuals should be monitored at regular intervals to detect any clinical complications to allow appropriate therapy to be given as soon as possible"},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}}]}}}},{"Surveillance":{"value":"ACSU538","properties":{"Key Text":{"value":"Homocysteine/methionine concentrations"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Plasma total homocysteine and methionine concentrations should be monitored in all persons receiving betaine."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM356","properties":{"Key Text":{"value":"Plasma amino acids and homocysteine"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Plasma concentrations of amino acids and total homocysteine should be measured in all at-risk siblings as soon as possible after birth so that morbidity and mortality can be reduced by early diagnosis and treatment."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}}]}}}},{"Family Management":{"value":"ACFM358","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"4"},"Recommendation Text":{"value":"If the CBS pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of the siblings."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}}]}}}},{"Family Management":{"value":"ACFM357","properties":{"Key Text":{"value":"Parent screening"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Because it is possible (though unlikely) that a parent has homocystinuria but has remained asymptomatic, it is appropriate to obtain a detailed medical history and perform an exam as well as plasma and urine amino acid analysis in both parents."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA436","properties":{"Key Text":{"value":"Oral contraceptives"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Oral contraceptives, which may tend to increase coagulability and increase the risk for thromboembolism, should be avoided in females with homocystinuria."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA435","properties":{"Key Text":{"value":"Surgery"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Surgery should be avoided, if possible, due to the increase in homocysteine concentrations during surgery and post-surgery which increases the risk for a thromboembolic event. If surgery is required, intravenous fluids at 1.5 times maintenance should be administered before, during, and after surgery until oral fluids are taken, with close monitoring to avoid fluid overload."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Tier":{"value":"3"},"Notes":{"value":"Most individuals worldwide are compound heterozygotes for novel pathogenic variants of CBS. No overall estimate of CBS mutation prevalence was found, though this estimate would be expected to be similar to the prevalence of homocystinuria due to CBS deficiency (estimates range from 1/120,000 to 1/344,000)."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE510","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Among untreated homocystinuria patients, age-related penetrance estimates are:\n\nEctopia lentis (by age 10): B₆-responsive=55%, B₆-nonresponsive=82%\nVascular event (by age 15): B₆-responsive=12%, B₆-nonresponsive=27%\nSpinal osteoporosis (by age 15): B₆-responsive=36%, B₆-nonresponsive=64%\nMortality (by age 30): B₆-responsive=4%, B₆-nonresponsive=23%\n\nIn addition, 51% of patients will have clinically significant psychiatric disorders, and 21% will have seizures if untreated."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Thromboembolism"}},{"Outcome":{"value":"Systemic manifestations"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000441"}},{"Reference":{"value":"/coll/reference_model/doc/RF000450"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR212","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was found."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN232","properties":{"Key Text":{"value":"The clinical picture is extremely heterogeneous with clinical findings ranging from multiple organ disease to individuals with no overt clinical involvement."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}},{"Reference":{"value":"/coll/reference_model/doc/RF000450"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI238","properties":{"Key Text":{"value":"Pyridoxine usually has no side effects when used in recommended doses. Sensory neuropathy and ataxia has been reported in some adults with misuse of megadoses, though symptoms improved with withdrawal of pyridoxine.\n\nBetaine has few side effects, and the increase in methionine produced is usually harmless. Some individuals develop a detectable body odor resulting in reduced compliance. Cerebral edema has occurred with extreme hypermethioninemia, resolved with discontinuation of betaine.\n\nA methionine-restricted diet may be burdensome, especially if begun in mid-childhood or later."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000439"}},{"Reference":{"value":"/coll/reference_model/doc/RF000450"}}]},"Tier":{"value":"Not provided"}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC231","properties":{"Key Text":{"value":"Most cases of B₆-non-responsive homocystinuria due to CBS deficiency are identified by newborn screening. However, milder B₆-responsive cases are preferentially missed given they rarely have elevated levels of methionine during the first two to three days of life."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000450"}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers Present":{"value":9,"items":[{"Scorer":{"value":"bieseckerl"}},{"Scorer":{"value":"weaverm"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"williamsm"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"sobreiran"}}]}}},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Pyridoxine Responsive: Thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements)","properties":{"Overall Score":{"value":"9CC"},"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Prophylactic anti-coagulation in pregnancy","properties":{"Overall Score":{"value":"8CC"},"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Pyridoxine Responsive: Systemic manifestations (includes CNS disease, skeletal findings, and ocular findings)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements)","properties":{"Overall Score":{"value":"8CC"},"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Pyridoxine Non-Responsive: Thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements)","properties":{"Overall Score":{"value":"8CC"},"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Prophylactic anti-coagulation in pregnancy","properties":{"Overall Score":{"value":"8CC"},"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Pyridoxine Non-Responsive: Systemic manifestations (includes CNS disease, skeletal findings, and ocular findings","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements)","properties":{"Overall Score":{"value":"8CC"},"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":0,"items":[]}}},"Scorers":{"value":9,"items":[{"Scorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Prophylactic anti-coagulation in pregnancy","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Systemic manifestations","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3A"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Thromboembolism","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"1"}}}},{"Intervention":{"value":"Prophylactic anti-coagulation in pregnancy","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"1"}}}}]}}}},{"Outcome":{"value":"Systemic manifestations","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"1"}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Prophylactic anti-coagulation in pregnancy","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Systemic manifestations","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First 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Name":{"value":"Lee"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Prophylactic anti-coagulation in pregnancy","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Systemic manifestations","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Prophylactic anti-coagulation in pregnancy","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Systemic manifestations","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Prophylactic anti-coagulation in pregnancy","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Systemic manifestations","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Prophylactic anti-coagulation in pregnancy","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Systemic manifestations","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"Scorer":{"value":"sobreiran","properties":{"First Name":{"value":"Nara"},"Last Name":{"value":"Sobreira"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Prophylactic anti-coagulation in pregnancy","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Systemic manifestations","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modifications","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"correcting to include the gene-disease pair.\nInternal system migration related to score text replacement from E to 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{"ActionabilityDocID":{"value":"AC098","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"BTD","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:1122"},"GeneOMIM":{"value":"609019"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"253260"}}]}}}}]},"Syndrome":{"value":"Biotinidase Deficiency","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"253260"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"- Biotinidase deficiency is a form of multiple carboxylase deficiency\r- Characterized by cutaneous and neurologic abnormalities\r- Symptoms are due to the patient's inability to reutilize biotin, a necessary nutrient"},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Biotinidase deficiency (AR)"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"\"Biotinidase Deficiency\"[Mesh]","properties":{"NumberOfHits":{"value":4},"Date":{"value":"2016-04-04"}}}},{"SearchString":{"value":"\"Multiple Carboxylase Deficiency\"[Mesh]","properties":{"NumberOfHits":{"value":4},"Date":{"value":"2016-04-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-04-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-04-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-04-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-04-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-04-04"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological complications","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Biotin therapy"}}]}}}},{"Outcome":{"value":"Cutaneous manifestations","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Biotin therapy"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"Worldwide screening of biotinidase deficiency (BTD) has estimated an incidence of 1/137,401 for profound BTD and 1/109,921 for partial BTD, with a combined incidence of 1/61,067. Based on US newborn screening outcome data from 2007 to 2008, the incidence of profound biotinidase deficiency is estimated at 1/80,000 births and that of partial biotinidase deficiency 1/31,000-1/40,000. Incidence estimates are higher in Hispanic and lower in African American populations."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000272"}},{"Reference":{"value":"/coll/reference_model/doc/RF000273"}},{"Reference":{"value":"/coll/reference_model/doc/RF000435"}},{"Reference":{"value":"/coll/reference_model/doc/RF000275"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"BTD is an inborn error of metabolism due to reduced activity of biotinidase, an enzyme essential for recycling biotin. Profound BTD is due to <10% of mean normal serum biotinidase activity, while partial BTD is due to 10-30% of mean enzyme activity. If untreated, patients with profound BTD usually exhibit neurologic abnormalities (seizures, hypotonia, ataxia, developmental delay, and sensorineural vision problems and hearing loss), cutaneous abnormalities (alopecia, skin rash, and/or candidiasis), and respiratory problems. Metabolically, patients may also have ketolactic acidosis, organic academia, and mild hyperammonemia. A milder expression of these symptoms may occur in patients with partial BTD."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000272"}},{"Reference":{"value":"/coll/reference_model/doc/RF000273"}},{"Reference":{"value":"/coll/reference_model/doc/RF000435"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Symptoms of untreated profound BTD usually appear between ages 1 week and 10 years, with a mean age of 3.5 months. In a few cases, individuals with profound BTD have remained asymptomatic or developed symptoms after adolescence. Patients with partial BTD are typically asymptomatic, but may develop symptoms such as hypotonia, skin rash, and hair loss during periods of stress (e.g., illness, infection, fever, or fasting). Individuals who are diagnosed before they develop symptoms and are treated with biotin have normal development. Symptomatic individuals improve with biotin therapy, with the exception of vision problems, hearing loss, and developmental delay which are usually irreversible."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000272"}},{"Reference":{"value":"/coll/reference_model/doc/RF000273"}},{"Reference":{"value":"/coll/reference_model/doc/RF000435"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1005","properties":{"Key Text":{"value":"Evaluations after diagnosis"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with BTD, the following evaluations are recommended:\n\n\n•History of seizures, balance problems, feeding problems, breathing problems, loss of hair, fungal infections, skin rash, and conjunctivitis\n\n•Physical examination for hypotonia, ataxia, eye findings, eczematous skin rash, alopecia, conjunctivitis, breathing abnormalities, thrush, and candidiasis\n\n•Evaluation for sensorineural hearing loss and psychomotor deficits\n\n•Identification of biochemical abnormalities such as metabolic ketolactic acidosis, hyperammonemia and organic aciduria\n\n•Identification of cellular immunologic abnormalities\n\n•Quantitative determination of biotinidase enzyme activity in serum/plasma\n\n•Medical genetics consultation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000272"}}]}}}},{"Patient Management":{"value":"ACPM1004","properties":{"Key Text":{"value":"Biotin therapy"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Information specific to treatment of an individual diagnosed as an adult was not identified.  All individuals with profound BTD, even those with some residual biotinidase enzyme activity, should have lifelong treatment with biotin (typical dosage is 5-10mg per day). Because there is no known toxicity for biotin, children with partial BTD are usually treated with 1-10mg oral biotin per day. Biotin is an effective treatment of BTD. Children with BTD identified by newborn screening will remain asymptomatic with biotin therapy. All symptomatic children with BTD have improved after treatment with biotin. The biochemical abnormalities and seizures rapidly resolve after biotin therapy, followed by improvement of cutaneous abnormalities. Hair growth returns over a period of weeks to months in children who have alopecia. Optic atrophy and hearing loss may be resistant to therapy, especially if a long period has elapsed between onset and initiation of treatment. Some treated children have rapidly achieved developmental milestone, whereas others have continued to show developmental delay."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000273"}},{"Reference":{"value":"/coll/reference_model/doc/RF000272"}},{"Reference":{"value":"/coll/reference_model/doc/RF000435"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU540","properties":{"Key Text":{"value":"General surveillance"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Information specific to surveillance of an individual diagnosed as an adult was not identified.  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{"ActionabilityDocID":{"value":"AC099","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"NOTCH3","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:7883"},"GeneOMIM":{"value":"600276"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"125310"}}]}}}}]},"Syndrome":{"value":"Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukocenphalopathy, type 1","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"125310"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Progressive disorder of the small arterial vessels of the brain manifest by migraine, strokes, and white matter lesions, with resultant cognitive impairment in some."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"CADASIL1"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"(\"CADASIL\"[Mesh]) OR \"NOTCH3 protein, human\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":10},"Date":{"value":"2016-07-28"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":4,"items":[{"SearchString":{"value":"CADASIL","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-07-28"}}}},{"SearchString":{"value":"NOTCH3","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-07-28"}}}},{"SearchString":{"value":"Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-07-28"}}}},{"SearchString":{"value":"CASIL","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-07-28"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-07-28"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2016-07-28"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-07-28"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-07-28"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Stroke","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Specialist care and management"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"The exact prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is not known and is probably underdiagnosed. Multiple small and national registries have estimated the minimum prevalence between 2 and 4 per 100,000 in Europe."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000436"}},{"Reference":{"value":"/coll/reference_model/doc/RF000437"}},{"Reference":{"value":"/coll/reference_model/doc/RF000438"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"CADASIL is a disease of the small to medium-sized arteries, mainly affecting the brain. It is characterized by mid-adult onset of recurrent ischemic stroke (related to small vessel pathology), cognitive decline progressing to dementia, migraine with aura, mood disturbances/psychiatric disorders (variable, from personality changes to severe depression), and apathy (may be independent of depression).  Diffuse white matter lesions and subcortical infarcts are present on neuroimaging. Less common signs include reversible acute encephalopathy and epilepsy."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000436"}},{"Reference":{"value":"/coll/reference_model/doc/RF000437"}},{"Reference":{"value":"/coll/reference_model/doc/RF000438"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"The presenting symptoms, age at onset, and disease progression in CADASIL are variable. Migraine with aura occurs in 30%-40% of individuals with CADASIL. When present, it can be the first symptom, with a mean age of onset of 30 years (age range 6-48 years). Of those with migraine, 90% have migraine with aura. Transient ischemic attacks and ischemic stroke, the most frequent presentation, are present in 85% of symptomatic individuals. They occur at a mean age of 47 years (age range 20-70 years), in most cases without conventional vascular risk factors.  Ischemic episodes are often recurrent, leading to severe disability with gait disturbance, urinary incontinence, and pseudobulbar palsy. Cognitive decline, the second most frequent feature, may start as early as 35, with approximately 75% of affected individuals developing dementia. Cognitive decline usually manifests initially with executive dysfunction (mild cognitive impairment) and is progressive with a concurrent stepwise deterioration due to recurrent strokes. Mood disturbances/psychiatric disorders occur in about 30% of affected individuals, and apathy has been described in 40%. Epilepsy occurs in 10% of individuals and presents in middle age, usually secondary to stroke. Brain imaging abnormalities evolve as the disease progresses. MRI white matter hyperintensities, although sometimes very subtle, can be visualized from age 21 years onward. In the course of the disease, the load of white matter hyperintensity lesions increases, eventually coalescing to the point where, in some elderly individuals, normal-appearing white matter is barely distinguishable. \n\n\nPrognosis of CADASIL is poor. Based on a study of 411 individuals, the median age at onset of inability to walk without assistance was approximately 60 years old and the median age at which individuals became bedridden was 64 years. The median age at death was 68 years with a more rapid disease progression in men than in women. The most common cause of death was pneumonia, followed by sudden unexpected death and asphyxia."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000437"}},{"Reference":{"value":"/coll/reference_model/doc/RF000436"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1011","properties":{"Key Text":{"value":"Initial evaluations"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Initial evaluation of all patients should include:\n\n•  Neurologic evaluation, therapeutic management, and follow-up\n\n•  Psychological evaluation of cognitive disorders\n\n•  Brain MRI for overall assessment and follow-up\n\n•  Cervical and transcranial echodoppler for examination for associated atheromatous lesions\n\n•  Resting ECG\n\n•  Holter blood pressure\n\n•  Biochemical evaluation: complete blood count, C-reactive protein, fasting blood glucose, exploration of lipid abnormality (cholesterol, triglycerides, HDL, calculated LDL)"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000448"}}]}}}},{"Patient Management":{"value":"ACPM1009","properties":{"Key Text":{"value":"Antiplatelet therapy"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Antiplatelet therapy is frequently used, but has not been proven effective in CADASIL."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000436"}}]}}}},{"Patient Management":{"value":"ACPM1006","properties":{"Key Text":{"value":"Balanced diet"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should maintain a balanced diet aimed at controlling possible factors such as vascular risk associated with the disease."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000448"}}]}}}},{"Patient Management":{"value":"ACPM1007","properties":{"Key Text":{"value":"Monitoring during anesthesia"},"Tier":{"value":"2"},"Recommendation Text":{"value":"During surgery requiring anesthesia, patients should be monitored for cerebral region oxygen saturation and with close ECG monitoring. Invasive arterial blood pressure is recommended in the most invasive surgical procedures or if major blood loss is expected."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000449"}}]}}}},{"Patient Management":{"value":"ACPM1008","properties":{"Key Text":{"value":"Cholinesterase inhibitors"},"Tier":{"value":"1"},"Recommendation Text":{"value":"A systematic review of cholinesterase inhibitors included one RCT of donepezil in patients with CADASIL and documented cognitive impairment (n=161). After 18 weeks of treatment, no significant effects were found on primary cognitive scales and other measurements. However, some improvement was found on two secondary outcome measures of executive functioning."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000438"}}]}}}},{"Patient Management":{"value":"ACPM1010","properties":{"Key Text":{"value":"Psychological counseling"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Psychological counseling should be offered to patients and their families in order to give emotional support."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000437"}},{"Reference":{"value":"/coll/reference_model/doc/RF000436"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU541","properties":{"Key Text":{"value":"Neurologist follow-up"},"Tier":{"value":"4"},"Recommendation Text":{"value":"There are no standard international surveillance guidelines for CADASIL. However, yearly follow up by a neurologist with expertise in CADASIL is recommended from the time of diagnosis."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000436"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM360","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Testing of at-risk asymptomatic adult relatives of individuals with CADASIL is possible after molecular genetic testing has identified the specific NOTCH3 pathogenic variants in the family. Such testing should be performed in the context of formal genetic counseling."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000436"}},{"Reference":{"value":"/coll/reference_model/doc/RF000437"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA441","properties":{"Key Text":{"value":"Angiography and anticoagulants"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Angiography and anticoagulants are contraindicated in CADASIL as they may provoke cerebrovascular accidents."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000436"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA440","properties":{"Key Text":{"value":"Smoking"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Smoking increases the risk of stroke of individuals with CADASIL and should be avoided. One study of 127 patients with CADASIL reported that smoking was associated with an earlier onset of stroke/TIA."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000436"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA439","properties":{"Key Text":{"value":"Thrombolytic therapy"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Thrombolytic therapy (intravenous thrombolysis) is contraindicated because of the presumed increased risk for cerebral hemorrhage."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000436"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA438","properties":{"Key Text":{"value":"Hypo- and hypercapnia"},"Tier":{"value":"2"},"Recommendation Text":{"value":"In the context of anesthesia, both hypo- and hypercapnia should be avoided because of the limits of autoregulation of the diseased vessels are not known."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000449"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Tier":{"value":"3"},"Notes":{"value":"More than 95% of individuals with CADASIL have pathogenic variants in NOTCH3, and CADASIL is estimated to have close to 100% penetrance. Thus the prevalence of genetic mutations associated with CADASIL should be similar to the prevalence of CADASIL (estimated between 2 and 4 per 100,000)."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000436"}},{"Reference":{"value":"/coll/reference_model/doc/RF000437"}},{"Reference":{"value":"/coll/reference_model/doc/RF000438"}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE514","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Penetrance of CADASIL is probably 100%."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Stroke"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000436"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC066","properties":{"Recommendation":{"value":"Frequency among symptomatic individuals with CADASIL:\n\n\nTransient ischemic attacks and strokes = 85%\n\nDementia = 75%\n\nMigraine = 30-40%\n\nMood disturbances = 30%\n\nApathy = 40%\n\nEpilepsy = 10%."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000436"}}]}}}}]}}}},{"Penetrance":{"value":"ACPE515","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":""},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Stroke"}}]},"References":{"value":null,"items":[]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR214","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information on relative risk was not available."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN234","properties":{"Key Text":{"value":"CADASIL clinical expression varies in age of onset, severity of the clinical symptoms, and progression of the disease. The clinical presentation also varies among and within families."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000436"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI240","properties":{"Key Text":{"value":"Most interventions associated with CADASIL are avoidance of procedures, situations, and substances that could lead to cardiovascular episodes, which are associated with minimal risk and burden. 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Without treatment, patients with MFS with aortic dissection have a reduced long-term survival, 50-70% at 10 years after diagnosis of aortic dissection. Survival in patients with MFS has been significantly improved with medical and surgical management of the aortic disease and may approach that of the general population. There are no ethnic/racial or gender differences observed. 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{"ActionabilityDocID":{"value":"AC101","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"MEFV","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:6998"},"GeneOMIM":{"value":"608107"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"249100"}}]}}}}]},"Syndrome":{"value":"Familial Mediterranean Fever (AR)","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"249100"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":""},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Familial Mediterranean Fever, AR"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"(\"Familial Mediterranean Fever\"[Mesh]) OR \"marenostrin\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":24},"Date":{"value":"2016-05-23"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":3,"items":[{"SearchString":{"value":"MEFV","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-05-23"}}}},{"SearchString":{"value":"mediterranean fever","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-05-23"}}}},{"SearchString":{"value":"polyserositis","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-05-23"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-05-23"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-05-23"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-05-23"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"HuGE review AND MEFV; HuGE review AND mediterranean fever","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-05-23"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Recurrent serositis","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colchicine"}}]}}}},{"Outcome":{"value":"Amyloidosis","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colchicine"}}]}}}},{"Outcome":{"value":"Joint problems","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colchicine"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 1000"},"Notes":{"value":"Familial Mediterranean Fever (FMF) predominantly affects populations living in the southeastern Mediterranean region. Populations having a high prevalence (1/200-1/1000) include non-Ashkenazi Jews, Armenians, Turks, and Arabs. FMF is also seen in many other countries, although in much lower numbers."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000477"}},{"Reference":{"value":"/coll/reference_model/doc/RF000478"}},{"Reference":{"value":"/coll/reference_model/doc/RF000479"}},{"Reference":{"value":"/coll/reference_model/doc/RF000483"}},{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"FMF is an autoinflammatory fever syndrome characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritic, and, rarely, pericarditis and meningitis. Attacks can vary in frequency (as often as once a week or every few years), typically last 1-4 days, and resolve spontaneously.  Mild symptoms (myalgia, headache, nausea, dyspnea, arthralgia, low back pain, asthenia and anxiety) precede attacks and last about 17 hours in approximately 50% of patients. Attacks manifest as fever, diffuse or localized abdominal pain, constipation or diarrhea, arthralgias (in large joints), arthritis (in upper/lower limb/knee joints) chest pain caused by pleuritis and/or pericarditis, and skin eruption.  Joint attacks can result in severe damage to the joint and permanent deformity may require joint replacement. The main long-term complication is amyloid A (AA) amyloidosis, which is common in untreated individuals, can lead to renal failure, and has a poor prognosis.  Untreated individuals with FMF, especially those with multiple attacks and/or amyloidosis, are at higher risk for infertility."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000477"}},{"Reference":{"value":"/coll/reference_model/doc/RF000479"}},{"Reference":{"value":"/coll/reference_model/doc/RF000483"}},{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Disease onset usually occurs before the age of 30 (approximately 90% before age 20) with an earlier onset corresponding to a more severe phenotype. Recurrent fever manifests during early childhood and may be the only manifestation. A Type 2 version of FMF has been described that is characterized by amyloidosis as the first clinical manifestation in an otherwise asymptomatic individual. However, some experts believe these cases are previously undiagnosed, milder forms of the disorder. In addition, a Type 3 phenotype has been recently described in which individuals with two pathogenic variants do not express any clinical manifestations. There are no long-term follow-up studies of patients with this phenotype, and thus their outcome cannot be predicted (e.g., development of secondary amyloidosis). Furthermore, no data exist to know whether these individuals have elevated acute phase reactants despite the lack of clinical manifestations.\n\n\nPresentation of clinical features, particularly amyloidosis, can vary across genotypes, ethnicities, and geographical region. Patients who are homozygous for the M694V variant (or other pathogenic variants at position 680-694 on exon 10) or compound heterozygous with a M694V (or other pathogenic variant at position 680-694 on exon 10) and other pathogenic variant typically have a more severe phenotype, with an earlier age of onset and higher frequencies of arthritis and arthralgia than persons who are homozygous or compound heterozygous for other pathogenic variants. M694V mutations are also the most frequency genotype associated with amyloidosis. The association between M694V homozygosity and amyloidosis is less significant among Turkish patients compared to Armenians, Israelis, and Arabians.  Amyloidosis is particularly common in the Jewish population of North African origin. In untreated individuals, amyloidosis can occur in 60% of individuals of Turkish heritage and in up to 75% of North African Jews.  The age of onset of FMF attacks appears to be earlier in persons with amyloidosis than in those without amyloidosis. FMF-related manifestations of chest pain, arthritis, and erysipelas-erythema are more common in those with amyloidosis.  Long periods between disease onset and diagnosis are associated with a high risk of developing amyloidosis. Patients in Western countries are less likely to develop amyloidosis, despite their ethnicities or genotype."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000477"}},{"Reference":{"value":"/coll/reference_model/doc/RF000478"}},{"Reference":{"value":"/coll/reference_model/doc/RF000479"}},{"Reference":{"value":"/coll/reference_model/doc/RF000483"}},{"Reference":{"value":"/coll/reference_model/doc/RF000480"}},{"Reference":{"value":"/coll/reference_model/doc/RF000481"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1016","properties":{"Key Text":{"value":"Evaluations at initial diagnosis"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with FMF, the following evaluations are recommended:\n\n• Physical examination to assess joint problems\n• Urinalysis for the presence of protein. If proteinuria is found, further evaluation is required, including 24-hour urinary protein assay and renal function tests, and also, if indicated, rectal biopsy for the presence of amyloid.\n• Medical genetics consultation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}}},{"Patient Management":{"value":"ACPM1017","properties":{"Key Text":{"value":"Colchicine"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Treatment with colchicine should be started as soon as a clinical diagnosis is made. Colchicine is very efficacious in preventing FMF attacks and associated amyloidosis. A systematic review on treatment of FMF identified three studies on the prophylactic use of colchicine (n=48).  Overall, colchicine was found to consistently reduce the rate and severity of FMF attacks; however, these studies were found to be of low quality. In the first study (n=11), during the course of colchicine, compared to the course of placebo, patients reported fewer attacks (7 vs. 38 attacks, respectively; p<0.001) and milder attacks (p<0.002). In the second study (n=22), patients reported fewer attacks when on colchicine compared to receiving placebo (mean of 1.15 vs 5.25 per patient, respectively; p<0.01) during the first 2 months of treatment, though the risk ratio was not significant (risk ratio: 0.78 (95% CI: 0.49 to 1.23)). A third study (n=15), patients reported fewer attacks on colchicine compared to placebo (5 vs. 59 attacks, respectively; p<0. 002) with a risk ratio of 0.21 (95% CI: 0.05 to 0.95)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000483"}},{"Reference":{"value":"/coll/reference_model/doc/RF000482"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC229","properties":{"Recommendation":{"value":"In addition, colchicine is the only current treatment for the prevention of secondary amyloidosis in FMF. A longitudinal study indicated that of the 960 patients on colchicine who had no evidence of amyloidosis, only 4 who adhered to the prophylactic schedule developed proteinuria, while 16 of the 54 who admitted non-compliance developed proteinuria."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000481"}}]}}}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU549","properties":{"Key Text":{"value":"Close evaluation of asymptomatic patients"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals homozygous for M694V who do not report symptoms, should be evaluated and followed closely in order to consider therapy."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000477"}}]}}}},{"Surveillance":{"value":"ACSU548","properties":{"Key Text":{"value":"Close evaluation of asymptomatic patients"},"Tier":{"value":"2"},"Recommendation Text":{"value":"For individuals with two pathogenic mutations for FMF who do not report symptoms, if there are risk factors for AA amyloidosis (e.g., country, family history, and persistently elevated inflammatory markers (particularly serum amyloid A protein)), close follow-up should be started and treatment considered."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000477"}}]}}}},{"Surveillance":{"value":"ACSU550","properties":{"Key Text":{"value":"Physical exams"},"Tier":{"value":"3"},"Recommendation Text":{"value":"All individuals with FMF, including those not currently being treated, those being treated with colchicine, and those receiving medication other than colchicine should undergo an annual physical examination, a urine spot test for protein, and an evaluation for hematuria."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}}},{"Surveillance":{"value":"ACSU551","properties":{"Key Text":{"value":"Acute-phase reactants"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Monitoring of acute-phase reactants (ESR and fibrinogen levels) at regular intervals during attack-free periods is recommended, particularly in those with the M694V variant."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM364","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Routine genetic testing for MEFV mutations is not recommended in siblings of an index case. However, parents or siblings should be made aware of clinical signs of FMF in order to give them the possibility of seeking advice from a physician in case of suspected symptoms. In cases where the parents of a patient are very concerned about their other children, screening for acute phase reactants can be done. In case of elevated inflammatory markers on two successive blood tests in totally asymptomatic individuals, genetic testing should be considered, as elevated acute phase reactants may unveil a hidden disease."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000481"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA446","properties":{"Key Text":{"value":"Cisplatin"},"Tier":{"value":"3"},"Recommendation Text":{"value":"A single report has suggested that cisplatin worsens symptoms of FMF."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA445","properties":{"Key Text":{"value":"Cyclosporin"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Cyclosporin appears to adversely affect renal transplant graft survival in individuals with FMF.  It has also been reported to trigger FMF attacks, which responded well to colchicine in a previously asymptomatic individual with myelodysplastic syndrome who was heterozygous for the MEFV pathogenic variant M694I."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"4"},"Notes":{"value":"No information on the frequency of MEFV mutations in the general population was identified. \n\nPathogenic variants in MEFV are detected in more than 90% of all cases of FMF. The pathogenic variant M694V is found in more than 90% of affected Jewish persons of North African origin."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC059","properties":{"Recommendation":{"value":"About 85% of patients of Mediterranean origin that meet clinical criteria have a mutation in both copies of the MEFV gene, with only one mutation identified in about 20% of affected cases."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000478"}}]}}}}]}}},"Penetrances":{"value":4,"items":[{"Penetrance":{"value":"ACPE520","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Information on penetrance in a population defined by genotype alone was not identified. The following prevalence figures are based on individuals with a clinical diagnosis of FMF:\n\nAbdominal attacks = 90%\nArticular attacks = 75%\nCutaneous involvement = 7-40%\nProtracted arthritic attacks = 5%\nProdrome = 50%\nPleural attacks = 45%."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Recurrent serositis"}},{"Outcome":{"value":"Amyloidosis"}},{"Outcome":{"value":"Joint problems"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000479"}},{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC067","properties":{"Recommendation":{"value":"Genetic and non-genetic factors appear to affect the rates of amyloidosis in FMF. A study of patients from 14 countries found amyloidosis in 260/2277 (11.4%) patients. The country of recruitment was the most important determinant of risk for development of amyloidosis, followed by the presence of homozygous M694V variants in Armenian, Israelis and Arabian patients. However, another study of 100 Armenian FMF patients living in the USA found no cases of amyloidosis, although M694V was demonstrated to be the most frequent MEFV mutation."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}}}]}}}},{"Penetrance":{"value":"ACPE521","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":""},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Recurrent serositis"}}]},"References":{"value":null,"items":[]}}}},{"Penetrance":{"value":"ACPE519","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":""},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Amyloidosis"}}]},"References":{"value":null,"items":[]}}}},{"Penetrance":{"value":"ACPE522","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":""},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Joint problems"}}]},"References":{"value":null,"items":[]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR216","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information on relative risk was not identified."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN236","properties":{"Key Text":{"value":"Symptoms and severity vary among affected individuals, even among members of the same family suggesting that manifestations are also influenced by other genes and/or environmental factors."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI242","properties":{"Key Text":{"value":"Colchicine toxicity is a serious complication that should be given adequate consideration and be prevented. Colchicine is an alkaloid with a narrow therapeutic range. High concentrations may cause serious toxicity that can be life threatening. Complications of colchicine use occasionally include myopathy and toxic epidermal necrolysis-like reaction. Colchicine treatment may induce oligospermia/azoospermia.  Other identified interventions include blood and urine tests, associated with low burden and risk."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}},{"Reference":{"value":"/coll/reference_model/doc/RF000481"}},{"Reference":{"value":"/coll/reference_model/doc/RF000482"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC235","properties":{"Key Text":{"value":"Symptoms associated with FMF (e.g., fever, pain) are not specific and may not direct the correct diagnosis."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers 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Populations having a high prevalence (1/200-1/1000) include non-Ashkenazi Jews, Armenians, Turks, and Arabs. FMF is also seen in many other countries, although in much lower numbers.  However, the proportion of cases attributed to a single MEFV pathogenic variant is unknown."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000477"}},{"Reference":{"value":"/coll/reference_model/doc/RF000478"}},{"Reference":{"value":"/coll/reference_model/doc/RF000479"}},{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"FMF is an autoinflammatory fever syndrome characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritic, and, rarely, pericarditis and meningitis. Attacks can vary in frequency (as often as once a week or every few years), typically last 1-4 days, and resolve spontaneously.  Mild symptoms (myalgia, headache, nausea, dyspnea, arthralgia, low back pain, asthenia and anxiety) precede attacks and last about 17 hours in approximately 50% of patients. Attacks manifest as fever, diffuse or localized abdominal pain, constipation or diarrhea, arthralgias (in large joints), arthritis (in upper/lower limb/knee joints) chest pain caused by pleuritis and/or pericarditis, and skin eruption.  Joint attacks can result in severe damage to the joint and permanent deformity may require joint replacement. The main long-term complication is amyloid A (AA) amyloidosis, which is common in untreated individuals, can lead to renal failure, and has a poor prognosis.  Untreated individuals with FMF, especially those with multiple attacks and/or amyloidosis, are at higher risk for infertility.\n\n\nHeterozygotes are typically asymptomatic, though some manifest a spectrum of findings from classic to mild FMF. Clinical features in individuals with a single pathogenic MEFV mutation are typically milder and the attacks shorter and less frequent than patients with two MEFV mutations. Most patients have an incomplete abdominal attack as the major criterion of the disease. 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However, clinical signs have been reported to completely disappear at puberty in some cases, indicating that a single pathogenic variant may not necessarily predict lifelong illness."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1018","properties":{"Key Text":{"value":"Evaluations at initial diagnosis"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with FMF, the following evaluations are recommended:\n\n• Physical examination to assess joint problems\n\n• Urinalysis for the presence of protein. If proteinuria is found, further evaluation is required, including 24-hour urinary protein assay and renal function tests, and also, if indicated, rectal biopsy for the presence of amyloid.\n\n• Medical genetics consultation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}}},{"Patient Management":{"value":"ACPM1019","properties":{"Key Text":{"value":"Colchicine"},"Tier":{"value":"3"},"Recommendation Text":{"value":"The presence of a single MEFV pathogenic variant together with clinical symptoms is sufficient to warrant the initiation of a trial of colchicine. Therefore, manifesting heterozygotes should be treated. However, since the natural history and outcome for persons with FMF who are heterozygous for a single MEFV pathogenic variant are unknown, there is no recommendation of lifelong treatment with colchicine for this group. A report of clinical diagnosed FMF patients with a single MEFV variation indicated that 21 of 25 (84%) either completely or partially responded to colchicine therapy. A second report of 94 heterozygous patients with recurrent fever indicated that 82% required colchicine treatment, which was effective in over 90%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU553","properties":{"Key Text":{"value":"Regular exams"},"Tier":{"value":"3"},"Recommendation Text":{"value":"No recommendations specific to surveillance in heterozygous patients were identified. The following recommendations are made generally about FMF patients. \n\n\nAll individuals with FMF, including those not currently being treated, those being treated with colchicine, and those receiving medication other than colchicine should undergo an annual physical examination, a urine spot test for protein, and an evaluation for hematuria."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}}},{"Surveillance":{"value":"ACSU552","properties":{"Key Text":{"value":"Acute-phase reactants"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Monitoring of acute-phase reactants (ESR and fibrinogen levels) at regular intervals during attack-free periods is recommended, particularly in those with the M694V variant."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000480"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM365","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Routine genetic testing for MEFV mutations is not recommended in siblings of an index case. 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It is estimated that 1-3% of gastric cancers arise as a result of inherited gastric cancer predisposition syndromes, including hereditary diffuse gastric cancer (HDGC).  The population prevalence of HDGC is rare, estimated at <0.1 per 100,000 in the general population."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000469"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000315"}},{"Reference":{"value":"/coll/reference_model/doc/RF000309"}},{"Reference":{"value":"/coll/reference_model/doc/RF000311"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"HDGC associated with CDH1 mutations is characterized by the development of diffuse (singlet ring cell) gastric cancer.  Early stage HDGC is characterized by the presence of multiple foci of diffuse gastric cancer, which initially spreads within the mucosa only and at a later stage invades the gastric wall. Symptoms associated with this early stage are nonspecific and by the time specific symptoms appear, affected individuals are typically in an advanced stage of the disease. Symptoms in the late stage may include abdominal pain, nausea, vomiting, dysphagia, postprandial fullness, loss of appetite, and weight loss. Late in the course of gastric cancer, a palpable mass may be present.  Tumor spread or metastasis may lead to an enlarged liver, jaundice, ascites, skin nodules, and fractures. Female carriers of CDH1 mutations have an additional risk of developing lobular breast cancer."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000312"}},{"Reference":{"value":"/coll/reference_model/doc/RF000316"}},{"Reference":{"value":"/coll/reference_model/doc/RF000469"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"It is estimated that early stage cancer in HDGC typically develops in most carriers before 20-30 years of age, while advanced disease is generally prolonged with an increasing risk with age:  1% at age 20, 4% for men and women at age 30 and 21% in men and 46% in women at age 50. The average age of diagnosis of gastric cancer for HDGC is around 32-40 years, with a reported range of 14 to 85 years. The average age of onset for breast cancer is 53 years.\n\n\nWhen sporadic (i.e., non-hereditary) diffuse gastric cancer (DGC) is detected early prior to invasion into the stomach wall, the 5-year survival rate can be greater than 90%. However, the 5-year survival rate drops to lower than 20% when the diagnosis is made at a late stage. Survival of individuals with CDH1 pathogenic variants is believed to be the same as in individuals with sporadic DGC."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000312"}},{"Reference":{"value":"/coll/reference_model/doc/RF000316"}},{"Reference":{"value":"/coll/reference_model/doc/RF000313"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1020","properties":{"Key Text":{"value":"Centralized care"},"Tier":{"value":"2"},"Recommendation Text":{"value":"It is of great importance to centralize the intensive care for HDGC families in specialized centers with multidisciplinary medical teams."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000312"}},{"Reference":{"value":"/coll/reference_model/doc/RF000315"}},{"Reference":{"value":"/coll/reference_model/doc/RF000313"}}]}}}},{"Patient Management":{"value":"ACPM1022","properties":{"Key Text":{"value":"Risk reducing gastrectomy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Carriers of pathogenic CDH1 mutations are currently advised to undergo prophylactic total gastrectomy due to their high lifetime risk of developing gastric cancer and the limited value of surveillance modalities. Most guidelines recommend gastrectomy by age 18 to 20, though the timing may be guided by patient preferences and age at onset within the family."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000309"}},{"Reference":{"value":"/coll/reference_model/doc/RF000312"}},{"Reference":{"value":"/coll/reference_model/doc/RF000316"}},{"Reference":{"value":"/coll/reference_model/doc/RF000315"}},{"Reference":{"value":"/coll/reference_model/doc/RF000313"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC230","properties":{"Recommendation":{"value":"The results of a recent systematic review indicated that of 220 previously reported patients who were positive for CHD1 mutations, 77% underwent a prophylactic gastrectomy while 23% declined. However, there was a high rate of gastric cancer detection at the time of prophylactic gastrectomy. Of the 169 patients who underwent prophylactic gastrectomy, 63% were asymptomatic and had negative preoperative endoscopic and radiologic imaging findings, while 12% tested positive for cancer in their preoperative screening.  The final pathology results displayed positive histology in 87% of all cases."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000310"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1021","properties":{"Key Text":{"value":"Risk reducing mastectomy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Risk-reducing mastectomy could be considered, but not uniformly recommended, as it may be a reasonable option for some women who carry CDH1 mutations. Literature about prophylactic mastectomy in HDGC is scarce, and it is reasonable to consider prophylactic mastectomy on a case-by-case basis, taking into account the family pedigree."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000309"}},{"Reference":{"value":"/coll/reference_model/doc/RF000317"}},{"Reference":{"value":"/coll/reference_model/doc/RF000315"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU555","properties":{"Key Text":{"value":"Gastric cancer surveillance"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Gastric cancer surveillance may be used before prophylactic gastrectomy and for patients who decline gastrectomy. It is recommended that at risk individuals undergo screening every 6-12 months beginning at age 20 or 5-10 years before the earliest cancer diagnosis in the family. The surveillance protocol should include gastroscopy with high definition endoscope, random biopsy plus biopsy of any mucosal abnormalities, and H. pylori testing and eradication. However, the efficacy and safety is uncertain and should be used with caution. All patients should be informed that given the very focal and often endoscopically invisible nature of these lesions, it is quite possible that lesions will not be detected by random biopsies."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000309"}},{"Reference":{"value":"/coll/reference_model/doc/RF000312"}},{"Reference":{"value":"/coll/reference_model/doc/RF000316"}},{"Reference":{"value":"/coll/reference_model/doc/RF000315"}},{"Reference":{"value":"/coll/reference_model/doc/RF000313"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]}}}},{"Surveillance":{"value":"ACSU554","properties":{"Key Text":{"value":"Breast cancer surveillance"},"Tier":{"value":"2"},"Recommendation Text":{"value":"There is currently insufficient data on the role and outcome of breast cancer screening in CDH1 mutation carriers, but the high lifetime risk of breast cancer, particularly the lobular subtype, and the precedents established in other hereditary breast cancer syndromes (e.g. due to BRCA1 or BRCA2 mutation) establish a rationale and protocol. Referral to a high risk breast clinic is recommended. Patients who choose to undergo screening, monthly breast self-examinations, biannual clinical breast exams, and annual breast MRI (which can be combined with mammography) starting at age 30-35 are recommended."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000309"}},{"Reference":{"value":"/coll/reference_model/doc/RF000317"}},{"Reference":{"value":"/coll/reference_model/doc/RF000316"}},{"Reference":{"value":"/coll/reference_model/doc/RF000315"}},{"Reference":{"value":"/coll/reference_model/doc/RF000313"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM366","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Once a CDH1 mutation has been identified in a family with HDGC, all at-risk individuals should be tested. The recommended youngest age at which to offer testing to relatives at risk is not well established. However, consideration of genetic testing can begin at the age of consent (typically 16 years), but that family members should consider the earliest age of onset of a gastric cancer diagnosis in their family."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000315"}},{"Reference":{"value":"/coll/reference_model/doc/RF000316"}}]}}}},{"Family Management":{"value":"ACFM367","properties":{"Key Text":{"value":"Gastric cancer surveillance"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Intense surveillance for gastric cancer (see Surveillance) is advised for individuals at 50% risk of being a carrier who are not (yet) willing to be tested for the mutation."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000315"}},{"Reference":{"value":"/coll/reference_model/doc/RF000313"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA449","properties":{"Key Text":{"value":"Gastric cancer risk factors"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Surveillance should be accompanied by advice to minimize known gastric cancer risk factors such as smoking and the intake of salted, cured, and preserved foods, and to increase fresh fruit and vegetable intake"},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000316"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"The population prevalence of CDH1 germline mutations was not available.\n\n\nCDH1 mutations are found in approximately 25-50% of all families fulfilling the HDGC clinical criteria."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000312"}},{"Reference":{"value":"/coll/reference_model/doc/RF000315"}},{"Reference":{"value":"/coll/reference_model/doc/RF000313"}},{"Reference":{"value":"/coll/reference_model/doc/RF000311"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE524","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Penetrance estimates have indicated a high penetrance for CHD1 mutations, with risk of gastric cancer by age 80 of 67-80% for men and 56-83% for women and risk of breast cancer by age 80 of 39-60% for women. The combined risk for gastric and breast cancer in women was estimated as 90% by age 80."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Gastric cancer"}},{"Outcome":{"value":"Breast cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000309"}},{"Reference":{"value":"/coll/reference_model/doc/RF000312"}},{"Reference":{"value":"/coll/reference_model/doc/RF000316"}},{"Reference":{"value":"/coll/reference_model/doc/RF000315"}},{"Reference":{"value":"/coll/reference_model/doc/RF000313"}},{"Reference":{"value":"/coll/reference_model/doc/RF000469"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR218","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information on relative risk was not available."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN238","properties":{"Key Text":{"value":"The age of onset is variable between and within families."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000313"}},{"Reference":{"value":"/coll/reference_model/doc/RF000469"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI244","properties":{"Key Text":{"value":"The major intervention is prophylactic gastrectomy, which has a low but existent perioperative mortality in a high volume cancer center (<1% for fit patients), and which has post-surgical, lifelong morbidity. Total gastrectomy can have a psychological, physiological, and metabolic impact on the patient. Eating habits must be altered, requiring support from a dietician; dumping syndrome can result in pain, nausea, fatigue, and diarrhea.  Other complications may include lactose intolerance, fat malabsorption and steatorrhea, bacterial overgrowth, and post-prandial fullness. Lifelong vitamin B12 supplementation and close monitoring for anemia, hypocalcemia, osteoporosis, and trace element deficiencies are required. \n\nEndoscopic surveillance comes with a bleeding risk given the number of biopsies taken. \n\nSome female CDH1 mutation carriers who are at high risk of lobular breast cancer may elect risk-reducing mastectomy to remove target organs."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000309"}},{"Reference":{"value":"/coll/reference_model/doc/RF000316"}},{"Reference":{"value":"/coll/reference_model/doc/RF000315"}},{"Reference":{"value":"/coll/reference_model/doc/RF000469"}}]},"Tier":{"value":"Not provided"}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC237","properties":{"Key Text":{"value":"Because early symptoms of HDGC are nonspecific, most cases are not diagnosed until late-stage disease when survival rates are much lower.  In addition, the characteristic microscopic disease foci are often not readily detectable by routine upper endoscopy screening and random biopsies."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000315"}},{"Reference":{"value":"/coll/reference_model/doc/RF000469"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC025","properties":{"Recommendation":{"value":"Because of the relative low incidence of gastric cancer, gastric surveillance is not routinely part of medical care in Western countries."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000313"}}]}}}},{"RecommendationID":{"value":"REC024","properties":{"Recommendation":{"value":"Lobular breast carcinoma often escapes detection on mammography due to its unusual growth pattern of diffuse infiltration of single rows of malignant cells, which does not incite a substantial connective tissue reaction. Thus breast MRI is really needed for early detection."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000318"}}]}}}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"bieseckerl"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"williamsm"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"evansjames"}}]}}},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Gastric cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance","properties":{"Overall Score":{"value":"8CB"},"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Risk 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gene-disease pairs\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36104},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-10"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC104","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"GBA","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:4177"},"GeneOMIM":{"value":"606463"},"SyndromeOMIMs":{"value":5,"items":[{"OMIM":{"value":"230800"}},{"OMIM":{"value":"230900"}},{"OMIM":{"value":"231000"}},{"OMIM":{"value":"231005"}},{"OMIM":{"value":"608013"}}]}}}}]},"Syndrome":{"value":"Gaucher Disease","properties":{"OmimIDs":{"value":5,"items":[{"OmimID":{"value":"230800"}},{"OmimID":{"value":"230900"}},{"OmimID":{"value":"231000"}},{"OmimID":{"value":"231005"}},{"OmimID":{"value":"608013"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":""},"Acronyms":{"value":5,"items":[{"Acronym":{"value":"Gaucher disease, Type I"}},{"Acronym":{"value":"Gaucher disease, Type II"}},{"Acronym":{"value":"Gaucher disease, Type III"}},{"Acronym":{"value":"Gaucher disease, Type IIIC"}},{"Acronym":{"value":"Gaucher disease, Perinatal lethal"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"\"Gaucher Disease\"[Mesh]","properties":{"NumberOfHits":{"value":39},"Date":{"value":"2016-04-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":5,"items":[{"SearchString":{"value":"Gaucher disease","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-04-04"}}}},{"SearchString":{"value":"Gaucher","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-04-04"}}}},{"SearchString":{"value":"GBA","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-04-04"}}}},{"SearchString":{"value":"Glucocerebrosidase","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-04-04"}}}},{"SearchString":{"value":"Acid beta-glucosidase","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-04-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-04-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":5},"Date":{"value":"2016-04-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":6},"Date":{"value":"2016-04-04"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-04-04"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Prevention of major manifestations (including hepatosplenomegaly, pancytopenia, and bone disease)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and initiation of ERT"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Notes":{"value":"Gaucher disease (GD) has a frequency of 1/40,000 in the US. Type 1 is the most common form of GC and affects 1/40,000 to 1/100,000 in the population worldwide. The disorder is panethnic, though it is most common among the Ashkenazi Jewish population, with a prevalence of 1/400 to 1/850. Types 2 and 3 are more rare and occur in less than 1/100,000 live births."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000461"}},{"Reference":{"value":"/coll/reference_model/doc/RF000462"}},{"Reference":{"value":"/coll/reference_model/doc/RF000463"}},{"Reference":{"value":"/coll/reference_model/doc/RF000464"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"GD is a lysosomal storage disorder caused by a deficiency of glucocerebrosidase which results in the multisystemic accumulation of glucosylceramide-laden macrophages (Gaucher cells) in various tissues: spleen, liver, bone marrow, bone mineral, and less often the lungs, skin, eyes, kidneys, lymphatic system, and heart. Clinical manifestations and symptoms include hepatosplenomegaly, abdominal discomfort, bone pain, anemia, fatigue, thrombocytopenia, excessive bleeding, increased risk of infections, cardiovascular complications, and pulmonary disease. Some forms of GD include neuronal involvement. GD consists of a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. However, there are three broad clinical types:\n\n\n•    Type 1 (non-neuronopathic form) accounts for 95% of cases. It is characterized by bone disease, hepatosplenomegaly, thrombocytopenia, anemia, and pulmonary disease. \n\n\n•    Type 2 (acute neuropathic form) accounts for 1% of cases. It is the most severe form and is associated with systemic toxicity, hepatosplenomegaly, thrombocytopenia, anemia, pulmonary disease, and dermatologic changes. Primary neurological involvement is severe and can include bulbar signs, pyramidal signs, and cognitive impairment. A perinatal-lethal subtype is associated with ichthyosiform or collodion skin abnormalities and nonimmune hydrops fetalis.\n\n\n•    Type 3 (chronic neuropathic form) accounts for 4% of cases. It is associated with bone disease, hepatosplenomegaly, thrombocytopenia, anemia, and pulmonary disease. Primary neurological involvement is minimal and can include oculomotor apraxia, seizures, and progressive myoclonic epilepsy. A cardiovascular subtype is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000464"}},{"Reference":{"value":"/coll/reference_model/doc/RF000465"}},{"Reference":{"value":"/coll/reference_model/doc/RF000069"}},{"Reference":{"value":"/coll/reference_model/doc/RF000466"}},{"Reference":{"value":"/coll/reference_model/doc/RF000494"}},{"Reference":{"value":"/coll/reference_model/doc/RF000461"}},{"Reference":{"value":"/coll/reference_model/doc/RF000462"}},{"Reference":{"value":"/coll/reference_model/doc/RF000467"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"GD is a progressive disorder whose natural course and extent of disease is highly variable. Clinical presentation, age at onset, and disease course can vary by clinical type:\n\n•    Type 1 affects children and adults at any age, with an average age of diagnosis of 20. Some patients are asymptomatic. Clinical presentation and disease progression vary and survival may be normal depending on the severity of complications. In general, clinical manifestations presenting in the 1st or 2nd decades of life are typically more aggressive and progress to greater severity than those manifesting at a later stage in life. Bone disease is typically the most painful and debilitating aspect of Type 1. Among a cohort of 2876 patients with Type 1 GD, life expectancy was estimated as 68 years, 9 years earlier than the reference population. Splenectomized patients had a life expectancy of 64 years, earlier than nonsplenectomized at 72 years.\n\n\n•    Type 2 typically has onset before age 2 years (sometimes in utero) and a rapidly progressive course with death by age 2 to 4 years, typically due to lung failure.\n\n\n•    Type 3 typically has onset before age 2 for systemic involvement, but the neurological involvement may manifest at any age. It has a more slowly progressive course than Type 2 with survival into the 3rd or 4th decade."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000464"}},{"Reference":{"value":"/coll/reference_model/doc/RF000465"}},{"Reference":{"value":"/coll/reference_model/doc/RF000069"}},{"Reference":{"value":"/coll/reference_model/doc/RF000466"}},{"Reference":{"value":"/coll/reference_model/doc/RF000494"}},{"Reference":{"value":"/coll/reference_model/doc/RF000461"}},{"Reference":{"value":"/coll/reference_model/doc/RF000462"}},{"Reference":{"value":"/coll/reference_model/doc/RF000467"}},{"Reference":{"value":"/coll/reference_model/doc/RF000468"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1023","properties":{"Key Text":{"value":"Multidisciplinary team"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with GD should be regularly monitored and treated by a multidisciplinary team with expertise in treating GD to assess disease course and effects of therapy."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000464"}},{"Reference":{"value":"/coll/reference_model/doc/RF000494"}}]}}}},{"Patient Management":{"value":"ACPM1025","properties":{"Key Text":{"value":"Enzyme replacement therapy (ERT)"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Enzyme replacement therapy (ERT) with recombinant glucocerebrosidase (e.g., imiglucerase) is the current standard of care for symptomatic patients with GD Types 1 and 3, but has little effect on the course of patients with Type 2 disease and is not recommended.\n\n•  To initiate ERT in Type 1, at least 2 of the following manifestations must be present: hepatic, splenic (or prior splenectomy), cardiac, pulmonary, or renal compromise; anemia; low levels of platelets; pain or bone crisis; active bone disease; and impaired quality of life.\n\n\n•  All patients with Type 3 GD should be given ERT as soon as possible after diagnosis.\n\n\n•  ERT is effective in improving hematological and visceral manifestations, reducing bone marrow burden, and improvement in overall quality of life. Clinical improvement of asthenia, abdominal pain, and bone pain occurs after 3 to 6 months. Reduction in hepatomegaly and splenomegaly is noted after 1-2 years and continues to be stabilized for 3-4 years. Response of bone anomalies occurs after 3-4 years. \n\n\n•  Some manifestations are irreversible and do not respond to ERT: fibrous splenomegaly, secondary osteoarthritis, osteofibrosis, osteonecrosis, deformities due to vertebral compression, hepatic fibrosis, lung fibrosis, and lytic lesions. However, timely initiation of ERT can prevent these manifestations. \n\n\n•  There is currently no evidence that ERT reverses, prevents, or slows neurological progression in patients with Type 3 GD."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000463"}},{"Reference":{"value":"/coll/reference_model/doc/RF000464"}},{"Reference":{"value":"/coll/reference_model/doc/RF000069"}},{"Reference":{"value":"/coll/reference_model/doc/RF000466"}},{"Reference":{"value":"/coll/reference_model/doc/RF000494"}},{"Reference":{"value":"/coll/reference_model/doc/RF000461"}}]}}}},{"Patient Management":{"value":"ACPM1024","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Pregnancy can exacerbate GD by worsening of thrombocytopenia and coagulation disorders and the onset of bone pain, especially for women who have not yet received ERT or whose manifestations are not controlled by treatment. The question of pregnancy and its possible outcomes should be discussed with women of childbearing age and, whenever possible, pregnancy in women with GD must be anticipated. Therapeutic goals should be achieved before considering a pregnancy. After delivery, women should be monitored for infection, bleeding, appearance of bone crises, and bone rarefaction."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000494"}},{"Reference":{"value":"/coll/reference_model/doc/RF000461"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU556","properties":{"Key Text":{"value":"Regular evaluations"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Following the initial diagnosis, all patients with GD (from asymptomatic to severely affected) should undergo the following assessments to establish the baseline disease characteristics, determine candidacy for treatment, and develop therapeutic goals and a monitoring strategy. Patients should continue to undergo regular monitoring to assess the course of the disease. The frequency of assessments varies by guideline and may be adjusted according to disease progression.:\n\n\n•  Comprehensive medical history of patient and family, including a family pedigree\n\n•  Comprehensive physical examination\n\n•  Clinical evaluations: assessment for anemia/thrombocytopenia; hepatosplenomegaly ocular, pulmonary, cardiac, and skeletal pathology; and asthenia\n\n•  Biochemical markers: glucocerebrosidase, chitotriosidase, ACE, and TRAP\n\n•  Laboratory evaluations:  general hematology and coagulation screens; liver function tests; thyroid/parathyroid panel; vitamin D level; inflammation, HIV, and hepatitis; baseline for antibodies to ERT \n\n•  Patients predicted to have neuronopathic GD should also undergo assessment of neurological impairment\n\n•  Quality of life questionnaire."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000463"}},{"Reference":{"value":"/coll/reference_model/doc/RF000464"}},{"Reference":{"value":"/coll/reference_model/doc/RF000069"}},{"Reference":{"value":"/coll/reference_model/doc/RF000466"}},{"Reference":{"value":"/coll/reference_model/doc/RF000494"}},{"Reference":{"value":"/coll/reference_model/doc/RF000462"}},{"Reference":{"value":"/coll/reference_model/doc/RF000467"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM368","properties":{"Key Text":{"value":"Genetic counseling and testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Genetic counseling and carrier testing is important for families with a history of GD and should include patients and their parents, siblings, children, and spouses.  Screening for GD in spouses may only useful in the case of consanguinity or if the spouse is of Ashkenazi origin."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000466"}},{"Reference":{"value":"/coll/reference_model/doc/RF000494"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA450","properties":{"Key Text":{"value":"NSAIDS"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in individuals with moderate to severe thrombocytopenia."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000468"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Tier":{"value":"4"},"Notes":{"value":"The Ashkenazi Jewish population is estimated to have a carrier frequency of 1/18. Estimates of prevalence in other populations were not available. Given that a GBA mutation is detected in 99% of clinically diagnosed patients with GD and the prevalence of GD is 1/40,000 in the US, then the carrier frequency can be estimated as 1/100."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000465"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE525","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Type 1:\n\nSplenomegaly: 90-95%\n\nHepatomegaly: 80%\n\nBone disease: 70-100%."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Prevention of major manifestations (including hepatosplenomegaly, pancytopenia, and bone disease)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000465"}},{"Reference":{"value":"/coll/reference_model/doc/RF000494"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR219","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information on relative risk was not available."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN239","properties":{"Key Text":{"value":"GD is characterized by variable clinical expression and severity. Even patients with the same genotype, including siblings and monozygotic twins, may show distinct patterns of disease."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000461"}},{"Reference":{"value":"/coll/reference_model/doc/RF000464"}},{"Reference":{"value":"/coll/reference_model/doc/RF000465"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI245","properties":{"Key Text":{"value":"Surveillance recommendations are extensive and likely involve multiple providers, which could be burdensome to the patient. ERT with imiglucerase has demonstrated an excellent safety profile in patients with GD, and is generally well tolerated. Adverse reactions are generally mild to moderate and do not prevent ongoing treatment. Roughly 15% of patients develop antibodies to imiglucerase, increasing the risk of hypersensitivity to the product. Significant events that result in the discontinuation of treatment (e.g., anaphylaxis) are rare. (Tier 3)"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000463"}},{"Reference":{"value":"/coll/reference_model/doc/RF000464"}},{"Reference":{"value":"/coll/reference_model/doc/RF000465"}},{"Reference":{"value":"/coll/reference_model/doc/RF000069"}},{"Reference":{"value":"/coll/reference_model/doc/RF000466"}},{"Reference":{"value":"/coll/reference_model/doc/RF000494"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC238","properties":{"Key Text":{"value":"Almost 25% of patients with Type 1 GD do not gain timely access to therapy because of delays in diagnosis after the onset of symptoms. The rarity of the disease and nonspecific and heterogeneous nature of GD symptoms may impede consideration of this disease in the differential diagnosis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000462"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"bieseckerl"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"williamsm"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"evansjames"}}]}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Prevention of major manifestations (including hepatosplenomegaly, pancytopenia, and bone 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Name":{"value":"Slavotinek"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Prevention of major manifestations (including hepatosplenomegaly, pancytopenia, and bone disease)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and initiation of ERT","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Prevention of major manifestations (including hepatosplenomegaly, pancytopenia, and bone disease)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and initiation of ERT","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Prevention of major manifestations (including hepatosplenomegaly, pancytopenia, and bone disease)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and initiation of ERT","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Prevention of major manifestations (including hepatosplenomegaly, pancytopenia, and bone disease)","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and initiation of ERT","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Prevention of major manifestations (including hepatosplenomegaly, pancytopenia, and bone disease)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and initiation of ERT","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Prevention of major manifestations (including hepatosplenomegaly, pancytopenia, and bone disease)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and initiation of ERT","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"updated to include the 5 missing gene-disease pairs\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36106},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-10"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC105","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"F5","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:3542"},"GeneOMIM":{"value":"612309"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"188055"}}]}}}}]},"Syndrome":{"value":"Factor V Leiden, Homozygous (also includes  compound heterozygous FVL + prothrombin G20210A)","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"188055"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Factor V Leiden thrombophilia is characterized by a poor anticoagulant response to activated protein C (APC) and an increased risk for venous thromboembolism (VTE). Deep venous thrombosis (DVT) is the most common VTE, with the legs being the most common site. Thrombosis in unusual locations is less common. Evidence suggests that a heterozygous factor V Leiden mutation has at most a modest effect on recurrence risk after initial treatment of a first VTE. The risk for recurrent VTE in factor V Leiden homozygotes is not well defined, but presumed to be higher than in heterozygotes."},"Acronyms":{"value":2,"items":[{"Acronym":{"value":"Factor V Leiden Thrombophilia"}},{"Acronym":{"value":"(also includes  compound heterozygous FVL + prothrombin G20210A)"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":3,"items":[{"SearchString":{"value":"\"Activated Protein C Resistance\"[Mesh]","properties":{"NumberOfHits":{"value":6},"Date":{"value":"2015-11-02"}}}},{"SearchString":{"value":"\"factor V Leiden\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":84},"Date":{"value":"2015-11-02"}}}},{"SearchString":{"value":"\"Thrombophilia due to Activated Protein C Resistance\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-11-02"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"factor v thrombophilia","properties":{"NumberOfHits":{"value":16},"Date":{"value":"2015-11-02"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-11-02"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Enter new entry title.","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2016-04-04"},"Notes":{"value":""},"Label":{"value":"Enter search label."}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-11-02"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"\"huge review\" AND (leiden OR \"factor 5\" OR \"factor v\" OR f5 OR \"activated protein c\") in PubMed","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-11-02"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"No"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Interventions":{"value":4,"items":[{"Intervention":{"value":"Assessment for VTE risk factors"}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk"}},{"Intervention":{"value":"Pharmacological prophylaxis for pregnant women"}},{"Intervention":{"value":"Pharmacological prophylaxis for men and non-pregnant women"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 10000"},"Notes":{"value":"Venous thromboembolism (VTE) was estimated to occur at an annual rate of 117 per 100,000 per year in U.S. and European populations; the estimate for deep vein thrombosis (DVT) was 48-66 per 100,000 and for pulmonary embolism (PE) was 33-69 per 100,000. A factor V Leiden (FVL) mutation is present in 15-20% of individuals with an initial episode of VTE."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000263"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Factor V Leiden refers to a single base change in the F5 gene (G1691A) that eliminates 1 of its 3 activated protein C cleavage sites. Consequently, factor V is inactivated at a lower rate, leading to more thrombin generation and enhanced potential for clot formation. FVL is associated with an increased risk for DVT and PE, collectively referred to as venous thromboembolism. FVL is the most common known heritable risk factor for thrombosis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000490"}},{"Reference":{"value":"/coll/reference_model/doc/RF000263"}},{"Reference":{"value":"/coll/reference_model/doc/RF000264"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"VTE contributes to an estimated 60,000 to 100,000 deaths annually. DVT of the lower extremities is the most frequent manifestation of VTE; clot formation in the venous sinuses results in cerebral venous thrombosis (CVT), a type of stroke.  The most common life-threatening manifestation of DVT is the subsequent development of PE, resulting in an 18-fold higher risk of early death compared to patients with DVT alone.  In one study, DVT survival at 1 week was 93% whereas PE survival at 1 week was 71%.  VTE recurs frequently, most often in the first 6 months to a year after the first event, but the hazard recurrence rate never drops to zero after that, suggesting that VTE is a chronic disease with episodic recurrence. Approximately 30% of patients with DVT develop post-thrombotic leg syndrome, characterized by chronic leg pain, swelling, dermatitis, and ulcers. It is more likely to occur after recurrent episodes of DVT.\\n\\n\\nVTE incidence may be higher in African American populations and lower in Asian, Asian American, and Native American populations. VTE increases with age, with marked increases after age 60. Incidence rates are somewhat higher in women during childbearing years compared to men, but higher in men after age 45. Independent predictors of VTE risk include prior VTE, family history of VTE, malignancy, major surgery, trauma, hospitalization, nursing home residency, and obesity. In women, risk of VTE is also increased during and shortly after pregnancy, and with use of combined (estrogen-containing) oral contraceptives or hormone replacement therapy. FVL interacts with clinical risk factors to compound the risk of incident VTE.  For example, FVL increases the pre-existing risk of VTE in pregnancy, and of CVT in women who use oral contraceptives.  Similarly, interactions between more than one genetic risk factor further increase the risk of incident VTE. The effect of FVL on VTE risk is heightened in the homozygous state or in the presence of other heritable thrombophilic factors (including the next most common heritable thrombophilia, heterozygous prothrombin G20210A mutation), and in those with a personal or family history of VTE."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000263"}},{"Reference":{"value":"/coll/reference_model/doc/RF000490"}},{"Reference":{"value":"/coll/reference_model/doc/RF000265"}},{"Reference":{"value":"/coll/reference_model/doc/RF000457"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1027","properties":{"Key Text":{"value":"Relatively consistent recommendations and/or evidence regarding patients homozygous for FVL or heterozygous for FVL + prothrombin G20210A were found for the following clinical scenarios of thrombotic risk: \\n  \\nTreatment of idiopathic venous thromboembolism  or cerebral thromboembolism"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Homozygosity (OR, 2.6; 95% CI, 1.2-6.0) for FVL in probands is predictive of recurrent VTE compared with individuals without FVL. Compound heterozygosity for FVL and prothrombin G20210A also predicts recurrent VTE (OR, 4.8; 95% CI, 0.5-46). Thus, moderate evidence supports that homozygosity for FVL and compound FVL-prothrombin G20210A heterozygosity is predictive of recurrent VTE among individuals who have had a prior VTE. Studies demonstrate that pharmacological prophylaxis (usually low molecular weight heparin [LMWH] or warfarin, as appropriate) reduces recurrent events in patients with FVL (not homozygous-specific; likely mostly heterozygous); however, the magnitude of this relative reduction is comparable with that seen in individuals without mutations. This suggests that other nongenetic factors may be as important in determining the risk of recurrence and the absolute magnitude of benefit conferred by anticoagulation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000266"}}]}}}},{"Patient Management":{"value":"ACPM1028","properties":{"Key Text":{"value":"VTE in Pregnancy"},"Tier":{"value":"1"},"Recommendation Text":{"value":"VTE in Pregnancy\\n Women who are homozygous for FVL (especially those who have a family history of VTE) should be referred to a local expert and considered for antenatal pharmacological prophylaxis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000492"}},{"Reference":{"value":"/coll/reference_model/doc/RF000267"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC236","properties":{"Recommendation":{"value":"The risk of pregnancy-related VTE in homozygous FVL carriers has been reported as 1.5 to 5% (and ~5% in compound heterozygotes for FVL and prothrombin G20210A) in unrelated individuals with no VTE history and 10 to 17% (95% CI, 6.3-25.8) in FVL homozygous individuals with personal or family history of VTE."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000267"}},{"Reference":{"value":"/coll/reference_model/doc/RF000496"}}]}}}},{"RecommendationID":{"value":"REC234","properties":{"Recommendation":{"value":"Women who are homozygous for FVL should be considered for postpartum  pharmacological prophylaxis for 6 weeks regardless of VTE personal or family history."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000492"}},{"Reference":{"value":"/coll/reference_model/doc/RF000267"}}]}}}},{"RecommendationID":{"value":"REC231","properties":{"Recommendation":{"value":"The effects of antenatal plus postpartum low molecular weight heparin prophylaxis vs none were estimated from indirect evidence of pharmacological prophylaxis in patients undergoing hip arthroplasty:\\n\\n •  FVL Homozygotes with VTE family history: 47 (56 to 31) fewer VTE compared to baseline 70 VTE per 1000\\n •  FVL Homozygotes: 13 (16 to 6) fewer VTE compared to baseline 20 VTE per 1000\\n •  No significant difference in antepartum or postpartum bleeding events."},"Tier":{"value":"Not provided"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000267"}}]}}}},{"RecommendationID":{"value":"REC235","properties":{"Recommendation":{"value":"After cesarean section, for women at increased risk of VTE due to FVL homozygosity, extended postpartum pharmacological prophylaxis is suggested; the optimal duration is not established. Indirect evidence from  randomized controlled trials in patients undergoing general surgery suggests prophylaxis for women with an absolute VTE risk of more than 3% would result in 21 fewer symptomatic VTEs per 1000 (baseline 40 VTE per 1000) with an additional 20 major bleeding events per 1000 (baseline 20 per 1000)."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000492"}},{"Reference":{"value":"/coll/reference_model/doc/RF000267"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1026","properties":{"Key Text":{"value":"Pregnancy loss"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Pregnancy loss\\n For women with inherited thrombophilia and a history of pregnancy complications including pregnancy loss, it is suggested not to use pharmacological prophylaxis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000267"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC237","properties":{"Recommendation":{"value":"Two meta-analyses of poorly documented case-control and/or cohort studies report that the odds of pregnancy loss in women with FVL was higher as compared with women without FVL; OR=1.52 (95% CI, 1.06-2.19) and OR=2.03  (95% CI: 1.29-3.17).  Two randomized trials found no difference in loss rates in women (few FVL carriers) with recurrent pregnancy loss among groups treated with LMWH plus aspirin, aspirin only, or placebo. Meta-analyses have also reported insufficient evidence that these treatments reduce loss rates in women with recurrent pregnancy loss who do not have antiphospholipid syndrome.  No specific trials of pharmacological prophylaxis in FVL carriers were cited."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000268"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1029","properties":{"Key Text":{"value":"Screening when FVL status is unknown"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Screening when FVL status is unknown\\n There is adequate evidence to recommend against routine testing for FVL in adults with VTE given testing does not influence the initial management of VTE (see \" Treatment of idiopathic venous thromboembolism or cerebral thromboembolism.\""},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000263"}},{"Reference":{"value":"/coll/reference_model/doc/RF000492"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC233","properties":{"Recommendation":{"value":"Routine screening of all women for FVL and other thrombophilias before initiating combination contraception is not recommended. Despite the increased relative risk, the absolute population risk is low because of the low prevalence of this and other thrombophilias and of VTE. In general, screening for thrombophilia is not recommended except in case of personal history of unprovoked VTE or a first-degree relative with a history of high-risk thrombophilia."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000458"}}]}}}},{"RecommendationID":{"value":"REC232","properties":{"Recommendation":{"value":"Routine laboratory screening for heritable thrombophilias prior to additional risk situations such as hormone replacement therapy, pregnancy, or elective major surgery is not recommended."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000492"}}]}}}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU557","properties":{"Key Text":{"value":"(None)"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":""},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM369","properties":{"Key Text":{"value":"Adult family members of patients with VTE and an FVL mutation"},"Tier":{"value":"1"},"Recommendation Text":{"value":"There is adequate evidence to recommend against FVL testing in asymptomatic adult family members of patients with VTE and an FVL mutation, for the purpose of considering primary pharmacological prophylaxis. There is no direct evidence of particular benefit to family members. Potential net harm is possible if primary prophylaxis is administered to asymptomatic family members with one or more mutations, because the absolute risk of an initial VTE event is low, and the risk of anticoagulant-induced hemorrhage is relatively high."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000263"}}]}}}},{"Family Management":{"value":"ACFM370","properties":{"Key Text":{"value":"First-degree relatives of people with a history of VTE"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Do not routinely offer thrombophilia testing to first-degree relatives of people with a history of VTE except in rare circumstances where this testing could affect treatment options."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000264"}}]}}}},{"Family Management":{"value":"ACFM371","properties":{"Key Text":{"value":"Asymptomatic at-risk family members"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Molecular genetic testing can establish the genetic status of asymptomatic at-risk family members; however, the indications for family testing are unresolved. Clarification of FVL allele status may be useful in at-risk relatives considering hormonal contraception or pregnancy or in families with a strong history of recurrent venous thrombosis at a young age. In the absence of evidence that early diagnosis of FVL reduces morbidity or mortality, decisions regarding testing should be made on an individual basis."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000264"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA452","properties":{"Key Text":{"value":"Contraception"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Contraception\\n Alternative methods of postpartum contraceptive options should be considered instead of combined oral contraceptives for women known to carry FVL."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000496"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC052","properties":{"Recommendation":{"value":"FVL homozygous women with or without prior VTE should avoid estrogen-containing contraception."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000264"}}]}}}},{"RecommendationID":{"value":"REC050","properties":{"Recommendation":{"value":"In one study the annual risk of venous thromboembolism was 5.7 per 10,000 among FVL carriers, compared with 28.5 per 10,000 among FVL heterozygous women using estrogen-containing contraceptives."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000496"}}]}}}},{"RecommendationID":{"value":"REC051","properties":{"Recommendation":{"value":"The risk for VTE is markedly increased in users of combined oral contraceptive who are compound heterozygous for FVL and prothrombin G20210A, with reported odds ratios ranging from 17 to 110 compared to oral contraceptive users without either mutation.  No data on risk among FVL homozygous women was available."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000460"}}]}}}}]}}}},{"Circumstance to Avoid":{"value":"ACCA451","properties":{"Key Text":{"value":"Hormone replacement therapy"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Hormone replacement therapy\\n FVL homozygous women with or without prior VTE should avoid estrogen-containing HRT.  FVL heterozygotes who used hormone replacement therapy had a 7 to 15-fold higher thrombotic risk than non-users without the mutation. No data was found on homozygotes.  Some evidence suggests that the thrombotic risk from transdermal HRT is lower than the thrombotic risk from oral preparations, in women with and without prothrombotic mutations.  However, there are no prospective trials confirming the safety in women with thrombophilia."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000264"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 5000"},"Tier":{"value":"3"},"Notes":{"value":"In the United States, approximately 5.1%, 2.0%, and 1.2% of the non-Hispanic white, Hispanic white, and African American populations are heterozygous for the FVL mutation, respectively. Corresponding rates of homozygosity are much lower (65, 10, and 4 per 100,000 individuals, respectively). Individuals with both an FVL mutation and a prothrombin G20210A mutation occur at the rate of 22 per 100,000."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000263"}},{"Reference":{"value":"/coll/reference_model/doc/RF000266"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE526","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"VTE penetrance in Factor V Leiden homozygotes is incomplete; estimates have not been reported. FVL homozygotes identified from general population screening had an absolute incidence of approximately 15 VTE events/1000 persons/year. (NOTE:  Lifetime risk for thrombosis in a heterozygote is approximately 10%.)"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"VTE"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000264"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR220","properties":{"Key Text":{"value":">3"},"Notes":{"value":"Information on relative risk was not available.  Meta-analyses report odds ratios for VTE in FVL homozygotes or compound heterozygotes although odds ratios may not estimate relative risk in this setting."},"References":{"value":null,"items":[]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC013","properties":{"Recommendation":{"value":"In a comprehensive meta-analysis, the pooled OR for risk of VTE in FVL homozygotes compared to controls without FVL was 9.45 (95% CI, 6.72-13.3, p<0.00001)."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000270"}}]}}}},{"RecommendationID":{"value":"REC012","properties":{"Recommendation":{"value":"In another meta-analysis, relatives who were homozygous for FVL compared with family members without the mutation had a pooled OR for first VTE of 18 (95% CI, 7.8- 40). Similarly, in family members who were compound heterozygotes for FVL and prothrombin G20210A mutations, the pooled OR for first VTE was 6.7 (95% CI, 2.9-16) The pooled OR for recurrence in FVL homozygotes was 2.65 (95% CI, 1.18-5.97) and for FVL - prothrombin G20210A compound heterozygotes was 4.81 (95%CI, 0.50-46.3)."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000266"}}]}}}}]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN240","properties":{"Key Text":{"value":"Although a factor V allele is an established risk factor, it does not predict thrombosis with certainty because the clinical course is variable, even within the same family."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000264"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI246","properties":{"Key Text":{"value":"Interventions include pharmacological prophylaxis (usually low molecular weight heparin [LMWH] or warfarin, as appropriate), as well as avoidance of certain types of medications.  Pharmacological prophylaxis carries a risk of bleeding; risks and benefits of pharmacological prophylaxis must be balanced against the risk of VTE.  A systematic review of studies using LMWH during and/or immediately following pregnancy reported an overall frequency of significant bleeding of 1.98% (95% CI, 1.50%-2.57%).  Bleeding rates while on warfarin treatment for VTE are approximately 1%."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000267"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC239","properties":{"Key Text":{"value":"Routine laboratory screening for heritable thrombophilias is not recommended. With respect to specific detection of FVL homozygotes, genetic evaluation may occur only in high-risk individuals with a history of recurrent VTE, especially at young age, or those with strong family history of VTE at young age. In a prospective study, the absolute ten-year risk for VTE among FVL homozygotes was 51% in smokers over age 60 with a BMI greater than 30 kg/m2, but only 3% in nonsmokers younger than age 40 years who were not overweight."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000264"}}]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers Present":{"value":9,"items":[{"Scorer":{"value":"bieseckerl"}},{"Scorer":{"value":"weaverm"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"williamsm"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"strandet"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"evansjames"}}]},"Notes":{"value":"severity of VTE rescored to match other topics"}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":4,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Overall Score":{"value":"IN"},"Effectiveness":{"value":"IN","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Overall Score":{"value":"9CD"},"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis for pregnant women","properties":{"Overall Score":{"value":"8CB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of 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{"ActionabilityDocID":{"value":"AC106","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"F5","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:3542"},"GeneOMIM":{"value":"612309"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"188055"}}]}}}}]},"Syndrome":{"value":"Factor V Leiden, Heterozygous","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"188055"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Factor V Leiden thrombophilia is characterized by a poor anticoagulant response to activated protein C (APC) and an increased risk for venous thromboembolism (VTE). Deep venous thrombosis (DVT) is the most common VTE, with the legs being the most common site. Thrombosis in unusual locations is less common. Evidence suggests that a heterozygous factor V Leiden mutation has at most a modest effect on recurrence risk after initial treatment of a first VTE."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Factor V Leiden Thrombophilia"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":3,"items":[{"SearchString":{"value":"\"Activated Protein C Resistance\"[Mesh]","properties":{"NumberOfHits":{"value":6},"Date":{"value":"2015-11-02"}}}},{"SearchString":{"value":"\"factor V Leiden\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":84},"Date":{"value":"2015-11-02"}}}},{"SearchString":{"value":"\"Thrombophilia due to Activated Protein C Resistance\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-11-02"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"factor v thrombophilia","properties":{"NumberOfHits":{"value":16},"Date":{"value":"2015-11-02"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-11-02"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-11-02"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-11-02"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"\"huge review\" AND (leiden OR \"factor 5\" OR \"factor v\" OR f5 OR \"activated protein c\") in PubMed","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-11-02"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"No"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors"}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk"}},{"Intervention":{"value":"Pharmacological prophylaxis"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 10000"},"Notes":{"value":"Venous thromboembolism (VTE) was estimated to occur at an annual rate of 117 per 100,000 per year in U.S. and European populations; the estimate for deep vein thrombosis (DVT) was 48-66 per 100,000 and for pulmonary embolism (PE) was 33-69 per 100,000. A factor V Leiden (FVL) mutation is present in 15-20% of individuals with an initial episode of VTE."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000263"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Factor V Leiden refers to a single base change in the F5 gene (G1691A) that eliminates 1 of its 3 activated protein C cleavage sites. Consequently, factor V is inactivated at a lower rate, leading to more thrombin generation and enhanced potential for clot formation. FVL is associated with an increased risk for DVT and PE, collectively referred to as venous thromboembolism. FVL is the most common known heritable risk factor for thrombosis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000490"}},{"Reference":{"value":"/coll/reference_model/doc/RF000263"}},{"Reference":{"value":"/coll/reference_model/doc/RF000264"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"VTE contributes to an estimated 60,000 to 100,000 deaths annually. DVT of the lower extremities is the most frequent manifestation of VTE; clot formation in the venous sinuses results in cerebral venous thrombosis (CVT), a type of stroke.  The most common life-threatening manifestation of DVT is the subsequent development of PE, resulting in an 18-fold higher risk of early death compared to patients with DVT alone.  In one study, DVT survival at 1 week was 93% whereas PE survival at 1 week was 71%.  VTE recurs frequently, most often in the first 6 months to a year after the first event, but the hazard recurrence rate never drops to zero after that, suggesting that VTE is a chronic disease with episodic recurrence. Approximately 30% of patients with DVT develop post-thrombotic leg syndrome, characterized by chronic leg pain, swelling, dermatitis, and ulcers. It is more likely to occur after recurrent episodes of DVT.\\n\\n\\nVTE incidence may be higher in African American populations and lower in Asian, Asian American, and Native American populations. VTE increases with age, with marked increases after age 60. Incidence rates are somewhat higher in women during childbearing years compared to men, but higher in men after age 45. Independent predictors of VTE risk include prior VTE, family history of VTE, malignancy, major surgery, trauma, hospitalization, nursing home residency, and obesity. In women, risk of VTE is also increased during and shortly after pregnancy, and with use of combined (estrogen-containing) oral contraceptives or hormone replacement therapy. FVL interacts with clinical risk factors to compound the risk of incident VTE. For example, FVL in the heterozygous state increases the pre-existing risk of VTE in pregnancy, and of CVT in women who use oral contraceptives. The effect of FVL on VTE risk is heightened in those with a personal or family history of VTE.  However, studies indicate that heterozygosity for FVL is not associated with an increase in mortality or reduction in normal life expectancy."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000490"}},{"Reference":{"value":"/coll/reference_model/doc/RF000263"}},{"Reference":{"value":"/coll/reference_model/doc/RF000265"}},{"Reference":{"value":"/coll/reference_model/doc/RF000264"}},{"Reference":{"value":"/coll/reference_model/doc/RF000457"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1031","properties":{"Key Text":{"value":"Treatment of idiopathic venous thromboembolism or cerebral thromboembolism"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Recommendations and/or evidence regarding patients heterozygous for FVL were found for the following clinical scenarios of additional thrombotic risk:\\n\\nTreatment of idiopathic venous thromboembolism or cerebral thromboembolism\\n Among 13 studies in a systematic review, the pooled OR for recurrent thrombosis was 1.56 (95% CI, 1.14-2.12) for individuals heterozygous for FVL compared with patients without the mutation.  However, when analyses were limited to 6 studies reporting only individuals with idiopathic VTE, the pooled OR for recurrent thrombosis was 1.17 (95% CI, 0.63-2.18) for those with heterozygous FVL relative to individuals without. Studies demonstrate that pharmacological prophylaxis (usually low molecular weight heparin [LMWH] or warfarin, as appropriate) reduces recurrent events in patients with FVL; however, the magnitude of this relative reduction is comparable with that seen in individuals without mutations. This suggests that other nongenetic factors may be as important in determining the risk of recurrence and the absolute magnitude of benefit conferred by anticoagulation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000266"}}]}}}},{"Patient Management":{"value":"ACPM1032","properties":{"Key Text":{"value":"VTE in Pregnancy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"VTE in Pregnancy\\n Heterozygous FVL carriers with no personal or family VTE history, or other thrombotic risk factors require no change in antepartum or postpartum management compared to those without heritable thrombophilia. The addition of heterozygous FVL status to other existing thrombotic risk factors, including a personal or family history of VTE, may warrant antepartum and/or postpartum pharmacological prophylaxis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000491"}},{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000267"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC242","properties":{"Recommendation":{"value":"Pregnant women with no personal or family history of VTE and who are heterozygous for FVL have been reported to have a VTE risk of approximately 0.5 to 1.2%, although the true risk is not well defined.  Pregnant women who do not carry FVL have a VTE risk that may be about 8-fold lower.  Pregnant women heterozygous for FVL and with a personal VTE history have a risk of recurrence during pregnancy that may be as high as 10 to 20%."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000492"}},{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000267"}}]}}}},{"RecommendationID":{"value":"REC241","properties":{"Recommendation":{"value":"The effects of antenatal plus postpartum low molecular weight heparin prophylaxis vs none were estimated from indirect evidence of pharmacological prophylaxis in patients undergoing hip arthroplasty:\\n•FVL Heterozygotes with VTE family history: 10 (12 to 5) fewer VTE compared to baseline 15 VTE per 1000\\n•No significant difference in antepartum or postpartum bleeding events (baseline antepartum risk of major bleeding events from a systematic review of the safety and efficacy of pharmacological prophylaxis during pregnancy)."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000267"}}]}}}},{"RecommendationID":{"value":"REC238","properties":{"Recommendation":{"value":"After cesarean section, women known to have inherited thrombophilia should be considered for pharmacological prophylaxis following delivery. Indirect evidence of VTE events from patients undergoing general surgery and treated with LMWH vs. placebo suggests prophylaxis for women at high risk (defined as absolute VTE risk of more than 3%), including women heterozygous for FVL.\\n•High risk women undergoing cesarean section and given prophylaxis:  21 fewer VTEs per 1000 compared to those not given pharmacological prophylaxis (baseline 40 VTE per 1000). \\n•Twenty more bleeding events per 1000 compared to a baseline of 20 events per 1000 in those not treated (baseline risk estimate from a decision model evaluating the risks and benefits of post-cesarean pharmacological prophylaxis)."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000267"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1030","properties":{"Key Text":{"value":"Pregnancy loss"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Pregnancy loss\\n For women with inherited thrombophilia and a history of pregnancy complications including pregnancy loss, it is suggested not to use pharmacological prophylaxis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000267"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC243","properties":{"Recommendation":{"value":"Two meta-analyses of poorly documented case-control and/or cohort studies report that the odds of pregnancy loss in women with FVL was higher as compared with women without FVL; OR=1.52 (95% CI, 1.06-2.19) and OR=2.03  (95% CI: 1.29-3.17).  Two randomized trials found no difference in loss rates in women (few FVL carriers) with recurrent pregnancy loss among groups treated with LMWH plus aspirin, aspirin only, or placebo. Meta-analyses have also reported insufficient evidence that these treatments reduce loss rates in women with recurrent pregnancy loss who do not have antiphospholipid syndrome.  No specific trials of pharmacological prophylaxis in FVL carriers were cited."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000268"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1033","properties":{"Key Text":{"value":"Screening when FVL status is unknown"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Screening when FVL status is unknown\\n There is adequate evidence to recommend against routine testing for FVL in adults with VTE given testing does not influence the initial management of VTE (see \" Treatment of idiopathic venous thromboembolism or cerebral thromboembolism.\""},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000492"}},{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000263"}},{"Reference":{"value":"/coll/reference_model/doc/RF000458"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC240","properties":{"Recommendation":{"value":"Routine screening of all women for FVL and other thrombophilias before initiating combination contraception is not recommended. Despite the increased relative risk, the absolute population risk is low because of the low prevalence of this and other thrombophilias and of VTE. In general, screening for thrombophilia is not recommended except in case of personal history of unprovoked VTE or a first-degree relative with a history of high-risk thrombophilia."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000458"}}]}}}},{"RecommendationID":{"value":"REC239","properties":{"Recommendation":{"value":"Routine laboratory screening for heritable thrombophilias prior to additional risk situations such as hormone replacement therapy, pregnancy, or elective major surgery is not recommended."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000492"}}]}}}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU558","properties":{"Key Text":{"value":"(None)"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":""},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM372","properties":{"Key Text":{"value":"Asymptomatic adult family members of patients with VTE and an FVL mutation"},"Tier":{"value":"1"},"Recommendation Text":{"value":"There is adequate evidence to recommend against FVL testing in asymptomatic adult family members of patients with VTE and an FVL mutation for the purpose of considering primary pharmacological prophylaxis. There is no direct evidence of particular benefit to family members. Potential net harm is possible if primary prophylaxis is administered to asymptomatic family members with one or more mutations, because the absolute risk of an initial VTE event is low, and the risk of anticoagulant-induced hemorrhage is relatively high."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000263"}}]}}}},{"Family Management":{"value":"ACFM373","properties":{"Key Text":{"value":"First-degree relatives of people with a history of VTE"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Do not routinely offer thrombophilia testing to first-degree relatives of people with a history of VTE except in rare circumstances where this testing could affect treatment options."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000493"}}]}}}},{"Family Management":{"value":"ACFM374","properties":{"Key Text":{"value":"Asymptomatic at-risk family members"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Molecular genetic testing can establish the genetic status of asymptomatic at-risk family members; however, the indications for family testing are unresolved. Clarification of FVL allele status may be useful in at-risk relatives considering hormonal contraception or pregnancy or in families with a strong history of recurrent venous thrombosis at a young age. In the absence of evidence that early diagnosis of FVL reduces morbidity or mortality, decisions regarding testing should be made on an individual basis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000264"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA454","properties":{"Key Text":{"value":"Contraception"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Contraception\\n Alternative methods of postpartum contraceptive options should be considered instead of estrogen-containing (combined) oral contraceptives for women known to carry FVL. In one study the annual risk of venous thromboembolism was 5.7 per 10,000 among FVL carriers, compared with 28.5 per 10,000 among FVL heterozygous women using estrogen-containing contraceptives."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000496"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC053","properties":{"Recommendation":{"value":"In another study the OR for ischemic stroke was 11.2 (95% CI, 4.2-29) for women using oral contraceptives who were heterozygous for FVL compared to non-users without an FVL allele. Non-FVL carriers who used oral contraceptives had an OR of 2.6 (95% CI, 1.7-4.0) for ischemic stroke compared to non-users."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000459"}}]}}}}]}}}},{"Circumstance to Avoid":{"value":"ACCA453","properties":{"Key Text":{"value":"Hormone replacement therapy"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Hormone replacement therapy\\n Women with an FVL allele and a history of VTE should avoid HRT. Asymptomatic women who are heterozygous for FVL should be counseled on the risks of HRT use and should be encouraged to consider alternative control of menopausal symptoms. Women found to be FVL heterozygotes and who used hormone replacement therapy had a 7 to 15-fold higher thrombotic risk than non-users without the mutation. (General population HRT users have a 2 to 4-fold increased risk of VTE compared to non-users.) Some evidence suggests that the thrombotic risk from transdermal HRT is lower than the thrombotic risk from oral preparations, in women with and without prothrombotic mutations. However, there are no prospective trials confirming the safety in women with thrombophilia."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000264"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Tier":{"value":"3"},"Notes":{"value":"In the United States, approximately 5.1%, 2.0%, and 1.2% of the non-Hispanic white, Hispanic white, and African American populations are heterozygous for the FVL mutation, respectively."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000263"}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE527","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"Lifetime risk for thrombosis in a heterozygote is approximately 10%. FVL heterozygotes identified from general population screening had an absolute incidence of VTE of approximately 2 VTE events per 1000 persons per year."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"VTE"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000264"}}]}}}},{"Penetrance":{"value":"ACPE528","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":""},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"VTE"}}]},"References":{"value":null,"items":[]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR221","properties":{"Key Text":{"value":">3"},"Notes":{"value":"In a systematic review of observational studies of relatives of FVL probands, the pooled relative risk of VTE for FVL carriers was 3.69 (95% CI, 2.27-6.00) in four retrospective studies. Another systematic review with slightly different inclusion criteria reported that the pooled OR for VTE in relatives with heterozygosity for FVL compared with relatives without the mutation was 3.5 (95% CI, 2.5-5.0) in seven observational studies. Finally, in a systematic review of case-control studies, the pooled OR of FVL for VTE was 4.9 (95% CI, 4.4- 5.5)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000270"}},{"Reference":{"value":"/coll/reference_model/doc/RF000269"}},{"Reference":{"value":"/coll/reference_model/doc/RF000266"}}]},"Tier":{"value":"1"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN241","properties":{"Key Text":{"value":"Although a FVL allele is an established risk factor, it does not predict thrombosis with certainty because the clinical course is variable, even within the same family."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000264"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI247","properties":{"Key Text":{"value":"Interventions include pharmacological prophylaxis (usually low molecular weight heparin [LMWH] or warfarin, as appropriate), as well as avoidance of certain types of medications. Pharmacological prophylaxis carries a risk of bleeding; risks and benefits of pharmacological prophylaxis must be balanced against the risk of VTE.  A systematic review of studies using LMWH during and/or immediately following pregnancy reported an overall frequency of significant bleeding of 1.98% (95% CI, 1.50%-2.57%).  Bleeding rates while on warfarin treatment for VTE are approximately 1%."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000267"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC240","properties":{"Key Text":{"value":"Routine laboratory screening for heritable thrombophilias is not recommended.  This includes testing prior to risk situations such as prescription of oral contraceptives or hormone replacement therapy, pregnancy, elective major surgery or central venous catheter insertion.  Because testing for FVL does not influence initial management of VTE, routine testing in this situation is also not recommended."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000492"}}]},"Tier":{"value":"1"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers Present":{"value":9,"items":[{"Scorer":{"value":"bieseckerl"}},{"Scorer":{"value":"weaverm"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"williamsm"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"strandet"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"evansjames"}}]},"Notes":{"value":"Severity readdressed by AWG on 3.19.18 to make consistent with other VTE scores."}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Overall Score":{"value":"IN"},"Effectiveness":{"value":"IN","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Overall Score":{"value":"8CB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis","properties":{"Overall Score":{"value":"5CA"},"Effectiveness":{"value":"0A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":9,"items":[{"FinalScoreOfScorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Effectiveness":{"value":"INA"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis","properties":{"Effectiveness":{"value":"0A"},"Nature Of Intervention":{"value":"1"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Effectiveness":{"value":"1A"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacological prophylaxis","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacological prophylaxis","properties":{"Effectiveness":{"value":"0A"},"Nature Of Intervention":{"value":"1"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Effectiveness":{"value":"1A"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacological prophylaxis","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Effectiveness":{"value":"0B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacological prophylaxis","properties":{"Effectiveness":{"value":"0A"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Effectiveness":{"value":"2A"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis","properties":{"Effectiveness":{"value":"0A"},"Nature Of Intervention":{"value":"1"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"strandet","properties":{"First Name":{"value":"Tasha"},"Last Name":{"value":"Strande"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Effectiveness":{"value":"INA"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacological prophylaxis","properties":{"Effectiveness":{"value":"0A"},"Nature Of Intervention":{"value":"1"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis","properties":{"Effectiveness":{"value":"0A"},"Nature Of Intervention":{"value":"1"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Effectiveness":{"value":"1D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"1"}}}},{"Intervention":{"value":"Pharmacological prophylaxis","properties":{"Effectiveness":{"value":"0A"},"Nature Of Intervention":{"value":"0"}}}}]}}}}]}}}}]}}},"Scorers":{"value":9,"items":[{"Scorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Effectiveness":{"value":"INA"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacological prophylaxis","properties":{"Effectiveness":{"value":"INA"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Effectiveness":{"value":"1A"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacological prophylaxis","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"VTE","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Assessment for VTE risk factors","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoid estrogen-containing compounds that exacerbate VTE risk","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacological prophylaxis","properties":{"Effectiveness":{"value":"1A"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last 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N"},"kbRevision-PairedKB":{"value":36110},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-04-09"},"ReleasedBy":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"}}}}}}}},
{"ActionabilityDocID":{"value":"AC107","properties":{"Status":{"value":"Released"},"Genes":{"value":4,"items":[{"Gene":{"value":"ENG","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:3349"},"GeneOMIM":{"value":"131195"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"187300"}}]}}}},{"Gene":{"value":"ACVRL1","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:175"},"GeneOMIM":{"value":"601284"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"600376"}}]}}}},{"Gene":{"value":"SMAD4","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:6770"},"GeneOMIM":{"value":"600993"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"175050"}}]}}}},{"Gene":{"value":"GDF2","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:4217"},"GeneOMIM":{"value":"605120"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"615506"}}]}}}}]},"Syndrome":{"value":"Hereditary Hemorrhagic Telangiectasia","properties":{"OmimIDs":{"value":4,"items":[{"OmimID":{"value":"187300"}},{"OmimID":{"value":"600376"}},{"OmimID":{"value":"615506"}},{"OmimID":{"value":"175050"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia leading to telangiectases and arteriovenous malformations of skin, mucosa, and viscera. Epistaxis and gastrointestinal bleeding are frequent complications of mucosal involvement. Visceral involvement includes that of the lung, liver, and brain."},"Acronyms":{"value":3,"items":[{"Acronym":{"value":"TELANGIECTASIA, HEREDITARY HEMORRHAGIC, OF RENDU, OSLER, AND WEBER; HHT"}},{"Acronym":{"value":"TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2; HHT2"}},{"Acronym":{"value":"TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 5; HHT5"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"\"Telangiectasia, Hereditary Hemorrhagic\"[Mesh] OR \"Juvenile Polyposis with Hereditary Hemorrhagic Telangiectasia\"[Supplementary Concept] OR \"ACVRL1 protein, human\"[Supplementary Concept] OR \"ENG protein, human\"[Supplementary Concept] OR \"Smad4 Protein\"[Mesh] OR \"SMAD4 protein, human\"[Supplementary Concept] OR \"GDF2 protein, human\"[Supplementary Concept]","properties":{"NumberOfHits":{"value":20},"Date":{"value":"2015-12-07"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":4,"items":[{"SearchString":{"value":"Hereditary Hemorrhagic Telangiectasia","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2015-12-07"}}}},{"SearchString":{"value":"ACVRL1 OR SMAD4 OR GDF2","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-12-07"}}}},{"SearchString":{"value":"ENG AND HHT","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-12-07"}}}},{"SearchString":{"value":"Osler-Weber-Rendu 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Disease","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-12-07"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":8,"items":[{"Outcome":{"value":"Anticipatory treatment to avoid CAVM-related morbidity (ENG)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cerebral MRI"}}]}}}},{"Outcome":{"value":"Anticipatory treatment to avoid PAVM-related morbidity (ENG)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"TTCE"}}]}}}},{"Outcome":{"value":"Anticipatory treatment to avoid CAVM-related morbidity (ACVRL1)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cerebral MRI"}}]}}}},{"Outcome":{"value":"Anticipatory treatment to avoid PAVM-related morbidity (ACVRL1)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"TTCE"}}]}}}},{"Outcome":{"value":"Anticipatory treatment to avoid CAVM-related morbidity (SMAD4)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cerebral MRI"}}]}}}},{"Outcome":{"value":"Anticipatory treatment to avoid PAVM-related morbidity (SMAD4)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"TTCE"}}]}}}},{"Outcome":{"value":"Anticipatory treatment to avoid CAVM-related morbidity (GDF2)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cerebral MRI"}}]}}}},{"Outcome":{"value":"Anticipatory treatment to avoid PAVM-related morbidity (GDF2)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"TTCE"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 10000"},"Notes":{"value":"The estimated prevalence of hereditary hemorrhagic telangiectasia (HHT) ranges from 1/10,000 to 1/5000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}},{"Reference":{"value":"/coll/reference_model/doc/RF000476"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"HHT is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. Small telangiectases close to the surface of the skin and mucous membranes often rupture and bleed after slight trauma and are most evident on the lips, tongue, buccal mucosa, face, chest and fingers. They are common in adulthood throughout the gastrointestinal mucosa.  Recurrent and spontaneous epistaxis (nosebleed) is the most common symptom of HHT and is the most common feature to bring young individuals with HHT to medical attention. It is caused by minor insults from drying air and repeated minor abrasions to the fragile nasal mucosa. Epistasis and/or GI bleeding can cause mild to severe anemia, often requiring iron replacement therapy or blood transfusion. HHT is often complicated by the presence of AVMs in the brain, lung, gastrointestinal tract, and liver. In contrast to complications of smaller telangiectases, the complications of AVMs often result from the shunting of blood, leading to increased cardiac output and, in the lung, desaturation of arterial blood. Patients with mutations in the SMAD4 genes may also be affected by a rare syndrome that combines HHT and juvenile polyposis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}},{"Reference":{"value":"/coll/reference_model/doc/RF000476"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Although HHT is a developmental disorder and infants are occasionally severely affected, in most people the features are age-dependent and the diagnosis is not suspected until adolescence or later. The average age of onset for epistaxis is 12 years, with 50-80% of patients affected before the age of 20 and 78-96% developing it eventually. Most patients report the appearance of telangiectasia of the mouth, face, or hands 5-30 years after the onset of nose bleeds, most commonly during the third decade.  GI bleeding, when present, usually presents in the 5th or 6th decades of life. Patients rarely develop significant GI bleeding before 40 years of age. Women are affected with GI bleeding in a ratio of 2-3:1. AVMs of the brain are typically present at birth, whereas those in the lung and liver typically develop over time. Hemorrhage is often the presenting symptom of cerebral AVMs, while visceral AVMs may cause transient ischemic attacks, embolic stroke, and cerebral or other abscesses. Hepatic AVMs can present as high-output heart failure, portal hypertension, or biliary disease."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}},{"Reference":{"value":"/coll/reference_model/doc/RF000476"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1034","properties":{"Key Text":{"value":"Medical examination"},"Tier":{"value":"3"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with HHT the following evaluations are recommended: \n\n-Medical history and physical exam\n-Complete blood count\n-Measurement of oxygen saturation via pulse oximetry\n-Contrast echocardiography for detection of pulmonary shunting/AVM and measurement of the pulmonary artery systolic pressure as a screen for pulmonary artery hypertension"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000476"}}]}}}},{"Patient Management":{"value":"ACPM1036","properties":{"Key Text":{"value":"Humidifying agents"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with HHT-related epistaxis should use agents that humidify the nasal mucosa to prevent endonasal crusting that can damage endonasal telangiectasia and cause bleeding.  There are small case series of various topical medications, including lubricants (e.g., saline, antibiotic ointments), as well as topical estrogen cream/ointment and antifibrinolytics, with variable success in decreasing HHT-related epistaxis. There are insufficient published data to recommend one topical therapy over another; however, expert experience is that there is mild benefit from humidification and that the risk of topical lubricants and saline is very low."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}}]}}}},{"Patient Management":{"value":"ACPM1035","properties":{"Key Text":{"value":"Nasal surgery"},"Tier":{"value":"2"},"Recommendation Text":{"value":"When considering nasal surgery for reasons other than epistaxis the patients and the clinician should obtain consultation from an otorhinolaryngologists with expertise in HHT-related epistaxis who can guide procedural interventions to minimize risk of worsening epistaxis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU563","properties":{"Key Text":{"value":"Annual evaluation"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Patients should undergo annual evaluation by a health care provider familiar with HHT, including interval history for epistaxis or other bleeding, shortness of breath or decreased exercise tolerance, and headache or other neurologic symptoms."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000476"}}]}}}},{"Surveillance":{"value":"ACSU559","properties":{"Key Text":{"value":"Cerebral MRI"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with HHT should be screened for cerebral vascular malformations (CVMs). Screening is recommended in the first 6 months of life (or at time of diagnosis), with unenhanced MRI and in an adult patient at age 18 using MRI with and without contrast. Those screening positive should be referred to a center with neurovascular expertise to be considered for invasive testing and individualized management. There is no evidence for any role of repeat MRI screening in adults after an initial negative study. While the rationale for screening for CVMs in HHT is that screening will detect a treatable CAVM before the development of a life-threating or debilitating complications, there no published studies of the efficacy or safety of any form of treatment of CVMs in HHT patients."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC040","properties":{"Recommendation":{"value":"No published studies of the efficacy or safety of any form of treatment of CAVMs in HHT patients were identified. This recommendation was based on the effectiveness presented in several large case studies of embolization, microsurgery and stereotactic radiation in patients with non-HHT CAVMs.  However, more recently in 2014, the results of A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA) indicated that individuals who were randomized to medical management alone (pharmacologic therapy for neurologic symptoms as needed) compared to medical management with interventional therapy (surgery, embolization, radiotherapy, alone or in combination) had a significantly decreased risk of death or stroke (hazard ratio 0.27, 95% CI 0.14-0.54). This trial included 223 randomized patients with a mean follow-up of 33.3 months.  No harms were identified, other than a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000303"}},{"Reference":{"value":"/coll/reference_model/doc/RF000304"}}]}}}},{"RecommendationID":{"value":"REC041","properties":{"Recommendation":{"value":"Studies of the natural history of cerebral AVMS in patients with HHT are limited. A study of 29 HHT patients with CAVMs found a bleeding risk of 0.4% to 0.7%. A more recent study of 153 HHT patients followed over three years found an overall bleeding rate of 1% per year, with a rupture rate of 0.4% per year for unruptured AVMs and 10% per year for ruptured AVMs. While not specific to HHT patients, the ARUBA study and a recent meta-analysis both found rupture rates of around 2.2% per year for unruptured AVMs."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000305"}}]}}}}]}}}},{"Surveillance":{"value":"ACSU561","properties":{"Key Text":{"value":"TTCE"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with HHT should be screened for pulmonary arteriovenous malformations (PAVMs) using transthoracic contrast echocardiography (TTCE). The rationale for screening HHT patients for PAVMs is that screening will detect a treatable PAVM before the development of a life-threatening or debilitating complication. Screening should be performed at the time of initial clinical evaluation to identify patients appropriate for treatment. In patients with negative initial screening, repeat screening should be considered every 5-10 years, within 5 years preceding a planned pregnancy, or after pregnancy. Embolization has been shown in several non-controlled series to be efficacious and have shown high rates of immediate technical success. Longer term, reperfusion did occur in up to 15% of patients and growth of small PAVMs in up to 18%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}}]}}}},{"Surveillance":{"value":"ACSU564","properties":{"Key Text":{"value":"Hemoglobin or hematocrit monitoring"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients over 35 should have annual measurements of hemoglobin or hematocrit levels due to the increased risk of GI bleeding with age. Oral and/or intravenous iron supplementation is recommended as first-line therapy for mild anemia and chronic bleeding secondary to HHT-related telangiectasia. There are no studies of iron replacement in HHT.  Directed endoscopic evaluation should be undertaken in patients with anemia disproportionate to epistaxis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}}]}}}},{"Surveillance":{"value":"ACSU560","properties":{"Key Text":{"value":"AVM screening prior to pregnancy"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Women should be screened and treated as indicated for pulmonary and cerebral AVMs before pregnancy to avoid serious complications."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000476"}}]}}}},{"Surveillance":{"value":"ACSU562","properties":{"Key Text":{"value":"Gastrointestinal screening"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals with SMAD4 mutations, which are also associated with juvenile polyposis, should undergo gastrointestinal screening for polyposis and gastrointestinal malignancy as per national juvenile polyposis screening recommendations. [This topic is addressed in a separate report on Juvenile Polyposis Syndrome]"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM376","properties":{"Key Text":{"value":"Genetic testing of relatives"},"Tier":{"value":"2"},"Recommendation Text":{"value":"If an HHT causing mutation is identified in the index case, diagnostic genetic testing for HHT can be offered to all at risk relatives."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}}]}}}},{"Family Management":{"value":"ACFM377","properties":{"Key Text":{"value":"Annual evaluation of relatives"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Family members at risk for HHT or in whom HHT has not been ruled out should undergo annual evaluation by a health care provider familiar with HHT, including interval history for epistaxis or other bleeding, shortness of breath or decreased exercise tolerance, and headache or other neurologic symptoms."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000476"}}]}}}},{"Family Management":{"value":"ACFM378","properties":{"Key Text":{"value":"Management of children"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Asymptomatic children of a parent with HHT should be considered to have possible HHT unless excluded by genetic testing. If genetic testing is not possible, the clinician should proceed as if the child has HHT and consider appropriate screening for visceral AVMs."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}}]}}}},{"Family Management":{"value":"ACFM379","properties":{"Key Text":{"value":"MRI in relatives"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with possible HHT should be screened for CVMs. Screening is recommended in the first 6 months of life (or at time of diagnosis) with an unenhanced MRI and in an adult patient at age 18 using MRI with and without contrast. All patients with a positive MRI should be referred to a center with neurovascular expertise for consideration of invasive testing and further management."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}}]}}}},{"Family Management":{"value":"ACFM375","properties":{"Key Text":{"value":"Gastrointestinal screening in relatives"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Family members with SMAD4 mutations should undergo gastrointestinal screening for polyposis and gastrointestinal malignancy as per national screening recommendations. [This topic is addressed in a separate report on Juvenile Polyposis Syndrome]"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA457","properties":{"Key Text":{"value":"Avoidance of medications"},"Tier":{"value":"2"},"Recommendation Text":{"value":"While HHT-related epistaxis is not an absolute contraindication to anticoagulation/antiplatelet therapy, these agents can increase the risk of epistaxis and the decision to use these agents should be based on the individual patient risks and benefits."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA456","properties":{"Key Text":{"value":"Activities to avoid"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals with significant epistaxis are advised to avoid vigorous nose blowing, lifting of heavy objects, straining during bowel movements, and finger manipulation in the nose."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000476"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA455","properties":{"Key Text":{"value":"Scuba diving"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Scuba diving should be avoided unless contrast echocardiography performed within the last five years was negative for evidence of a right to left shunt."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000476"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"Information on the prevalence of HHT-related mutations was unavailable."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE530","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"5"},"Notes":{"value":"No evidence was identified on the penetrance of HHT mutations among screen-identified mutation carriers . \nA French-Italian HHT network examined the frequency of manifestations among 343 patients including 135 probands and 208 relatives with ENG or ACVRL1 mutations (mean age of 50.) \nAmong those with an ENG mutation the frequency of manifestations were:\n\n• Epistaxis: 97%\n• Telangiectases: 98%\n• Pulmonary AVM: 54%\n• Cerebral AVM: 9%\n• Hepatic AVM: 44%\n• GI bleeding: 7% \n\n\nAmong those with an ACVRL1 mutation the frequency of manifestations were:\n• Epistaxis: 89%\n• Telangiectases: 93%\n• Pulmonary AVM: 13%\n• Cerebral AVM: 4%\n• Hepatic AVM: 57.6%\n• GI bleeding: 16.4%"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Anticipatory treatment to avoid CAVM-related morbidity (ENG)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000306"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC069","properties":{"Recommendation":{"value":"SMAD4: A retrospective review from 5 clinical centers identified 34 SMAD4 mutation carriers from 20 families with a mean age of 35.1 years. Features associated with HHT were documented in 76% of individuals. \n\n• Epistaxis: 61%\n• Telangiectases: 48%\n• Pulmonary AVM: 53%\n• Cerebral AVM: 4%\n• Hepatic AVM: 38% \n• Colon polyps: 97%"},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000307"}}]}}}},{"RecommendationID":{"value":"REC068","properties":{"Recommendation":{"value":"Only three HHT patients have been identified with GDF2 mutations. All three individuals had epistaxis and telangiectases. One patient was found to have abnormal liver enyzmes and portal hypertension. The other two patients were not screened for solid organ involvement."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000308"}}]}}}}]}}}},{"Penetrance":{"value":"ACPE529","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":""},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Anticipatory treatment to avoid PAVM-related morbidity (ENG)"}}]},"References":{"value":null,"items":[]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR222","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was identified."},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN242","properties":{"Key Text":{"value":"Intrafamilial variability is considerable among HHT with signs and symptoms presenting with various severities and at varying ages of onset."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000476"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI248","properties":{"Key Text":{"value":"Identified interventions include various forms of imaging."},"References":{"value":null}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC241","properties":{"Key Text":{"value":"Although HHT is a development disorder and infants are occasionally severely affected, in most people the features are age-dependent and the diagnosis is not suspected until adolescence or later. In addition, HHT is often not diagnosed, and entire families therefore remain unaware of available screening and treatment, and children and adults unnecessarily develop stroke or life-threatening hemorrhage."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000301"}},{"Reference":{"value":"/coll/reference_model/doc/RF000476"}}]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers Present":{"value":9,"items":[{"Scorer":{"value":"weaverm"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"williamsm"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"strandet"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"sobreiran"}}]}}},"Outcomes":{"value":8,"items":[{"Outcome":{"value":"Anticipatory treatment to avoid CAVM-related 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PALB2 pathogenic variants have been detected in 1-3% of breast cancer cases."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000511"}},{"Reference":{"value":"/coll/reference_model/doc/RF000630"}},{"Reference":{"value":"/coll/reference_model/doc/RF000509"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"PALB2 interacts with the BRCA2 protein and is involved in DNA repair and tumor suppression. PALB2 pathogenic variants are associated with an increased risk of breast cancer."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000509"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"For PALB2 heterozygotes, breast cancer risk increases with age in women with a pathogenic variant, with a 14% cumulative risk of cancer by age 50 and 35% by age 70. A prospective cohort analysis among heterozygotes of two founder mutations in Poland reported that women with a PALB2 pathogenic variant were diagnosed at a similar age to non-carriers (53.3 vs 53.5); however, PALB2 mutation carriers were found to be at an increased risk of breast cancer (OR=4.39, 95% CI: 2.30-8.37). In addition, patients with PALB2 pathogenic variants were more likely have triple-negative cancers (34% vs. 14%, p<0.0001) and bilateral cancer (10% vs. 3%, p=0.001). The 10-year survival was found to be worse for women with breast cancer and a PALB2 pathogenic variant at 48.0% (95% CI: 36.5–63.2), compared with 74.7% (95% CI: 73.5–75.8) for patients with breast cancer without a pathogenic variant (adjusted hazard ratio for death 2.27, 95% CI: 1.64–3.15; p<0.0001).The risk of breast cancer also increases with family history, with 33% breast cancer risk by age 70 for those with no affected first degree relatives compared to 58% in those with two affected first-degree relatives."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000516"}},{"Reference":{"value":"/coll/reference_model/doc/RF000630"}},{"Reference":{"value":"/coll/reference_model/doc/RF000509"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1038","properties":{"Key Text":{"value":"Chemoprevention"},"Tier":{"value":"1"},"Recommendation Text":{"value":"While no chemoprevention recommendations were identified for patients with PALB2 pathogenic variants specifically, guidelines based on lifetime risk levels similar to those associated with PALB2 pathogenic variants state that healthcare professionals within a specialist genetics clinic should discuss and give written information on the absolute risks and benefits of all options for chemoprevention to women at high risk or moderate risk of breast cancer.  No direct evidence on the effectiveness of chemoprevention in patients with PALB2 pathogenic variants was detected. Evidence cited in guidelines was based on patients defined as high-risk based on a family history of breast, ovarian or related (prostate/pancreatic cancer) or with a BRCA1, BRCA2, and/or TP53 pathogenic variant. Among these patients:\n- High quality evidence from two randomized trials suggests the incidence of breast cancer is lower in patients given tamoxifen than in those given a placebo (RR=0.65; 95% CI: 0.56-0.74). Longer term follow-up from one of these trials has subsequently been published; this study found that over a median of 16 years, there was a significant reduction in the occurrence of all breast cancers in the tamoxifen group (HR=0.71; 95% CI: 0.60 to 0.83; p<0.0001). However, no significant difference was found in breast-cancer specific mortality (OR=1.19; 95% CI: 0.68-2.10; p=0.8). \n- Low quality evidence from a single randomized trial suggests the incidence of breast cancer is lower in patients given exemestane compared with those given a placebo (HR=0.35; 95% CI: 0.18-0.70)"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000517"}}]}}}},{"Patient Management":{"value":"ACPM1039","properties":{"Key Text":{"value":"Mastectomy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Women with a PALB2 pathogenic variant could consider risk-reducing mastectomy based on their family history."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000630"}}]}}}},{"Patient Management":{"value":"ACPM1037","properties":{"Key Text":{"value":"Mastectomy"},"Tier":{"value":"1"},"Recommendation Text":{"value":"No direct evidence on the effectiveness of risk-reducing surgery in patients with PALB2 pathogenic variants was identified. Findings from 2 observational studies and 3 decision analysis studies suggest that risk-reducing subcutaneous/total mastectomy has a beneficial effect in terms of significantly reducing the risk of breast cancer in women with a family history of breast cancer, or with BRCA1 and BRCA2 pathogenic variants. One of the observational studies found that risk-reducing mastectomy was also associated with a reduction in breast cancer mortality in women with a family history of breast cancer. Among the two observational studies, one found no cases of invasive breast cancer among women who had undergone bilateral total mastectomy over 3 years (compared to 8/63 patients undergoing surveillance only). The second study showed a reduction in the risk of breast cancer of 89.5% in moderate-risk women who had undergone mastectomy and a reduction of 90-94% among high-risk women. The risk reduction for death among women undergoing mastectomy was 100% among moderate-risk women, and 81-94% among high-risk women."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000517"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU566","properties":{"Key Text":{"value":"Breast cancer surveillance"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Heterozygous female carriers of a PALB2 pathogenic variant are advised to undergo screening with annual mammography starting at age 30, the age when the average 5-year risk for breast cancer exceeds 1%, and may consider screening with breast MRI."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000630"}}]}}}},{"Surveillance":{"value":"ACSU565","properties":{"Key Text":{"value":"Breast cancer surveillance"},"Tier":{"value":"1"},"Recommendation Text":{"value":"No direct evidence on the effectiveness of breast cancer surveillance in patients with PALB2 pathogenic variants was identified.  Evidence cited in guidelines was based on patients with a BRCA1/2 pathogenic variant or a family history of breast cancer. One guideline summarizes that low quality evidence suggests a disease-specific survival benefit with mammographic surveillance in women aged less than 50 years with a family history of breast cancer. First, an observational study found that death from breast cancer was less likely in women aged less than 50 years with family history whose breast cancer was diagnosed during mammographic surveillance compared to a control group of unscreened women of similar age who developed breast cancer (lead time adjusted HR=0.24; 95% CI: 0.09-0.66]). Second, a study modeled death from breast cancer in a mammographic surveillance study in women with a family history aged less than 50 years and a control group from another study, using prognostic features at diagnosis and underlying risk. Projected ten-year death from breast cancer was lower in the mammographic surveillance group than in the control group of unscreened women of similar age (RR=0.80; 95% CI: 0.66-0.96). Third, a retrospective study found that death from any cause was less likely in BRCA1/2 mutation carriers aged between 28 and 77 years diagnosed with breast cancer during an intensive mammographic surveillance program than in those diagnosed outside this program (HR=0.44; 95% CI: 0.25-0.77])."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000517"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM380","properties":{"Key Text":{"value":"Family management"},"Tier":{"value":"1"},"Recommendation Text":{"value":"While no recommendations were identified for family members of individuals carrying a PALB2 pathogenic variant, it is recommended that family members at risk of carrying a BRCA1/2 pathogenic variant should undergo genetic testing to determine their genetic risk."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000203"}}]}}}},{"Family Management":{"value":"ACFM381","properties":{"Key Text":{"value":""},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"These recommendations may similarly apply to women at elevated risk due to other mutations."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]},"Circumstances to Avoid":{"value":null,"items":[]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"Information on PALB2 mutations in the general population was not identified."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE531","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"Breast cancer risk increases with age in women with PALB2 pathogenic variants, with a 14% cumulative risk by age 50 and a 35% cumulative risk by age 70."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000630"}},{"Reference":{"value":"/coll/reference_model/doc/RF000509"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR223","properties":{"Key Text":{"value":">3"},"Notes":{"value":"The breast cancer risk among females who have a germline pathogenic variant in PALB2 is estimated to increase by 2.3 to as high as 9-fold depending on the population, with a pooled risk estimate of 5.3 (90% CI: 3.0-9.4).  Relative risk increases when restricted to those at younger ages, with a relative risk 8-9 times higher in those younger than 40, 6-8 times higher in those 40-60, 5 times higher among those older than 60."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000630"}},{"Reference":{"value":"/coll/reference_model/doc/RF000509"}}]},"Tier":{"value":"3"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN243","properties":{"Key Text":{"value":""},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI249","properties":{"Key Text":{"value":"The interventions identified in this report include screening tests, prophylactic surgery to remove target organs, and medications with potential side 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Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Breast cancer surveillance","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Breast cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Mastectomy","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"1"}}}},{"Intervention":{"value":"Breast cancer surveillance","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last 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Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Mastectomy","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Breast cancer surveillance","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Breast cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Mastectomy","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"1"}}}},{"Intervention":{"value":"Breast cancer surveillance","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Breast cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Mastectomy","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"1"}}}},{"Intervention":{"value":"Breast cancer surveillance","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":6,"items":[{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last 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Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Breast cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":"Modest impact and none on breast cancer-specific mortality. So I gave it a \"1\"."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Mastectomy","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":"I couldn't bring myself to knock down the efficacy due to extrapolation from BRCA...that seemed too rigid to me..."}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Breast cancer surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Here I did knock down the evidence level since the biology of the process could have a big impact on whether screening is efficacious."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Breast cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Mastectomy","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Breast cancer surveillance","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":"As previously"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Breast cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Mastectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Breast cancer surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Breast cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Mastectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":"Based on BRCA1 and BRCA2 scoring"}}}}}},{"Intervention":{"value":"Breast cancer surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Breast cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"not sure 1 or 2? B b/c extrapolated"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Mastectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"B b/c extrapolated"}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Breast cancer surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"preventing cancer death"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"2.0.1","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36114},"ReasonCode":{"value":"Q4","properties":{"Reason":{"value":"Scoring pairs updated <strong>with</strong> major updates in the report"}}},"Date":{"value":"2017-10-30"},"ReleasedBy":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"}}}}}}}},
{"ActionabilityDocID":{"value":"AC110","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"PAH","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:8582"},"GeneOMIM":{"value":"612349"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"261600"}}]}}}}]},"Syndrome":{"value":"Phenylketonuria (PKU)","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"261600"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":""},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"PAH deficiency"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"(\"Phenylketonurias\"[Mesh]) OR \"Phenylalanine Hydroxylase\"[Mesh]","properties":{"NumberOfHits":{"value":55},"Date":{"value":"2016-07-08"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":5,"items":[{"SearchString":{"value":"phenylketonuria","properties":{"NumberOfHits":{"value":7},"Date":{"value":"2016-07-08"}}}},{"SearchString":{"value":"PKU","properties":{"NumberOfHits":{"value":4},"Date":{"value":"2016-07-08"}}}},{"SearchString":{"value":"PAH deficiency","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-07-08"}}}},{"SearchString":{"value":"phenylalanine hydroxylase deficiency","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-07-08"}}}},{"SearchString":{"value":"hyperphenylalaninemia","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-07-08"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-07-08"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-07-08"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-07-08"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-07-08"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Suboptimal plasma PHE levels","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Optimal dietary and medical management to achieve goal PHE levels"}}]}}}},{"Outcome":{"value":"Fetal teratogenicity (females only)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pregnancy management of PHE levels"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 10000"},"Notes":{"value":"Phenylalanine hydroxylase (PAH) deficiency has considerable geographic variation. Approximately 1 in 13,500 to 19,000 infants in the United States is born with PAH deficiency. The incidence of PAH deficiency varies based on ethnicity, with a higher prevalence among Native American and Caucasian individuals.  It has an estimated an incidence of 1/10,000 live births in Europe with a higher rate in some countries (e.g., 1/4500 in Ireland). Prevalence is particularly high in Turkey, with estimates from 1/2600 to 1/4000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000520"}},{"Reference":{"value":"/coll/reference_model/doc/RF000521"}},{"Reference":{"value":"/coll/reference_model/doc/RF000522"}},{"Reference":{"value":"/coll/reference_model/doc/RF000523"}},{"Reference":{"value":"/coll/reference_model/doc/RF000524"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"PAH deficiency is due to impaired activity of the hepatic enzyme PAH involved in the metabolism of the amino acid phenylalanine (PHE). This deficiency results in increased blood levels of PHE which is toxic to several tissues, particularly the brain. Clinical features of untreated PAH deficiency include:  intellectual disability, developmental delay, stunted growth, microcephaly, epilepsy, a musty body odor, decreased skin and hair pigmentation, eczema, behavior problems, emotional disorders, and structural brain changes visible on MRI.  Affected individuals also have decreased myelin formation and decreased dopamine, norepinephrine, and serotonin production. Further problems can emerge later in life and include exaggerated deep tendon reflexes, tremor, and paraplegia or hemiplegia, and osteopenia. \r\rPAH deficiency presents a spectrum of severity based on the degree of elevated PHE. The most severe cases have complete or near-complete deficiency of PAH activity. These cases are typically referred to as \"classic phenylketonuria\" or \"classic PKU\". Untreated, plasma PHE concentrations in classic PKU may be greater than 1200 μmol/L (mean normal level is 60umol/L) with a dietary PHE tolerance of less than 500 mg/day. Without dietary restriction of PHE, most children with classic PKU develop profound and irreversible intellectual disability. Cases that, when untreated, have blood PHE levels greater than normal but less than 1200 umol/L are typically referred to as having hyperphenylalaninemia (HPA). Individuals with HPA are at a much lower risk for cognitive and neuropsychological impairment in the absence of treatment. In addition to these terms, alternative classification schemes have been proposed. \r\rPHE is a potent teratogen, and elevated plasma PHE levels in pregnant women will result in a teratogenic syndrome in the offspring, even if the offspring do not have PAH deficiency. Maternal PKU syndrome can cause microcephaly, congenital heart defects, low birth weight, craniofacial abnormalities, and intellectual disability in the child."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000520"}},{"Reference":{"value":"/coll/reference_model/doc/RF000521"}},{"Reference":{"value":"/coll/reference_model/doc/RF000522"}},{"Reference":{"value":"/coll/reference_model/doc/RF000523"}},{"Reference":{"value":"/coll/reference_model/doc/RF000524"}},{"Reference":{"value":"/coll/reference_model/doc/RF000525"}},{"Reference":{"value":"/coll/reference_model/doc/RF000526"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Neonates with PAH deficiency show no physical signs. In the absence of neonatal diagnosis, symptoms develop within a few months of birth and may be very mild to severe. If left untreated, older children with PAH deficiency can develop clinical manifestations associated with PAH deficiency. However, with good control of PHE concentrations neonatally and during early childhood, most affected children have normal development measured at 5 years of age. Adults with classic PKU who had good control as children typically have normal intelligence or mild degrees of intellectual deficit.\r\rHistorically, children diagnosed with PKU were allowed to relax the dietary restriction of PHE in adolescence. However, it is been demonstrated that increased PHE levels in adulthood have been associated with significant adverse neurocognitive and psychiatric problems, including anxiety, depression, phobias, and deficits in executive functioning."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000520"}},{"Reference":{"value":"/coll/reference_model/doc/RF000521"}},{"Reference":{"value":"/coll/reference_model/doc/RF000522"}},{"Reference":{"value":"/coll/reference_model/doc/RF000523"}},{"Reference":{"value":"/coll/reference_model/doc/RF000525"}},{"Reference":{"value":"/coll/reference_model/doc/RF000526"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1046","properties":{"Key Text":{"value":"Initial evaluations"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with PAH deficiency, the following evaluations are recommended:\n\n• Blood PHE concentration and PHE tolerance at the time of diagnosis to classify infants with HPA.  The individual's diet should be tailored to calculate PHE tolerance irrespective of genotype\n\n• BH4 loading tests to determine which persons are BH4 responsive and which are not in order to relax or discontinue restriction of dietary PHE in those who are responsive."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000525"}}]}}}},{"Patient Management":{"value":"ACPM1044","properties":{"Key Text":{"value":"General PHE control"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Blood PHE levels should be maintained in the range of 120-360 μmol/l in patients of all ages, where untreated PHE levels are >360umol/L. There is strong evidence that treatment and maintenance of metabolic control throughout life is essential to optimal functioning and quality of life of individuals with PAH deficiency. A variety of adverse neurocognitive and psychiatric outcomes, including deficits in executive functioning and psychiatric symptoms such as anxiety, depression, and phobias can develop later in life when there is relaxation of PHE control. Patients with late or untreated PAH deficiency may benefit from institution of therapy. While it is unlikely that there will be improvement in cognitive abilities even if treatment successfully reduces blood PHE, there is anecdotal evidence suggesting that patients may exhibit improvements in behavior, psychiatric symptomatology, and seizure control."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000520"}},{"Reference":{"value":"/coll/reference_model/doc/RF000521"}},{"Reference":{"value":"/coll/reference_model/doc/RF000527"}}]}}}},{"Patient Management":{"value":"ACPM1040","properties":{"Key Text":{"value":"General PHE control"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Individuals with non-PKU HPA who have plasma PHE concentrations consistently below 600 μmol/L (10 mg/dL) are not at higher risk of developing intellectual, neurologic, and neuropsychological impairment than are individuals without PAH deficiency. While some specialists debate the advisability of non-treatment, others believe that dietary treatment is unnecessary for the individuals in this class. A study of thirty-one individuals with HPA who were never treated and whose plasma PHE concentrations did not exceed 600 μmol/L had normal cognitive neuropsychological development."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000525"}}]}}}},{"Patient Management":{"value":"ACPM1041","properties":{"Key Text":{"value":"Dietary restriction of PHE"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"The mainstay of treatment is dietary restriction of PHE, which results in decreased blood PHE levels. The initiation of dietary treatment depends on the extent of HPA. Most treatment centers initiate treatment at a PHE level of 360 μmol/l or higher, while the effects of treatment in the range of 360 to 600 μmol/l is unclear. Though a threshold for the adverse effects of elevated blood PHE has not been proven, treatment at PHE levels between 120 and 360 μmol/l is not recommended. (Tier 2)\n•  Information on the effectiveness of dietary treatment in adults diagnosed with PAH deficiency based on incidental or secondary findings were not identified.\n•  One systematic review assessed the results of RCTs of the low-PHE diet compared to relaxation or termination of dietary restrictions in children. Combined results of 2 studies conducted in young children (n=90) indicated that blood PHE concentrations were significantly lower in participants on the low-PHE diet than those on a less restricted diet (mean difference at 12 months was -751.54, 95% CI: -883.41 to - 619.67). In addition, one study (n=115) reported that participants who continued the low-PHE diet until age 6 achieved a higher IQ than those who discontinued the diet (mean difference at 12 months was 5.00, 95% CI 0.40 to 9.60). All of these studies were conducted in patients who were diagnosed in the neonatal period and started a low PHE diet in early infancy. None of these studies address the implementation of a restricted diet in an individual identified later in life. (Tier 1)\n•  A crossover RCT of the PHE restricted diet was conducted in a group of 34 adults (aged 21-61 years) who had never been treated and had severe challenging behavior. Only half completed the 60 week study, and significant challenges were encountered in instituting the PHE-restricted diet in this population. While levels of blood PHE were found to be lower during the treatment period, no differences were demonstrated in assessments of behavior. However, 76% of carers' comments were scored as positive during the active phase, compared with 54% during the placebo phase (p<0.001), indicating potential benefits of quality of life for individuals with PKU and their carers. (Tier 2)"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000520"}},{"Reference":{"value":"/coll/reference_model/doc/RF000521"}},{"Reference":{"value":"/coll/reference_model/doc/RF000527"}},{"Reference":{"value":"/coll/reference_model/doc/RF000528"}}]}}}},{"Patient Management":{"value":"ACPM1042","properties":{"Key Text":{"value":"Therapies to lower PHE levels"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"In addition to PHE restricted diet, additional therapies to reduce plasma PHE may include sapropterin, low PHE medical food, large neutral amino acids (LNAAs), and vitamin/mineral supplementation. Any combination of therapies that facilitate improvement in PHE levels for a given individual is appropriate. Therapies may be combined and should be individualized. (Tier 2)\n•  Information on the effectiveness of treatment in adults diagnosed with PAH deficiency based on incidental or secondary findings were not identified.\n•  Two randomized controlled trials and three uncontrolled open label studies indicate that sapropterin, a synthetic form of the PAH cofactor BH4, reduces blood PHE concentrations in patients with PKU. Studies included between 29 and 90 children and adults (n=284 after accounting for duplication) who were responsive to BH4 in initial loading trials. PHE levels were reduced by at least 30% (the usual research target) in up to half of treated patients (32-50%) compared to 9% of the placebo groups. No studies have linked these results to longer term clinical or patient-reported outcomes. These studies were conducted in individuals diagnosed with PKU, it is unclear how these results would apply patients discovered from secondary findings. (Tier 1)\n•  LNAAs have been proposed as a therapy for PAH deficiency based on their ability to block uptake of PHE from the intestine and at the blood-brain barrier. (Tier 2) However, one systematic review of 3 small studies (total n=47) could not draw conclusions about the effectiveness of LNAA formulations in affecting short- or long-term outcomes. These studies included patients with classic PKU and were short, with treatment between 1 and 8 weeks. One RCT of 16 patients found some improvements in executive functioning with LNAAs; however, there was considerable individual variable. The two other studies reported that PHE levels remained above clinically acceptable levels throughout treatment. (Tier 1)\n•  Assess the need for vitamin/mineral supplementation when a medical food without complete vitamins and minerals is used or when there is insufficient adherence with medical food intake. (Tier 2)"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000520"}},{"Reference":{"value":"/coll/reference_model/doc/RF000522"}},{"Reference":{"value":"/coll/reference_model/doc/RF000524"}},{"Reference":{"value":"/coll/reference_model/doc/RF000527"}}]}}}},{"Patient Management":{"value":"ACPM1045","properties":{"Key Text":{"value":"Assessment for osteopenia"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Assessment of the early risk of osteopenia should be considered in affected individuals. Screening for abnormal bone mineralization may be considered, though the optimal screening for treatment for osteopenia has not been determined though one guideline recommended assessment every 5 years for all adults. However, other guidelines state that the utility of routine scans has not yet been established. A study of screening 31 adult PKU patients (mean age 25) identified osteopenia in 11 patients (38.7%) and osteoporosis in 2 patients (6.5%)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000520"}},{"Reference":{"value":"/coll/reference_model/doc/RF000521"}}]}}}},{"Patient Management":{"value":"ACPM1043","properties":{"Key Text":{"value":"Pregnancy managment"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"PHE is a potent teratogen with both physical and cognitive consequences for the developing fetus.  Thus the management of women with PKU or HPA during childbearing years, pre-conception, during pregnancy, and post-conception should include care in consultation with practitioners from experienced PKU centers, genetic and nutritional evaluation, and counseling on the risks of adverse fetal outcomes associated with uncontrolled PHE concentrations during pregnancy. (Tier 2)\n•  It is strongly recommended that women with PAH deficiency use reliable methods of contraception to prevent unplanned pregnancies. (Tier 4)\n•  Girls and women in whom no treatment has been initiated but who have persistent blood PHE levels between 360 and 600 μmol/l should receive continued monitoring and education, as they will require treatment prior to and during pregnancy. (Tier 2)\n•  It is recommended that PHE levels of <360 umol/L (6 mg/dL) be achieved for at least 3 months before conception and maintained at 60-360 umol/L (or 2-6 mg/dL) during pregnancy to normalize PHE levels and optimize fetal development. After conception, maternal PHE levels should be maintained between 60 and 360 umol/L during pregnancy.  Women who become pregnant without appropriate PHE control will need significant support to attain PHE levels within the recommended therapeutic range in a timely fashion.  Maternal PHE requirements change significantly throughout gestation necessitating frequent testing and diet adjustments.  There is a linear relationship between maternal PHE levels >360 μmol/l throughout gestation and lower IQ of the developing fetus. Further, elevated blood PHE levels in the first 8-10 weeks of gestation are associated with an increased risk of congenital heart defects and poor fetal growth, and reduction of PHE levels before conception or by 8 weeks gestation reduces the fetal sequelae. (Tier 2)\n•  A systematic review assessed preconception care services among women with HPA (including PKU), where services included screening to detect PHE concentrations in addition to education and counseling regarding preconception and prenatal dietary control of PHE.  All four studies in the review showed that preconception dietary restrictions (resulting in reduced maternal PHE levels) were associated with improved neonatal outcomes in terms of one or more of the following: birth weight, length, head circumference, congenital malformations (particularly congenital heart defects), and neonatal deaths. In these studies preconceptional or very early prenatal dietary control was associated with better outcomes than was later prenatal dietary control alone. (Tier 1)\n•  Pregnancy management should include: fetal growth monitoring, detailed ultrasonographic examinations, and fetal echocardiography to detect fetal abnormalities. (Tier 2)\n•  Postpartum maternal PHE requirements will decrease from the increased anabolic requirements of the third trimester, and careful metabolic and nutritional monitoring should continue. (Tier 2)"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000520"}},{"Reference":{"value":"/coll/reference_model/doc/RF000521"}},{"Reference":{"value":"/coll/reference_model/doc/RF000526"}},{"Reference":{"value":"/coll/reference_model/doc/RF000527"}},{"Reference":{"value":"/coll/reference_model/doc/RF000525"}},{"Reference":{"value":"/coll/reference_model/doc/RF000529"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU570","properties":{"Key Text":{"value":"Regular clinical assessments"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with PAH should undergo regular clinical assessments:\r•  Nutrition visits in the clinic to assess dietary intake and nutrient analysis, nutrition-related physical findings, nutrition counseling and diet education. This should be done every 6-12 months in all adults, but more frequently during pregnancy (monthly to per trimester) and post-partum (at 6 weeks postpartum and then every 6 months). \r•  Every clinical visit should assess anthropometrics, including weight, length or height, and BMI.\r•  Interval nutrition visits should include diet adjustments based on blood PHE and/or counseling, and should occur monthly for all adults and more frequently during pregnancy (twice weekly to weekly) and postpartum (weekly to monthly)."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000527"}}]}}}},{"Surveillance":{"value":"ACSU569","properties":{"Key Text":{"value":"Mental health monitoring"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Due to the increased risk for neurocognitive and psychological issues in patients with PAH deficiency, regular mental health monitoring is warranted."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000520"}}]}}}},{"Surveillance":{"value":"ACSU568","properties":{"Key Text":{"value":"Biochemical screening"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with PAH should undergo regular biochemical screenings including: PHE, tyrosine, plasma amino acids, transthyretin, albumin/total protein, complete blood count, ferritin, vitamin D 25-OH,  comprehensive metabolic panel, serum vitamin B12, B6, erythrocyte folate, vitamin A, zinc, copper, selenium, and essential fatty acids.  The frequency of these screenings varies and should be performed more frequently during pregnancy and postpartum."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000527"}}]}}}},{"Surveillance":{"value":"ACSU567","properties":{"Key Text":{"value":"Ongoing assessment for treatment"},"Tier":{"value":"2"},"Recommendation Text":{"value":"If treatment is not required before 2 years of age, monitoring on an annual or biennial basis is adequate for subsequent assessment."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000520"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM382","properties":{"Key Text":{"value":"Testing of PHE levels"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Newborn sibs of an individual with PKU who have not been tested prenatally should have blood concentration of PHE measured shortly after birth (in addition to newborn screening) to allow earliest possible diagnosis and treatment."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000525"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA458","properties":{"Key Text":{"value":"Aspartame"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Aspartame, an artificial sweetener in widespread use, contains phenylalanine. Persons with PKU should either avoid products containing aspartame or calculate intake of PHE and adapt diet components accordingly."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000525"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Tier":{"value":"4"},"Notes":{"value":"The carrier frequency of PAH deficiency is approximately 1/60."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000521"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC061","properties":{"Recommendation":{"value":"However, carrier frequencies can be variable across populations: 1/26 in Turks, 1/33 in Irish, 1/50 in Northern European origin and East Asian, 1/200 in Japanese, and 1/225 in Finish and Ashkenazi Jewish populations."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000525"}}]}}}}]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE532","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"4"},"Notes":{"value":"Individuals with a genotype suggestive of PKU will always have hyperphenylalaninemia on a normal diet. The impact on the clinical phenotype, that is, cognitive development is variable."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Suboptimal plasma PHE levels"}},{"Outcome":{"value":"Fetal teratogenicity (females only)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000530"}}]}}}},{"Penetrance":{"value":"ACPE533","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Approximately 40% of young adults with PKU develop osteopenia."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Suboptimal plasma PHE levels"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000521"}}]}}}},{"Penetrance":{"value":"ACPE534","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"5"},"Notes":{"value":"For maternal teratogenicity, in untreated pregnancies in which the maternal blood PHE concentration was ≥20 mg/dL (1200 micromol/L), rates of outcomes reported in offspring include intellectual disability in 91-92%, microcephaly in 73-92%, and congenital heart disease in 12-15%."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Fetal teratogenicity (females only)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000584"}},{"Reference":{"value":"/coll/reference_model/doc/RF000585"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR224","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":""},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN244","properties":{"Key Text":{"value":"PAH deficiency is a multifactorial disorder with both environment (dietary intake of PHE) and genotype are necessary causal components of disease. Individuals with similar PAH genotypes may not have similar phenotypes."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000525"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI250","properties":{"Key Text":{"value":"Treatment for PAH deficiency is complex, costly, and lifelong. Adherence to recommendations diminishes with age. Many patients find the diet difficult to adhere to due to the unpalatable and bland nature of many PHE-free products as well as a variety of socioeconomic factors, such as economic and health care system issues. Trials of sapropterin did not identify any serious adverse events and side effects occurred as a similar rather in the treatment and placebo arms."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000520"}},{"Reference":{"value":"/coll/reference_model/doc/RF000521"}},{"Reference":{"value":"/coll/reference_model/doc/RF000522"}},{"Reference":{"value":"/coll/reference_model/doc/RF000524"}},{"Reference":{"value":"/coll/reference_model/doc/RF000526"}},{"Reference":{"value":"/coll/reference_model/doc/RF000527"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC243","properties":{"Key Text":{"value":"Since the initiation of newborn screening during the 1960's in North America, almost all cases of PAH deficiency are diagnosed following a positive newborn screening test."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000520"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC026","properties":{"Recommendation":{"value":"Since the appearance of universal newborn screening, symptomatic classic PKU is infrequently seen. Its predicted incidence in screened populations of fewer than one in a million live births reflects those children not detected by newborn screening."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000525"}}]}}}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"weaverm"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"williamsm"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"evansjames"}}]}}},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Suboptimal plasma PHE levels","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Optimal dietary and medical management to achieve goal PHE 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I'm releasing during the process of reviewing gene-disease pairs.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36116},"ReasonCode":{"value":"Q0","properties":{"Reason":{"value":"Initial Release"}}},"Date":{"value":"2018-01-10"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC112","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"OTC","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:8512"},"GeneOMIM":{"value":"300461"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"311250"}}]}}}}]},"Syndrome":{"value":"Ornithine Transcarbamylase Deficiency","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"311250"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Ornithine transcarbamylase deficiency is an X-linked inborn error of metabolism of the urea cycle which causes hyperammonemia. The disorder is treatable with supplemental dietary arginine and low protein diet."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Ornithine Transcarbamylase Deficiency"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":4,"items":[{"SearchString":{"value":"\"Ornithine Carbamoyltransferase Deficiency Disease\"[Mesh]","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2017-01-24"}}}},{"SearchString":{"value":"\"Urea Cycle Disorders, Inborn\"[Mesh]","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2017-01-24"}}}},{"SearchString":{"value":"\"Urea cycle disorders\"[All Fields]","properties":{"NumberOfHits":{"value":6},"Date":{"value":"2017-01-24"}}}},{"SearchString":{"value":"\"Ornithine Carbamoyltransferase Deficiency\"[All Fields]","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2017-01-24"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-01-24"}}}},{"SearchString":{"value":"Search2","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-01-24"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2017-01-24"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2017-01-24"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2017-01-24"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Ornithine Transcarbamylase Deficiency","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2017-01-24"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Hyperammonemic encephalopathy (women)","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modification (women)"}},{"Intervention":{"value":"Use of nitrogen scavengers (women)"}}]}}}},{"Outcome":{"value":"Hyperammonemic encephalopathy (men)","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modification (men)"}},{"Intervention":{"value":"Use of nitrogen scavengers (men)"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Notes":{"value":"Ornithine transcarbamylase (OTC) deficiency is thought to be the most common urea cycle defect. Estimates of prevalence range from 1 in 14,000 live births to 1 in 77,000 live births and may be biased toward the most severe and earliest presentations.  A U.S. longitudinal study of urea cycle disorders estimated an OTC prevalence of 1 in 63,000 at birth."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000497"}},{"Reference":{"value":"/coll/reference_model/doc/RF000498"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs urea cycle, of which OTC is one. The urea cycle, residing primarily in hepatocytes, is an essential biochemical pathway for metabolizing waste nitrogen. OTC deficiency is associated with hyperammonemia, leading to death or to severe neurological handicap in many survivors. The most severe acute consequence of an elevated ammonia level is cerebral edema and coma. Seizures are common during hyperammonemic coma but may also occur independently; they may be overt or detectable only by EEG. The duration and severity of hyperammonemia strongly correlates with subsequent brain damage. However, even asymptomatic carrier females have been shown to have mild cognitive impairments and executive function deficits."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000497"}},{"Reference":{"value":"/coll/reference_model/doc/RF000499"}},{"Reference":{"value":"/coll/reference_model/doc/RF000500"}},{"Reference":{"value":"/coll/reference_model/doc/RF000501"}},{"Reference":{"value":"/coll/reference_model/doc/RF000502"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"OTC deficiency can occur as a severe neonatal-onset disease in males and as a late-onset (partial) disease in males and females. Neonatal-onset disease in females is very rare. In one U.S. longitudinal study, 26% of participants with OTC presented as newborns whereas 69% presented later in life (5% remained asymptomatic). Males with severe OTC deficiency are typically normal at birth, but become symptomatic on the second to third day progressing quickly to catastrophic somnolence and coma. Neonatal onset is associated with 24% mortality, with survivors experiencing severe developmental delay and recurrent hyperammonemic crises. Following acute treatment, liver transplant is usually required to improve quality of life. \rHemizygous males and heterozygous females with partial OTC deficiency can present from infancy to later childhood, adolescence, or adulthood. A hyperammonemic crisis can be precipitated by stressors (e.g. pregnancy, cancer treatment, crush injury) and become a life-threatening event at any age and in any situation in life. In general, the milder the disease, the later the onset and the stronger the stressor required to precipitate symptoms. The phenotype of a heterozygous female can range from asymptomatic to subtle or significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs. non-favorable X-chromosome inactivation. When adults with late-onset disease become encephalopathic they may display erratic behavior, and combativeness. Liver transplant may be considered in late-onset cases due to disease severity or the fear of a hyperammonemic crisis, even if the disease has been manageable with treatment. The overall mortality rate in late-onset cases has been reported as 11%."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000497"}},{"Reference":{"value":"/coll/reference_model/doc/RF000498"}},{"Reference":{"value":"/coll/reference_model/doc/RF000499"}},{"Reference":{"value":"/coll/reference_model/doc/RF000501"}},{"Reference":{"value":"/coll/reference_model/doc/RF000503"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1047","properties":{"Key Text":{"value":"Establish the extent of disease and needs"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with OTC deficiency, the following evaluations are recommended:\\n-Plasma ammonia concentration\\n-Plasma amino acid analysis\\n-Nutrition labs (e.g., vitamin D level, ferritin, pre-albumin)\\n-Liver function tests (liver enzymes, bilirubin, albumin) \\n-Prothrombin time/Partial thromboplastin time and fibrinogen\\n-Neuropsychological/psychological evaluation"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000497"}}]}}}},{"Patient Management":{"value":"ACPM1053","properties":{"Key Text":{"value":"Peripartum and postpartum precautions"},"Tier":{"value":"4"},"Recommendation Text":{"value":"In an asymptomatic female known to be heterozygous, precautions should be taken in the peripartum and postpartum period to prevent catabolism; in addition, measurement of ammonia levels and administration of dextrose should be considered as heterozygous females have become symptomatic for the first time in the peripartum period."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000497"}}]}}}},{"Patient Management":{"value":"ACPM1050","properties":{"Key Text":{"value":"Elective surgery requirements"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Elective surgery should be performed in centers with a metabolic department, including emergency treatment options for hyperammonemia."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000501"}}]}}}},{"Patient Management":{"value":"ACPM1048","properties":{"Key Text":{"value":"Dietary treatment"},"Tier":{"value":"2"},"Recommendation Text":{"value":"In the absence of an acute event or clear symptoms, the following interventions may apply depending on individual evaluation. While all recommendations apply to patients of all ages, NOTE that the only evidence available was collected in patients who were diagnosed as infants or children (although not with severe newborn disease) and therefore may be less applicable to adults. \\n\\nDietary treatment with a reduced protein intake is an important part of therapy and is based on minimizing the nitrogen load on the urea cycle. This warrants the expertise of a specialist dietitian to balance nutritional requirements with metabolic stability. Patients should be trained on food protein calculation and provision of adequate energy and nutrient intake. They need to be aware of the [potential] need for life-long dietary treatment and regular dietary assessments. Restricted diets should be supplemented with essential amino acids, minerals, vitamins, and trace elements, as needed."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000501"}},{"Reference":{"value":"/coll/reference_model/doc/RF000504"}}]}}}},{"Patient Management":{"value":"ACPM1051","properties":{"Key Text":{"value":"Dietary treatment"},"Tier":{"value":"5"},"Recommendation Text":{"value":"In a study of 17 patients (age  0.2 to 39 months) with a UCD (6 with OTC deficiency) prescribed a restricted protein diet and a medical food containing essential amino acids, energy, minerals, and vitamins, length (p=0.04) and weight (p=0.01) z-scores increased significantly over 6 months.  At 10 months of age, weight gains were significantly and positively correlated with daily energy intakes. In another study, 26 infants with UCDs including 7 with OTC deficiency were treated for 7 to 62 months with reduced protein, essential amino acids, a nitrogen scavenger, and arginine. Overall, 22 survived, 19 with normal height, weight, and head circumference; 13 had normal intellectual development.  Of 7 OTC deficiency patients, 4 survived."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000505"}},{"Reference":{"value":"/coll/reference_model/doc/RF000506"}}]}}}},{"Patient Management":{"value":"ACPM1052","properties":{"Key Text":{"value":"Dietary Treatment"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Most UCD patients need supplementation with L-arginine or its precursor, L-citrulline."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000501"}}]}}}},{"Patient Management":{"value":"ACPM1049","properties":{"Key Text":{"value":"Dietary Treatment"},"Tier":{"value":"5"},"Recommendation Text":{"value":"In one study of 7 Japanese boys (age 3 to 5 years) with late onset OTC deficiency who had ceased arginine treatment a few years prior to the study, resumption of treatment reduced the frequency of hyperammonemic attacks to one-third the rate before re-starting therapy at a followup of 18 months. Arginine levels returned to slightly higher than normal age-matched controls."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000507"}}]}}}},{"Patient Management":{"value":"ACPM1055","properties":{"Key Text":{"value":"Nitrogen scavengers"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Nitrogen scavengers (sodium benzoate, sodium phenyl butyrate) should be taken at recommended doses 4 times daily during meals with abundant fluids to safely avoid mucositis or gastritis. However, information on nitrogen scavenger therapy during pregnancy is scarce."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000501"}}]}}}},{"Patient Management":{"value":"ACPM1054","properties":{"Key Text":{"value":""},"Tier":{"value":"5"},"Recommendation Text":{"value":"In one study of 32 symptomatic girls (age 1 to 17 years at baseline) with OTC deficiency treated with either sodium benzoate or sodium phenyl butyrate, survival over a mean treatment time of 7 years was 90% compared to a historical calculated average of 18% among untreated carrier females.  The frequency of hyperammonemic episodes per year was less than 1 in treated older children and young adults."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000508"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU572","properties":{"Key Text":{"value":"Clinical, biochemical and nutritional monitoring"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Clinical, biochemical and nutritional monitoring are essential and should follow an individualized plan\\n-Laboratory monitoring must include at a minimum plasma ammonia and amino acid profile. Monitoring of glutamine, hemoglobin, albumin, pre-albumin, and transferrin may also provide useful criteria to assess the nutritional status.\\n-Regular dietary assessments are essential.\\n-Clinical monitoring should include inspection for hair loss, skin rash, and other signs of protein/vitamin deficiency.\\n-To help predict clinical and neurocognitive outcome, it appears desirable to perform MRI early during an acute episode and at 2-year intervals. Regular neurocognitive testing for IQ and specific abilities/weaknesses is recommended."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000501"}},{"Reference":{"value":"/coll/reference_model/doc/RF000504"}}]}}}},{"Surveillance":{"value":"ACSU571","properties":{"Key Text":{"value":"Monitoring for hyperammonemia"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Monitoring for hyperammonemia is appropriate following a large fracture or other trauma in which significant internal bleeding occurs."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000503"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM383","properties":{"Key Text":{"value":"Evaluating at-risk relatives"},"Tier":{"value":"4"},"Recommendation Text":{"value":"It is appropriate to evaluate the older and younger at-risk relatives of an affected individual in order to identify as early as possible (before symptoms occur) those who would benefit from prompt intervention with dietary therapy and other measures to prevent hyperammonemia."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000503"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA462","properties":{"Key Text":{"value":"Sodium valproate, haloperidol, and systemic corticosteroids"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Avoid the use of sodium valproate, haloperidol, and systemic corticosteroids in patients with OTC deficiency as these may trigger hyperammonemic episodes and/or liver failure."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000497"}},{"Reference":{"value":"/coll/reference_model/doc/RF000499"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA459","properties":{"Key Text":{"value":"Dietary over-restriction"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Avoid over-restriction of protein/amino acids or fasting."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000497"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA461","properties":{"Key Text":{"value":"Respiratory and GI illness"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Minimize risk of respiratory and gastrointestinal illnesses."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000497"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA460","properties":{"Key Text":{"value":"Stress"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Avoid physical and psychological stress."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000497"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA463","properties":{"Key Text":{"value":"Ibuprofen vs acetaminophen"},"Tier":{"value":"2"},"Recommendation Text":{"value":"The use of ibuprofen for fever relief is preferred over acetaminophen, as acetaminophen in high doses is potentially toxic to the liver."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000504"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA464","properties":{"Key Text":{"value":"Antiemetics"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Extreme caution should be exercised in the use of antiemetics, as they may mask signs of hyperammonemia."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000504"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"X-linked"},"Notes":{"value":""},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000497"}},{"Reference":{"value":"/coll/reference_model/doc/RF000503"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Tier":{"value":"3"},"Notes":{"value":"Population prevalence of OTC genetic mutations was not available. However, a molecular defect in OTC was detected in 80-90% of patients with biochemically confirmed OTC deficiency."},"Outcomes":{"value":null},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000497"}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE535","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Penetrance for OTC deficiency is complete in hemizygous males."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Hyperammonemic encephalopathy (women)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000497"}}]}}}},{"Penetrance":{"value":"ACPE536","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Approximately 15% of heterozygous females are thought to become symptomatic during their lifetime."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000497"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR225","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":""},"References":{"value":null},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN245","properties":{"Key Text":{"value":"The same genetic defect can yield both mild and severe presentations even in different members of the same family."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000501"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI251","properties":{"Key Text":{"value":"The interventions are primarily non-invasive surveillance, a strict metabolic diet with any necessary oral supplementation, and oral nitrogen scavenger therapy (e.g. sodium benzoate), if required."},"References":{"value":null}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC244","properties":{"Key Text":{"value":"UCDs may present with acute or chronic symptoms at any age and are often triggered by catabolic events, protein load or by some drugs. In many cases a precipitating factor cannot be identified. Clinical signs and symptoms are nonspecific and commonly neurological, gastrointestinal or psychiatric."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000501"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Hyperammonemic encephalopathy (women)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modification (women)","properties":{"Overall Score":{"value":"8CN"},"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Use of nitrogen scavengers (women)","properties":{"Overall Score":{"value":"9CN"},"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Hyperammonemic encephalopathy (men)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modification (men)","properties":{"Overall Score":{"value":"9CN"},"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Use of nitrogen scavengers (men)","properties":{"Overall Score":{"value":"10CN"},"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":0,"items":[]}}}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"released to fix scoring import issue from Redcap\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36118},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-02-21"},"ReleasedBy":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"}}}}}}}},
{"ActionabilityDocID":{"value":"AC114","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"HFE","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:4886"},"GeneOMIM":{"value":"613609"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"235200"}}]}}}}]},"Syndrome":{"value":"Hemochromatosis, Type 1","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"235200"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Clinical HFE-HH is characterized by excessive storage of iron in the liver, skin, pancreas, heart, joints, and testes."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Hemochromatosis"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"(\"Hemochromatosis\"[Mesh]) OR \"HFE protein, human\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":69},"Date":{"value":"2016-04-05"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":3,"items":[{"SearchString":{"value":"familial hemochromatosis","properties":{"NumberOfHits":{"value":8},"Date":{"value":"2016-04-05"}}}},{"SearchString":{"value":"hereditary hemochromatosis","properties":{"NumberOfHits":{"value":3},"Date":{"value":"2016-04-05"}}}},{"SearchString":{"value":"hfe","properties":{"NumberOfHits":{"value":3},"Date":{"value":"2016-04-05"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-04-05"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2016-04-05"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2016-04-05"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-04-05"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinically apparent disease","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Monitoring of ferritin levels"}},{"Intervention":{"value":"Phlebotomy"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 500"},"Notes":{"value":"Hereditary hemochromatosis (HHC) is a common genetic disorder that can lead to iron overload. Estimates of prevalence in the general population vary due to a long pre-clinical period and lack of consistent definitions of \"case.\" The prevalence of hemochromatosis cases defined biochemically (elevated serum iron) will be higher than prevalence of cases based on documented iron overload, with or without clinical signs and symptoms. The prevalence will be lower for cases based on diagnosed disease (cirrhosis, diabetes).\n\n\nIn North America, an estimated 80% of clinically recognized cases are due to homozygosity of the HFE C282Y polymorphism, and an additional 4% are due to compound heterozygosity of the C282Y and H63D polymorphisms.  In Caucasians, the prevalence of HFE-associated HHC (HFE-HHC) has been estimated as 1/220-1/250. However, the prevalence of HFE-HHC with clinical manifestations is much lower, estimated as 1/2500."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000471"}},{"Reference":{"value":"/coll/reference_model/doc/RF000472"}},{"Reference":{"value":"/coll/reference_model/doc/RF000489"}},{"Reference":{"value":"/coll/reference_model/doc/RF000470"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"HHC is a disorder of iron metabolism characterized by an abnormally high absorption of dietary iron by the gastrointestinal mucosa. Iron overload may be detected biochemically as increased transferrin-iron saturation and increased serum ferritin concentrations. Clinical manifestations are due to excess iron which can be deposited in the liver, pancreas, heart joints, pituitary gland, skin, and testes. The rate of iron accumulation and the frequency and severity of clinical symptoms can vary markedly. Early symptoms include fatigue, weakness, joint pain, palpitations, abdominal pain, and weight loss. If left untreated, disease progression can lead to hyperpigmentation of the skin, arthritis, cirrhosis, diabetes mellitus, chronic abdominal pain, severe fatigue, hypopituitarism, hypogonadism, cardiomyopathy, primary liver cancer, or an increased risk of certain bacterial infections."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000470"}},{"Reference":{"value":"/coll/reference_model/doc/RF000471"}},{"Reference":{"value":"/coll/reference_model/doc/RF000473"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Symptoms of HHC typically appear between ages 40 and 60 in males and after menopause in females. The prevalence of both iron overload and clinical disease is generally higher in males than females. Presenting signs and symptoms of HHC also vary by sex, with women more likely to present with fatigue, arthralgia, and pigmentation changes and men presenting more often with symptoms of liver disease. Symptoms and disease complications increase with age. With disease progression, liver cirrhosis may develop and may be complicated by portal hypertension, hepatocellular carcinoma, and end-stage liver disease. By the time cirrhosis is recognized, approximately 50% have diabetes mellitus and 15% have congestive heart failure or arrhythmias. Patients diagnosed and treated prior to the development of cirrhosis have a normal life expectancy. Death most often occurs due to cirrhosis, primary liver cancer, diabetes, and cardiomyopathy. On the basis of clinically diagnosed or compatible disease age-adjusted mortality rates for hemochromatosis deaths in the US was 1.8 per million in 1992.  These rates were about twice as high in males as in females, and in white persons as in nonwhite persons.\n\n\nNot all cases of C282Y homozygotes or have iron overload and not all cases that have iron overload have iron deposits in tissues or organs to the degree that damage occurs. Additionally, no test can predict whether a C282Y homozygote will develop clinical disease manifestations. For cases of C282Y/H63D compound heterozygosity, few develop clinical manifestations, but among those who do, many have a complicating factor (e.g., fatty liver, viral hepatitis) that leads to iron overload."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000473"}},{"Reference":{"value":"/coll/reference_model/doc/RF000471"}},{"Reference":{"value":"/coll/reference_model/doc/RF000472"}},{"Reference":{"value":"/coll/reference_model/doc/RF000489"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1056","properties":{"Key Text":{"value":"Evaluations at diagnosis"},"Tier":{"value":"3"},"Recommendation Text":{"value":"To establish the extent of disease, the following evaluations are recommended at the initial diagnosis of an individual determined to be a C282Y homozygote:\n\n• Serum ferritin concentrations should be measured to establish disease status and prognosis. \n\n• MRI to estimate parenchymal iron content, including the liver and possibly the heart\n\n• When serum ferritin and liver enzyme levels are abnormal, liver biopsy can establish or exclude cirrhosis.\n\n• Consultation with a medical geneticist and/or genetic counselor."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000473"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU573","properties":{"Key Text":{"value":"Monitor ferritin levels"},"Tier":{"value":"2"},"Recommendation Text":{"value":"C282Y homozygotes without evidence for iron overload could be monitored annually and treatment instituted when the ferritin rises above normal. Phlebotomy is the mainstay of treatment once iron overload is present. There is little evidence to guide when to initiate phlebotomy, though the threshold is typically any ferritin level above the normal range. Though there is no survival data specific to homozygous C282Y, phlebotomy has been shown to be effective in clinically diagnosed hemochromatosis: 5-year survival of 93% for adequately phlebotomized patients compared to 48% for inadequately phlebotomized patients (10-year survival of 78% and 32%, respectively). Survival of treated patients without cirrhosis and diabetes has been found to be equivalent to that of the normal population, whereas those with these complications have a significantly reduced survival, indicating the benefits of the early initiation of iron removal."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000471"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM384","properties":{"Key Text":{"value":"Genetic testing in adult relatives"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Given the autosomal recessive transmission of HFE-HHC, genetic testing of siblings should be carried out. Siblings should be screened for serum ferritin and transferrin saturation. Genetic testing of other first degree relatives should also be considered."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000471"}}]}}}},{"Family Management":{"value":"ACFM385","properties":{"Key Text":{"value":"Genetic testing in child relatives"},"Tier":{"value":"2"},"Recommendation Text":{"value":"For children of an affected proband, HFE testing of the other parent is generally recommended to determine whether the child is an obligate heterozygote. Testing children in affected families is generally not recommended until age 18 years unless symptomatic."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000472"}},{"Reference":{"value":"/coll/reference_model/doc/RF000495"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA465","properties":{"Key Text":{"value":"Circumstances to avoid"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Medicinal iron, mineral supplements, excess vitamin C, uncooked seafood, and alcohol consumption in those with hepatic involvement."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000473"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Tier":{"value":"1"},"Notes":{"value":"The allelic frequency of the C282Y variant in the general population (worldwide) has been estimated as 6.2%. Based on Hardy-Weinberg, the frequency of C282Y homozygotes is estimated as 0.38%. However, reported frequencies (worldwide) of homozygotes are higher at 0.41%.  The US has an estimated prevalence of 0.44%. US prevalence estimates are lower among Hispanic persons (0.027%), Asian Americans (<0.001%), Pacific Islanders (0.012%), and black persons (0.014%). \n\n\nThe carrier frequency of the H63D mutations is estimated as 22% in Europe and 23% in North America.  C282Y/H63D compound heterozygosity of has a frequency of 2% in the European general population and in 2% in the for North America."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000471"}},{"Reference":{"value":"/coll/reference_model/doc/RF000489"}},{"Reference":{"value":"/coll/reference_model/doc/RF000470"}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE537","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"1"},"Notes":{"value":"Penetrance is incomplete and is generally higher in males than females. Differences in inclusion criteria and the definition of biochemical and disease penetrance have produced a range of estimates for the penetrance of C282Y homozygosity. A summary of penetrance estimates from two meta-analysis are presented:\n\n\nElevated transferrin saturation: Males = 75-94%, Females = 40-94%\n\nIncreased serum ferritin: Males = 32-76%, Females = 26-58%\n\nExcess liver iron: Males = 42%, Females = 19%, All = 24%\n\nDiabetes:                                                                All  = 0-5.6%\n\nLiver fibrosis: Males = 18%, Females = 5%, All = 6%\n\nCirrhosis: Males = 6%, Females = 2%, All = 1.4%"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinically apparent disease"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000471"}},{"Reference":{"value":"/coll/reference_model/doc/RF000489"}},{"Reference":{"value":"/coll/reference_model/doc/RF000474"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC070","properties":{"Recommendation":{"value":"A recent study has published penetrance estimates from the eMERGE Network:\n\nC282Y homozygotes: \n\nElevated transferrin saturation: Males = 100%, Females = 50%\n\nIncreased serum ferritin: Males = 78%, Females = 31%\n\nDiabetes: Males = 45%, Females = 12%\n\nCirrhosis: Males = 5%, Females = 3%\n\n\n\nC282Y/H63D compound heterozygotes:\n\nElevated transferrin saturation: Males = 38%, Females = 38%\n\nIncreased serum ferritin: Males = 33%, Females = 30%\n\nDiabetes: Males = 28%, Females = 20%\n\nCirrhosis: Males = 5%, Females = 5%"},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000474"}}]}}}}]}}}},{"Penetrance":{"value":"ACPE538","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":""},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinically apparent disease"}}]},"References":{"value":null,"items":[]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR226","properties":{"Key Text":{"value":">3"},"Notes":{"value":"A meta-analysis of 202 case-control studies indicated an increased risk for several outcomes among clinically ascertained (i.e. cases defined by disease status related to an organ):\n\n\nC282Y homozygotes compared to controls:\n\n• Liver disease: OR=3.9 (99% CI: 1.9-8.1)\n• Hepatocellular carcinoma: OR=11 (99% CI: 3.7-34)\n• Hepatitis C: OR=4.1 (99% CI: 1.2-14)\n• Nonalcoholic steahohepatitis: OR=10 (99% CI: 2.1-53) \n• Porphyria cutanea tarda: OR=48 (99% CI: 24-95).\n• Diabetes mellitus: OR=3.4 (99% CI: 1.1-11; among North Europeans only).\n\n\nC282Y/H63D compound heterozygotes compared to controls:\n• Porphyria cutanea tarda: OR=8.1 (99% CI: 3.9-17)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000475"}}]},"Tier":{"value":"1"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN246","properties":{"Key Text":{"value":"The phenotypic expression of HFE-HHC is highly variable, including the rate of iron accumulation and the frequency and severity of clinical outcomes."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000470"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI252","properties":{"Key Text":{"value":"Surveillance to monitor serum iron levels is noninvasive and likely well tolerated in patients. Following initial diagnosis and/or presentation of symptoms, weekly or biweekly phlebotomy may be needed to reduce serum ferritin concentration to below 50ng/mL. However, maintenance therapy to keep serum ferritin concentrations below 50ng/mL typically occurs every 3 to 4 months for men and once or twice a year for women."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC245","properties":{"Key Text":{"value":"Given that the early symptoms of HFE-HHC (fatigue, joint pain, etc.) are nonspecific, HFE-HHC is often not diagnosed at the early stages. Even advanced complications (cardiomyopathy, liver cancer, etc.) are also common primary disorders, and thus iron overload can be missed unless it is screened for specifically."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000470"}}]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Scorers Present":{"value":8,"items":[{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"williamsm"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"strandet"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"sobreiran"}}]}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinically apparent disease","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2A"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Monitoring of ferritin levels","properties":{"Overall Score":{"value":"10AB"},"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Phlebotomy","properties":{"Overall Score":{"value":"10AB"},"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]},"FinalScoreOfScorers":{"value":8,"items":[{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinically apparent disease","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2A"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Monitoring of ferritin levels","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Phlebotomy","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First 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disease","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2A"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Monitoring of ferritin levels","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Phlebotomy","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Clinically apparent disease","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2A"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Monitoring of ferritin levels","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Phlebotomy","properties":{"Effectiveness":{"value":"3B"},"Nature Of 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ferritin levels","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Phlebotomy","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36120},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-10"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC115","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"STK11","properties":{"GeneFunction":{"value":""},"HGNCId":{"value":"HGNC:11389"},"GeneOMIM":{"value":"602216"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"175200"}}]}}}}]},"Syndrome":{"value":"Peutz-Jeghers Syndrome","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"175200"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Characterized by gastrointestinal polyps, mucocutaneous pigmentation, and cancer predisposition.\rHamartomatous polyps are most common in the small intestine, but can also occur in the stomach, large intestine, and extraintestinal sites such as renal pelvis, bronchus, gall bladder, nasal passages, urinary bladder, and ureters.\rHyperpigmented macules on the fingers are common."},"Acronyms":{"value":1,"items":[{"Acronym":{"value":"Peutz Jeghers syndrome"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":6,"items":[{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"\"Peutz-Jeghers Syndrome\"[Mesh] OR  \"STK11 protein, human\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":10},"Date":{"value":"2014-01-30"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"peutz jeghers syndrome OR hamartomatous intestinal polyposis OR stk11","properties":{"NumberOfHits":{"value":3},"Date":{"value":"2014-01-30"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2014-01-30"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2014-01-30"}}}},{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-03-10"},"Label":{"value":"OMIM"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"Orphanet","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2014-01-30"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"HuGE","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2014-01-30"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Breast Cancer","properties":{"Interventions":{"value":3,"items":[{"Intervention":{"value":"Risk Reducing Surgery"}},{"Intervention":{"value":"Cancer-Specific Surveillance"}},{"Intervention":{"value":"Chemoprevention"}}]}}}},{"Outcome":{"value":"Ovarian Cancer","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Risk Reducing Surgery"}},{"Intervention":{"value":"Cancer-Specific Surveillance"}}]}}}},{"Outcome":{"value":"Colorectal Cancer","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cancer-Specific Surveillance"}}]}}}}]},"Status":{"value":"Complete"},"Summary":{"value":null},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"There are roughly 13,028,000 people, or 4.1% of the US population, currently living with cancer.  PJS is a rare cancer syndrome, which likely represents a small proportion of cancer prevalence. Specifically for colorectal cancer (CRC), PJS accounts for less than 0.01% of cases."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000016"}},{"Reference":{"value":"/coll/reference_model/doc/RF000017"}},{"Reference":{"value":"/coll/reference_model/doc/RF000018"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"PJS is associated with mucocutaneous pigmentation, gastrointestinal polyps, and increased cancer risk. The hamartomatous (benign, tumor-like) polyps are most common in the small intestine but can also occur in the stomach, colon, and extra-intestinal sites such as the bladder and bronchus. Patients are at an increased risk for a variety of epithelial cancers including CRC, gastric, pancreatic, breast, and ovarian cancers as the most common. Women are at risk of ovarian sex-cord tumors with annular tubules, a benign neoplasm, and adenoma malignum of the cervix, a rare aggressive cancer. Males are at risk of testicular tumors of sex cord and Sertoli-cell type."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000018"}},{"Reference":{"value":"/coll/reference_model/doc/RF000019"}},{"Reference":{"value":"/coll/reference_model/doc/RF000020"}},{"Reference":{"value":"/coll/reference_model/doc/RF000021"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Roughly 45% of individuals with PJS have no family history. Mucocutaneous pigmentation is typically the first sign of PJS, presenting in childhood and typically fading in puberty or adulthood. Polyp-related symptoms (bleeding, anemia, and abdominal pain due to intussusception, obstruction, or infarction) appear by age 10 in 33% of cases and by age 20 in 50% of cases. No differences in cancer risk by sex have been noted.\r\rThe average age of a cancer diagnosis is estimated at 42, with 5% being diagnosed with any cancer by age 30, 31% by age 50, and 85% by age 70."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000018"}},{"Reference":{"value":"/coll/reference_model/doc/RF000019"}},{"Reference":{"value":"/coll/reference_model/doc/RF000020"}},{"Reference":{"value":"/coll/reference_model/doc/RF000021"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1058","properties":{"Key Text":{"value":"Breast Awareness"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Women should be 'breast aware' and alert their doctor to any changes. No evidence was identified for the effectiveness of either clinical or self-breast examination as the sole screening modality in women with a family history of breast cancer and/or BRCA1/2 mutations."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000022"}}]}}}},{"Patient Management":{"value":"ACPM1059","properties":{"Key Text":{"value":"Chemoprevention"},"Tier":{"value":"1"},"Recommendation Text":{"value":"For chemoprevention of breast cancer, tamoxifen should be offered to premenopausal women and postmenopausal women without a uterus, and tamoxifen or raloxifene should be offered to postmenopausal women with a uterus. This recommendation for women with PJS was based on on evidence from randomized trials conducted in women considered 'high risk' for breast cancer based on factors such as age of onset and family history. Results indicated breast cancer incidence was lower in patients given tamoxifen compared to placebo (RR=0.65, 95% CI: 0.56-0.74)."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000022"}}]}}}},{"Patient Management":{"value":"ACPM1057","properties":{"Key Text":{"value":"Risk Reducing Surgery"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Prophylactic mastectomy and bilateral salpingo-oophorectomy can be offered to reduce the risk of breast and ovarian cancers. This recommendation for women with PJS was based on evidence showing risk reductions of roughly 90% and 50-75%, respectively, for breast cancer and ovarian cancer among women with BRCA1/2 mutations after bilateral mastectomy and oophorectomy."},"Outcomes":{"value":null},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000022"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU575","properties":{"Key Text":{"value":"Colonoscopy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"A baseline colonoscopy and gastro-duodenoscopy are recommended followed by colonoscopy and gastro-duodenoscopy every 2-5 years from age 20-25 and small bowel video capsule endoscopy (VCE) or MRI/enteroclysis are recommended every 2-4 years.  However, the age to begin surveillance and its recommended frequency can vary across guidelines. PJS is rare, so evidence on the effectiveness of surveillance is limited to pooled case series and anecdotal case reports. However, the high risk of gastrointestinal malignancy provides substantial rationale for cancer surveillance."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000019"}},{"Reference":{"value":"/coll/reference_model/doc/RF000020"}},{"Reference":{"value":"/coll/reference_model/doc/RF000023"}},{"Reference":{"value":"/coll/reference_model/doc/RF000024"}},{"Reference":{"value":"/coll/reference_model/doc/RF000531"}}]}}}},{"Surveillance":{"value":"ACSU574","properties":{"Key Text":{"value":"Mammography"},"Tier":{"value":"1"},"Recommendation Text":{"value":"For breast cancer surveillance, women can consider annual mammography at age 30, and are recommended to begin annual mammography by age 40. Women should not be offered MRI at any age.  This recommendation for women with PJS was based on evidence that suggests a disease specific survival benefit with mammographic surveillance in women aged less than 50 years who were considered 'high risk' or medium risk' for breast cancer based on family history."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000022"}}]}}}},{"Surveillance":{"value":"ACSU576","properties":{"Key Text":{"value":"Physical Exams"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should have annual physical exams (including testicular palpitation) and hemoglobin analysis as well as annual pancreatic MRI and endoscopic ultrasonography from age 30. 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Familial CCM (FCCM) represents about 20% of all CCM cases with an estimated prevalence of 1/5,000 to 1/10,000.  The fairly common occurrence of asymptomatic vascular lesions in individuals with FCCM suggests that the population incidence of FCCM has been routinely underestimated. A strong founder effect has been found in Hispanic-American families, resulting in a high incidence of FCCM."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000533"}},{"Reference":{"value":"/coll/reference_model/doc/RF000534"}},{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"FCCM is a vascular malformation disorder characterized by closely clustered irregular dilated capillaries (caverns) that can be asymptomatic or can cause variable neurological manifestations such as seizures, nonspecific headaches, progressive or transient focal neurologic deficits, and/or cerebral hemorrhages. The number of lesions can vary from none to hundreds, depending on age and the quality and type of brain imaging. The diameter of CCMs can range from a few millimeters to several centimeters. CCMs typically occur in the brain, but have also been reported in the spinal cord and outside of the central nervous system, including the skin, retina, and liver."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000533"}},{"Reference":{"value":"/coll/reference_model/doc/RF000534"}},{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"FCCM is a dynamic disease, with CCM size increasing or decreasing over time and new lesions estimated to appear at a rate of 0.2 to 0.4 lesions per patient per year. Although CCMs have been reported in infants and children, the majority of cases become evident between the second and fifth decades.  An estimated 50-60% of individuals with FCCM are clinically asymptomatic, although at least half of these individuals have identifiable CCM lesions on head imaging. Clinically affected individuals most often present with seizures (40%-70%), focal neurologic deficits (35%-50%), nonspecific headaches (10%-30%), and cerebral hemorrhage (32-41%). The hemorrhagic event rate is estimated at 2-5% per lesion per year and the new onset seizure rate is 2.4%. Functional outcome is mostly conditioned by the location of CCM, with brainstem and basal ganglia lesions having a worse prognosis. The long-term prognosis of FCCM is not well known, but an estimated 80% of cases have preserved autonomy. CCMs can lead to death from intracranial hemorrhage or from complications of surgery, particularly when found in the brainstem.\n\nThe clinical course can vary by genotype. Individuals with a pathogenic variant in PDCD10 in general have the most severe clinical phenotype and are most likely to present with hemorrhage and have symptom onset before age 15 years. While individuals with a heterozygous pathogenic variant in CCM2 typically have fewer brain lesions and slower lesion development compared to individuals with a pathogenic variant in KRIT1, some studies indicate that individuals with a heterozygous pathogenic variant in KRIT1 may have a less severe clinical phenotype than those with a pathogenic variant in CCM2."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000533"}},{"Reference":{"value":"/coll/reference_model/doc/RF000534"}},{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1061","properties":{"Key Text":{"value":"Initial Evaluations"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs of an individual diagnosed with FCCM, the following evaluations are recommended:\n•  MRI imaging of the brain and/or spinal cord\n•  Consultation with a clinical geneticist and/or genetic counselor\n•  In those with epilepsy: electroencephalogram (EEG), Wada testing to determine which hemisphere is language dominant, and magnetoencephalography to confirm the localization of the epilepsy and to exclude other epileptogenic lesions."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}},{"Patient Management":{"value":"ACPM1062","properties":{"Key Text":{"value":"Treatment of CCMs"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"Guidelines for the treatment of CCMs do not distinguish between the surgical and medical treatment of sporadic CCMs and those due to germline mutations. In addition, seizures and headache due to CCM are treated with standard approaches."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000535"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC247","properties":{"Recommendation":{"value":"• Surgical removal of CCMs has traditionally been indicated for lesions associated with intractable seizures or focal deficits from recurrent hemorrhage or mass effect.\n- A retrospective study reported clinical outcomes of neurosurgical intervention in 13 patients with CCMs (7 with epilepsy and 6 with focal neurological deficits; unspecified as sporadic or familial CCMs) with 1-6 years (mean=3.3 years) of follow-up. Patients with epilepsy had reduction in seizure frequency, with 4 becoming seizure-free. Patients with neurological deficits due to intracerebral hemorrhage (5 patients) or mass effect (1 patient) showed improvements with 2 making full recoveries. There was no mortality or morbidity resulting  from the surgery, and no patients required re-operation during the follow-up period. There was no comparison group that received conservative management.\n- A prospective, non-randomized, population-based study reported outcomes among 134 adults with CCM who underwent surgical or conservative management concluded that excision may worsen neurological outcomes. The 25 patients who underwent CCM excision were more likely to be younger and to present with symptomatic intracranial hemorrhage or focal neurologic deficit than those managed conservatively (non-surgically) (48% vs 26%). During 5 years of follow-up, surgical CCM excision was associated with worse neurological outcomes and the occurrence of symptomatic intracranial hemorrhage or new focal neurologic deficit (HR=3.60, 95% CI: 1.29–10.03).\n- A study reported outcomes in 298 symptomatic patients with CCM who had been treated with gamma knife surgery (mean time from presentation was 33 months with mean follow-up time of 68 months). Among those who presented with seizures (n=35) and had sufficient follow-up time (n=27), 48% were seizure free after treatment. Among those who had presented with hemorrhage (n=255), the hemorrhage rate went from 28.7% from the first symptomatic episode to radiosurgery to 4.8% after radiosurgery. New or recurrent bleeding occurred in 61 (24%) with 3 (1%) dying from rebleeding. Radiation-induced edema occurred in 7% of patients. Cases treated with doses below 15 Gy were associated with fewer complications as were smaller lesions. However it is unclear how this evidence applies to symptomatic or incidentally discovered lesions as the natural history between symptomatic and asymptomatic lesions are very different. Asymptomatic lesions have been associated with bleeding rates of 0.6% for individuals without a previous hemorrhage."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}},{"RecommendationID":{"value":"REC245","properties":{"Recommendation":{"value":"• Certain medications (e.g., simvastatin, fasudil) can be used to stabilize CCM lesions by improving vascular integrity. Preventing progression of CCM lesions could be reached by using sorafenib. Trials on the use of these medications are ongoing. Current evidence is limited to in vitro data and animal models."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000534"}}]}}}},{"RecommendationID":{"value":"REC244","properties":{"Recommendation":{"value":"• Standard treatment for focal seizures using antiepileptic medication with early evaluation for surgical resection is appropriate."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}},{"RecommendationID":{"value":"REC246","properties":{"Recommendation":{"value":"• Standard treatment and management of headaches is indicated unless the headache is severe, prolonged, or progressive, or associated with new or worsening neurologic deficits. In this circumstance, urgent brain imaging could lead to surgical management."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1060","properties":{"Key Text":{"value":"Delivery"},"Tier":{"value":"3"},"Recommendation Text":{"value":"There is no contraindication for pregnancy and normal delivery in patients with identified small lesions, without recent clinical signs of hemorrhage. Pregnant women with FCCM who have had recent brain or spinal cord hemorrhage, epilepsy, or migraine require closer monitoring during pregnancy.  Baseline MRI one year prior to delivery is recommended to determine lesion locations. Seizure is the most common symptom of CCM hemorrhage during pregnancy. Exposure to antiepileptic medication during pregnancy may increase the risk for adverse fetal outcome, but is generally recommended because the fetal risk is typically less than that associated with fetal exposure to an untreated maternal seizure disorder. One review of 16 women with symptomatic CCMs (number of familial cases not reported) reported that hemorrhage occurred in 10, 2 patients opted for pregnancy termination, preterm delivery occurred in 4 cases with 1 case due to neurological symptoms at 30 weeks' gestation, and 9 women had a Caesarean section with a concern over CCM as the indication in 8 of these cases. Affected women and obstetricians are frequently concerned that the risk of increased blood pressure and intrathoracic pressure during stage 3 labor (pushing phase) could lead to CCM hemorrhage. However, in a study of 168 pregnancies (64 women), 28 with sporadic CCM and 36 with FCCM, only 5 symptomatic cerebral hemorrhages were reported, most commonly manifesting as seizures. Nineteen deliveries in this study were by Caesarean section, mostly due to fear of possible intracranial hemorrhage. The risk of CCM hemorrhage was higher in the familial cases (3.6% compared with 1.8% in sporadic cases)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU578","properties":{"Key Text":{"value":"Regular check-ups"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Regular check-ups, generally with an MRI once a year, are recommended after the discovery of a CCM, as additional asymptomatic lesions may appear with time."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000533"}},{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}},{"Surveillance":{"value":"ACSU577","properties":{"Key Text":{"value":"MRI"},"Tier":{"value":"4"},"Recommendation Text":{"value":"MRI is recommended in individuals experiencing new neurologic symptoms; however, interpretation can be difficult because new hemorrhages may be asymptomatic."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM388","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"4"},"Recommendation Text":{"value":"It is appropriate to evaluate both symptomatic and apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of screening and preventive measures. Evaluations can include molecular genetic testing if the pathogenic variant in the family is known and brain and/or spinal cord MRI imaging if the pathogenic variant in the family is not known."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA468","properties":{"Key Text":{"value":"Agents that increase risk of hemorrhage"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Patients should avoid agents that increase risk of hemorrhage; however, evidence cited for this recommendation indicates that these agents likely do not precipitate hemorrhage on patients with known CCMs. This recommendation includes certain analgesic medications such as nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen) and aspirin. Individuals with headaches and other pain should avoid these medications if suitable substitutes are available. Other medications that increase risk of hemorrhage (e.g., heparin, sodium warfarin [Coumadin]) should be avoided or, when such medications are necessary for treatment of life-threatening thrombosis, should be closely monitored by the affected individual’s medical team. One prospective study of 16 patients with CCMs, with no history of CCM hemorrhage, and taking antithrombotic therapy for the treatment of concurrent cardiovascular disease, including 5 taking warfarin and 11 using antiplatelet therapy by either aspirin (n=9) or clopidogrel (n=2), reported that none had a CCM hemorrhage during follow-up (mean period of 3.9 years). In a separate study, 40 patients with CCMs, 5 who presented with hemorrhage, were placed on antiplatelets alone (n=32), anticoagulants alone (n=6), or both (n=2) for the treatment of cardiovascular disease. One patient developed a prospective hemorrhage over the 258 person-years of follow-up (prospective hemorrhage rate 0.41% per person-year). Within a hospital thrombolysis registry, 1 of 9 patients with CCM versus 11 of 341 without CCM had a symptomatic intracerebral hemorrhage (p=0.27). Parenchymal hemorrhage occurred in 2 of the 9 patients with CCM versus 27 of 341 patients without CCM (p=0.17)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000534"}},{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA467","properties":{"Key Text":{"value":"Radiation"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Radiation to the central nervous system is associated with de novo lesion formation in FCCM. The pathology of these lesions appears to be histologically different from the cavernomas found prior to radiation. A case study of 2 patients with FCCM reported that, following therapeutic radiation, both patients developed very high numbers of CCMs within the radiation ports, supporting radiation as an accelerator of lesion formation and suggesting implications for risks of radiation in this disease."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 10000"},"Tier":{"value":"4"},"Notes":{"value":"The exact prevalence of pathogenic variants that lead to FCCM is unknown, though 40%-65% of cases of FCCM are attributable to pathogenic variants in KRIT1, 15-20% of cases are attributable to CCM2, and approximately 10-40% are attributable to PDCD10."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000534"}},{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}},"Penetrances":{"value":5,"items":[{"Penetrance":{"value":"ACPE543","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"It is estimated that up to 50% of persons with FCCM caused by a heterozygous pathogenic variant in KRIT1, CCM2, or PDCD10 are clinically asymptomatic, although at least least half of these asymptomatic individuals having identifiable CCM lesions on head imaging."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}},{"Penetrance":{"value":"ACPE544","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"One study of 64 probands and 138 relatives (mean age 42 years) who were heterozygous for a KRIT1 pathogenic variant reported a mean age of clinical onset of 30 years. Of all 202 individuals, 62% were symptomatic with the most common presenting events being seizure (55%) and cerebral hemorrhage (32%). Among the 138 non-proband relatives, 62 (45%) were asymptomatic; however, upon imaging 85% of asymptomatic relatives who underwent MRI were found to have CCM lesions. In all, 58% of those who were at least age 50 years had symptoms related to CCM."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}},{"Penetrance":{"value":"ACPE542","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Vascular skin lesions have been reported in 9% of individuals with a heterozygous pathogenic variant in KRIT1."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}},{"Penetrance":{"value":"ACPE545","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Spinal cord lesions are considered rare, reportedly occurring in fewer than 5% of affected\nIndividuals."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}},{"Penetrance":{"value":"ACPE541","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Retinal vascular lesions have been reported in 5% of FCCM individuals."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN248","properties":{"Key Text":{"value":"The clinical course of FCCM varies within and between families."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI254","properties":{"Key Text":{"value":"Interventions included in this report include regular MRI surveillance, surgical excision of CCMs, enhanced pregnancy monitoring, avoidance of antithrombotic and certain analgesic medications, and avoidance of radiation."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC248","properties":{"Key Text":{"value":"Most CCMs are detected incidentally or suspected when symptoms become evident. Up to 41% of cases with symptoms present with cerebral hemorrhage."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000533"}},{"Reference":{"value":"/coll/reference_model/doc/RF000534"}},{"Reference":{"value":"/coll/reference_model/doc/RF000532"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC027","properties":{"Recommendation":{"value":"However, general guidelines recommend EEG and neuroimaging following unprovoked seizures to identify structural abnormalities that may cause certain epilepsies, thus CCMs that lead to epilepsy are likely to be detected at this point."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000536"}}]}}}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2017-03-13"},"Scorers Present":{"value":2,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"williamsm"}}]}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Overall Score":{"value":"7CD"},"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"MRI","properties":{"Overall Score":{"value":"7CC"},"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Delivery management","properties":{"Overall Score":{"value":"8CC"},"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]},"FinalScoreOfScorers":{"value":9,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"1N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"1D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"sobreiran","properties":{"First Name":{"value":"Nara"},"Last Name":{"value":"Sobreira"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":9,"items":[{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"Of course it is possible that someone could have sudden death due to a bleed or seizure but I believe this is quite uncommon. So I went with a 2 instead of a 3."}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"I found it hard to parse between the penetrance for seizures and hemorrhage. If you do you might get below 40% for them individually, but these data are a \"snapshot\" and we know that the phenotype progresses. So I went with the higher estimate."}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":"Only evidence is in vitro and in animals. I think that falls firmly within the category of \"unknown\""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"We don't typically score burden/risk when efficacy is in question, right? So I'm not sure my \"3\" should be counted (but the system won't let me save something unless I've scored everything)."}}}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":"One waits for symptoms before doing imaging so I went with a zero"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"See my first comment"}}}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"1N","properties":{"Notes":{"value":"Again here, it seems that it's symptoms that trigger different care. Just having the mutation/condition without symptoms doesn't seem to be a persuasive argument for managing delivery differently. So I went with minimally effective"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"See my prior comment"}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"might need original reference search for this GeneTests section to parse out pathology:\nCerebral cavernous malformation (CCM) has been reported in infants and children, but the majority of individuals with FCCM present with symptoms between the second and fifth decades. In one study, 9% of individuals were symptomatic before age ten years, 62%-72% between ages ten and 40 years, and 19% after age 40 years [Gunel et al 1996]. A more recent study of affected individuals found that 20% were younger than age ten years and 33% younger than age 18 years at the time of referral for genetic testing; the age of symptom onset was not cited [Spiegler et al 2014].\nClinically affected individuals most often present with seizures (40%-70%), focal neurologic deficits (35%-50%), nonspecific headaches (10%-30%), and cerebral hemorrhage (32%) [Denier et al 2004b]."}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"Trials on the use of these medications are ongoing. Current evidence is limited to in vitro data and animal models"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"unclear that seeing the lesions helps the patient in any specific manner. Esp if surgical intervention is of questionable value."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"I was between 2 and 3 here, but because the risk of catastropic ICH was pretty low, I went with 2."}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"Evidence from just the one study so I used the prevalence of hemorrhage and seizure from that study to choose."}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":"No outcomes data available at this point."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"MR should be highly effective to identify lesions."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":"The one large study didn't indicate a difference in outcomes between C-section and vag deliveries."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"Used the 32% cerebral hemorrhage figure."}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"If I'm reading correctly, there are no data on effectiveness in humans."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Dropped to 2 because of statin side effects."}}}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"cerebral hemorrhage (32%)"}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"scored minimally effective b/c many legions remain asymptomatic"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"from Nat History data"}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"IND","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"MRI","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"??"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Delivery management","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"possible early delivery"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Hemorrhage","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Medication (simvastatin, fasudil)","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of 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Release"}}},"Date":{"value":"2017-09-08"},"ReleasedBy":{"value":"genbadmin","properties":{"First Name":{"value":"Genboree"},"Last Name":{"value":"Administrator Account"}}}}}}}},
{"ActionabilityDocID":{"value":"AC117","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"ABCD1","properties":{"HGNCId":{"value":"HGNC:61"},"GeneOMIM":{"value":"300371"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"300100"}}]}}}}]},"Syndrome":{"value":"Adrenoleukodystrophy","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"300100"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"139396"}}]},"Overview":{"value":""},"Acronyms":{"value":0,"items":[]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"ABCD1","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-11-16"},"Label":{"value":"ABCD1"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT"}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed"}}]}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Notes":{"value":"The birth incidence of X-linked adrenoleukodystrophy  (X-ALD) is estimated at 1:17,000 when including male hemizygotes and female heterozygotes. The estimated incidence in males ranges from 1:20,000 to 42,000. Based on US cases, female heterozygotes X-ALD cases are approximately 1.5 times more prevalent than male X-ALD."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000540"}},{"Reference":{"value":"/coll/reference_model/doc/RF000541"}},{"Reference":{"value":"/coll/reference_model/doc/RF000539"}},{"Reference":{"value":"/coll/reference_model/doc/RF000543"}},{"Reference":{"value":"/coll/reference_model/doc/RF000544"}},{"Reference":{"value":"/coll/reference_model/doc/RF000538"}},{"Reference":{"value":"/coll/reference_model/doc/RF000537"}},{"Reference":{"value":"/coll/reference_model/doc/RF000542"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"X-ALD is a metabolic disorder that affects the adrenal glands and central nervous system and is characterized by elevated serum very-long-chain fatty acids (VLCFA). The most severe form of X-ALD is childhood cerebral ALD (CCALD). CCALD is associated with adrenal insufficiency and cerebral demyelination with initial symptoms of emotional lability, hyperactive behavior, school failure, and visuo-spatial impairment followed by worsening cognitive and neurologic disability. \n\nAdult males with or without CCALD may develop adrenomyeloneuropathy (AMN) which is characterized by gradually progressive spastic paraparesis, sensory ataxia with impaired vibration sense, spinal cord symptoms, sphincter dysfunction (mostly urinary), pain in the legs, and impotence. An increased risk of psychiatric morbidity has been reported with depression often observed in patients with severe motor disability. Of those with AMN approximately 20% will also develop cerebral disease. After an initial progression, demyelinating lesions can stabilize spontaneously leading to moderate cognitive defections. However, the prognosis may be as poor as in CCALD. \n\nAdrenocortical insufficiency (AI, Addison’s disease) can be the presenting symptoms of X-ALD in boys and men years or decades before neurological symptoms. AI is often latent, but may present as fatigue, nausea, or even acute primary AI.  Hair of patients is often thin and sparse and patients often show baldness at an early age. AI generally presents without evidence of neurologic abnormality, however some decrease of neurologic disability (most commonly AMN) usually develops later. \n\nAn estimated 50-65% of heterozygous females can develop symptoms, usually of AMN, in mid- to late adulthood. In general the symptoms are similar, though less severe, in women; however, sensory ataxia, fecal incontinence, and pain in the legs are often more prominent in women with AMN.  Addison disease and cerebral disease are rare, occurring in 1-2% in heterozygotes."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000540"}},{"Reference":{"value":"/coll/reference_model/doc/RF000541"}},{"Reference":{"value":"/coll/reference_model/doc/RF000539"}},{"Reference":{"value":"/coll/reference_model/doc/RF000543"}},{"Reference":{"value":"/coll/reference_model/doc/RF000544"}},{"Reference":{"value":"/coll/reference_model/doc/RF000537"}},{"Reference":{"value":"/coll/reference_model/doc/RF000542"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"X-ALD phenotypes are not static. Presymptomatic males are nearly all at risk to develop neurologic (cerebral ALD, MMN) or endocrinologic (AI) symptoms.\n\nCCALD impacts between 31-57% of hemizygous males and typically presents between ages 2 and 12 and is associated with rapid cognitive and neurologic decline. ALD can also present in adolescence and adulthood, though much less frequently. If not treated with hematopoietic cell transplantation (HCT) and lifelong hormone replacement therapy, CCALD patients deteriorate, with severe disability within 2 to 5 years of symptom onset followed shortly by death.\n\nThe typical age of onset of AMN is after age 28-30; however, neurological symptoms can begin to manifest in childhood or adolescence. The course of AMN is highly variable. Within a mean of 13 years from recognized onset in adults, the rate of death or severe disability is 12%. The phenotype in most cases is slowly progressive, causing severe motor disability of the lower limbs over one or two decades. Progression in a specific individual cannot be predicted. There is a marked variability ranging from men with that are wheelchair bound by age 35 and others who can walk with a cane into their seventies.\n\nAI presents between age two and adulthood, most commonly by age 7.5 years. For 10% of affected individuals AI is the only presentation. Although the treatment of AI is very effective, the identification is often delayed and may lead to significant morbidity or even death.\n\nAffected heterozygous females generally have onset of symptoms in the 4th or 5th decade of life."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000539"}},{"Reference":{"value":"/coll/reference_model/doc/RF000543"}},{"Reference":{"value":"/coll/reference_model/doc/RF000544"}},{"Reference":{"value":"/coll/reference_model/doc/RF000537"}},{"Reference":{"value":"/coll/reference_model/doc/RF000542"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1064","properties":{"Key Text":{"value":"Establish extent of disease"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with X-ALD the following evaluations are recommended:\n- Neurologic examination\n- Brain MRI\n- Adrenal function tests\n- Medical genetics consultation"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000537"}}]}}}},{"Patient Management":{"value":"ACPM1065","properties":{"Key Text":{"value":"Adrenal hormone therapy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"If ACTH or cortisol abnormalities develop (indicative of AI), adrenal hormone therapy should be instituted. In addition, patients should be educated on the need for lifelong therapy and the management of physiologic stresses such as fever, vomiting, and surgery."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Adrenal insufficiency (males only)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000542"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC249","properties":{"Recommendation":{"value":"No data regarding the specific benefit of presymptomatic detection of AI were identified. Cortisol for adrenal hormone insufficiency has been studied in many other conditions and is recognized as efficacious. However, little is known about adrenal insufficiency specifically associated with X-ALD, including long-term prognosis, adherence to cortisol treatment, or the clinical consequences of incomplete treatment."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000543"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1063","properties":{"Key Text":{"value":"HCT"},"Tier":{"value":"2"},"Recommendation Text":{"value":"The only effective treatment for cerebral X-ALD is hematopoietic cell therapy (HCT).Due to the risk of mortality related to the procedure, HCT is recommended only for males with evidence of brain involvement."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurological/Cognitive decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000542"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC250","properties":{"Recommendation":{"value":"HCT remains the only therapeutic intervention that can arrest or slow the progression of cerebral demyelination in X-ALD, provided the procedure is performed very early (e.g., when affected boys or men have no or minor symptoms due to cerebral demyelinating disease)."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000539"}}]}}}},{"RecommendationID":{"value":"REC248","properties":{"Recommendation":{"value":"It seems likely that HCT is effective in adults with early stage cerebral ALD, but there are no published studies or cases describing this treatment. No published study directly compares treatment outcomes for individuals detected presymptomatically with those diagnosed symptomatically. Indirect evidence suggests that earlier age of treatment with HCT is associated with better outcomes.  However, HCT does not modify the course of AI or other types of myelopathy and neuropathy."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000539"}},{"Reference":{"value":"/coll/reference_model/doc/RF000543"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1066","properties":{"Key Text":{"value":"Physical therapy and counseling"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Physical therapy, management of urologic complications, and family and vocational counseling are of value for men with AMN."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000537"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU580","properties":{"Key Text":{"value":"Neurologic screening"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Women and men with X-ALD, with or without signs of AMN, should be evaluated yearly or bi-annual by a neurologist to screen for symptoms of AMN. These screens allow for timely administration of symptomatic treatment and specialist referral."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurological/Cognitive decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000539"}}]}}}},{"Surveillance":{"value":"ACSU579","properties":{"Key Text":{"value":"MRI"},"Tier":{"value":"2"},"Recommendation Text":{"value":"In asymptomatic men, serum ACTH, cortisol, and a brain MRI without contrast should be done annually starting at age 18. These recommendations are based on evidence that cerebral demyelination visible on brain MRI is the first evidence of the disease."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurological/Cognitive decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000544"}},{"Reference":{"value":"/coll/reference_model/doc/RF000542"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM389","properties":{"Key Text":{"value":"Family management"},"Tier":{"value":"3"},"Recommendation Text":{"value":"The diagnosis of X-ALD must be followed by extended family screening the enable the detection of 1) heterozygous women who can be offered prenatal/preimplantation diagnosis for future pregnancies and 2) boys or adult males who are asymptomatic but at risk to develop cerebral demyelination or adrenocortical insufficiency."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000539"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA469","properties":{"Key Text":{"value":""},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"No recommendations on circumstances to avoid were identified."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"X-linked"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Tier":{"value":"Not provided"},"Notes":{"value":"Given that the ABCD1 mutation is the only cause of X-ALD the prevalence of the genetic mutation is estimated to be the same as that of X-ALD among males.  The birth incidence of X-linked adrenoleukodystrophy  (X-ALD) is estimated at 1:17,000 when including male hemizygotes and female heterozygotes. The estimated incidence in males ranges from 1:20,000 to 42,000 and 1:28,000 in heterozygous females."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000540"}},{"Reference":{"value":"/coll/reference_model/doc/RF000541"}},{"Reference":{"value":"/coll/reference_model/doc/RF000539"}},{"Reference":{"value":"/coll/reference_model/doc/RF000543"}},{"Reference":{"value":"/coll/reference_model/doc/RF000538"}},{"Reference":{"value":"/coll/reference_model/doc/RF000537"}},{"Reference":{"value":"/coll/reference_model/doc/RF000542"}}]}}},"Penetrances":{"value":6,"items":[{"Penetrance":{"value":"ACPE549","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"The biochemical phenotype of elevated plasma concentration of VLCFA has nearly 100% penetrance in males."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000537"}}]}}}},{"Penetrance":{"value":"ACPE550","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Males with an ABCD1 mutation have a 31-57% risk of developing CCALD."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000539"}},{"Reference":{"value":"/coll/reference_model/doc/RF000543"}},{"Reference":{"value":"/coll/reference_model/doc/RF000544"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC071","properties":{"Recommendation":{"value":"Virtually all males with an ABCD1 mutation who reach adulthood will develop AMN."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000539"}}]}}}}]}}}},{"Penetrance":{"value":"ACPE547","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"20% of adult males with the AMN phenotype will develop cerebral demyelination later in life."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurological/Cognitive decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000539"}}]}}}},{"Penetrance":{"value":"ACPE551","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"Adrenal insufficiency has been reported in up to 35% of in males with an ABCD1 mutation."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Adrenal insufficiency (males only)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000539"}}]}}}},{"Penetrance":{"value":"ACPE546","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Symptoms similar to AMN develop in about 50-65% of women with a heterozygous ABCD1 mutation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000543"}}]}}}},{"Penetrance":{"value":"ACPE548","properties":{"Key Text":{"value":"1-4 %"},"Tier":{"value":"4"},"Notes":{"value":"Adrenal insufficiency and cerebral disease are rare in women with a heterozygous ABCD1 mutation (1%)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000543"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR228","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN249","properties":{"Key Text":{"value":"Widely varying phenotypes often co-occur in a single kindred or sibship."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000537"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC025","properties":{"Recommendation":{"value":"X-ALD has a highly variable phenotype even within families that ranges in age of onset, presenting symptoms, and severity from childhood through adulthood. Most mutations are unique and there is no recognized genotype-phenotype correlation within or across families, even with identical gene mutations."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000544"}}]}}}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI255","properties":{"Key Text":{"value":"Interventions include MRI, screening of hormone levels, physical therapy, and potentially adrenal hormone therapy and hematopoietic cell therapy. \nHSCT is associated with a 20% risk for morbidity and mortality."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000537"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC249","properties":{"Key Text":{"value":"The differences in symptom onset across the full lifespan, clinical area affected (e.g., adrenal cortex, cerebral or peripheral nervous system), and severity of symptoms in the affected area have complicated and delayed diagnosis of X-ALD by a mean of 9.9 years (range 1-33 years)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000544"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC028","properties":{"Recommendation":{"value":"In adults the diagnosis of X-ALD is often delayed; particularly when no family history of X-ALD is present and when clinical symptoms of Addison's disease are absent."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000539"}}]}}}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"1970-01-01"},"Scorers Present":{"value":0,"items":[]}}},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Overall Score":{"value":"11CC"},"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Overall Score":{"value":"9CC"},"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]},"FinalScoreOfScorers":{"value":7,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"3D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":7,"items":[{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"it's highly efficacious. I don't think that the extrapolation from different causes of AI warrants reducing the evidence as this is a well understood condition."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"appears to be unknown for adults if reading this right."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"could use scoring category that says degree of efficacy extrapolated from other conditions with this phenotype."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"I scored prevalence of AMN, not demyelination associated with AMN. This seems to be true for men and women."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"Surveillance is highly effective in identifying decline."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"I scored a 1 rather than 2 in that Addison's is amenable to treatment, although at presentation it can be a significant illness."}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"I scored C evidence level based on B level for AI, but not specifically studied in X-ALD (decrease in one evidence tier from extrapolation)"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"Wasn't sure how to account for males and females. Did we discuss scoring separately?"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Not much data on effectiveness, but went with 2 because of \"arrest or slow the progression\"."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"3 if we're just focused on MRI and neuro exam. 0 or 1 if we include HCT."}}}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"Will take the lead from physician colleagues here - appears that there can be wide variability in severity."}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Neurological/Cognitive decline","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"high % of men get AMN, and >50% women"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Neurological surveillance to plan initiation of HCT","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"No evidence in adult patients"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Adrenal insufficiency (males only)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Monitoring adrenal hormones with replacement as needed","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.3","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36126},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-03-07"},"ReleasedBy":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"}}}}}}}},
{"ActionabilityDocID":{"value":"AC118","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"SLC25A13","properties":{"HGNCId":{"value":"HGNC:10983"},"GeneOMIM":{"value":"603859"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"603471"}}]}}}}]},"Syndrome":{"value":"Adult‑onset type II citrullinemia","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"603471"}}]},"OrphanetIDs":{"value":2,"items":[{"OrphanetID":{"value":"247585"}},{"OrphanetID":{"value":"247582"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"SLC25A13","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-12-13"},"Label":{"value":"SLC25A13"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}},"Scorers Stage1":{"value":2,"items":[{"Scorer Stage1":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}},{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Hepatic encephalopathy","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modification with arginine and sodium pyruvate supplementation"}}]}}}},{"Outcome":{"value":"Liver failure","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplantation"}}]}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"The prevalence of adult‑onset type II citrullinemia (CTLN2) in Japan is 1 in 100,000-230,000. Until recently, citrin deficiency was thought to be restricted to Japan; however it is now recognized to be pan ethic with individuals in Israel, Pakistan, the United States, the United Kingdom, China, and the Czech Republic."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000546"}},{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Citrin deficiency can manifest in newborns as neonatal intrahepatic cholestasis caused by\ncitrin deficiency (NICCD) characterized by cholestasis and variable hepatic dysfunction with some children developing liver cirrhosis. Citrin deficiency can also manifest in older children as growth retardation and abnormalities of serum lipid concentrations characterized as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD).  CTLN2 can manifest in children or adults as recurrent hyperammonemia with neuropsychiatric symptoms.\n\nCTLN2 is associated with decreased activity of argininosuccinate synthase activity and protein in the liver but normal levels in other tissues such as the kidney, brain, and fibroblasts. Manifestations of CTLN2 are sudden and may resemble those of encephalopathy or urea cycle disorders and are often provoked by alcohol and surgery intake, medication and/or surgery. Symptoms may include nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma due to hyperammonemia. Death may result from brain edema. Complications occurring in more than 10% of individuals include: pancreatitis, hyperlipidemia, fatty liver, and hepatoma. Intrahepatic cholestasis may occur in rare cases; however these individuals may have had signs of NICCD in early childhood.\n\nCTLN2 patients are often characterized by fondness for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. Most individuals are thin with a BMI lower than 20 in 90% and below 17 in 40% of individuals."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000546"}},{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Symptoms of NICCD are generally not severe and symptoms often resolve by age one with appropriate treatment including vitamin supplementation and modified formula; however, in some rare cases infants succumb to infection and liver cirrhosis and others require liver transplantation. Onset of FTDCD is typically around age one to two years. One or more decades later, some individuals with NICCD or FTTDCD may develop CTLN2; however individuals with CTLN2 may or may not have a prior history of NICCD or FTTDCD.  The proportion of persons with NICCD or FTTDCD that evolves into CTLN2 is unknown. Historically, the time between NICCD and CTLN2 has been considered a silent, apparently healthy phase. However, laboratory and clinical abnormalities have been identified during this time and characterized as FTTDCD. \n\nOnset of CTLN2 is sudden, with a mean age of onset of 34.4 years with a range of 11-79 years.  The male to female ratio of CTLN is 2.4 to 1; the reasons for unequal expression of the phenotype is unknown. Some patients may present with nonalcoholic hepatic steatosis or may develop hepatic fibrosis or hepatocellular carcinoma. In some cases, rapid progression can lead to brain edema and death within a few years of onset if liver transplantation is not possible."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000546"}},{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1068","properties":{"Key Text":{"value":"Initial evaluation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs of an individual diagnosed with a phenotype of CTLN2 individuals should undergo an investigation of the carbohydrate, protein, and lipid composition of their diet and a medical genetics consultation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}}},{"Patient Management":{"value":"ACPM1069","properties":{"Key Text":{"value":"Dietary modification"},"Tier":{"value":"3"},"Recommendation Text":{"value":"To prevent hyperammonemia a diet rich in protein and lipids and low in carbohydrates is recommended. A low-protein/high-caloric (high carbohydrate) diet is harmful for individuals with CTLN2. A high carbohydrate diet may increase NADH production, disturb urea synthesis, and stimulate the citrate-malate shuttle, resulting in hyperammonemia, fatty liver, and hypertriglyceridemia."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Hepatic encephalopathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}}},{"Patient Management":{"value":"ACPM1067","properties":{"Key Text":{"value":"Arginine and sodium pyruvate"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Arginine and sodium pyruvate administration may be effective in preventing hyperammonemic crises (by reducing blood ammonia concentrations) and fatty liver, thereby delaying the need for liver transplantation."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Hepatic encephalopathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}}},{"Patient Management":{"value":"ACPM1071","properties":{"Key Text":{"value":"Liver transplantation"},"Tier":{"value":"3"},"Recommendation Text":{"value":"To date the most successful therapy for symptomatic patients has been liver transplantation which prevents episodic hyperammonemic crises, corrects the metabolic disturbances, and eliminates preferences for protein rich foods. Nearly all individuals with CTLN2 required liver transplantation in the past; however the introduction of arginine and sodium pyruvate has altered the situation."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Liver failure"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000546"}},{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}}},{"Patient Management":{"value":"ACPM1070","properties":{"Key Text":{"value":""},"Tier":{"value":"5"},"Recommendation Text":{"value":"No evidence was identified on the effectiveness of dietary treatment prior to the onset of symptoms of CTLN2. \n\nA review of CTLN2 case reports identified 77 cases with a mean age of onset was 34.1 years (range 12-60 years). 21 patients were treated with liver transplantation and all showed good prognosis with a survival rate of 100%. 56 patients received conservative treatment (without liver transplantation) and 29 died within a few years of onset (48% survival rate). Survival of patients treated with conservative medical treatment improved to 76.5% when limited to patients treated after 2003 compared to 39.5% survival prior to 2002. This improvement was attributed to the identification of the SLC25A13 gene as the cause of CTLN2 and development of more effective conservative therapy (arginine with carbohydrate-restricted diet). In addition, recent case reports have found that arginine and sodium pyruvate administration combined with a carbohydrate-restricted diet may be effective therapy for CTLN2."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Hepatic encephalopathy"}},{"Outcome":{"value":"Liver failure"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000547"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU581","properties":{"Key Text":{"value":"Biochemical monitoring"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Increases in plasma citrulline concentration and serum pancreatic secretory trypsin inhibitor (PSTI) suggest onset of CTLN2 and should prompt initiation of treatment. It is recommended that the following be measured every several months:\n-  Plasma ammonia concentration (especially in the evening or 2 hours after feeding)\n-  Plasma citrulline concentration\n-  Serum PSTI concentration."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM390","properties":{"Key Text":{"value":"Family management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"It is appropriate to clarify the genetic status of at risk asymptomatic sibs of a proband for citrin deficiency so that appropriate dietary management of infants (discontinuation of breast feeding and introduction of lactose free and/or MCT-enriched formulas) can be instituted before symptoms occur. Because asymptomatic or presymptomatic individuals with citrin deficiency do not always show biochemical abnormalities, definitive diagnosis of at risk relatives such as sibs would depend heavily on the molecular genetic findings in SLC25A13 in the index case. If both SLC25A13 pathogenic variants in the index case have been identified, molecular genetic testing can be used reliably. If only one SLC25A13 pathogenic variant is ascertained in the index case, it may not be feasible to definitively exclude the diagnosis in at risk relatives who have the one identified pathogenic variant. In such cases, serial clinical and biochemical assessment will be needed over time to confirm or rule out the diagnosis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA472","properties":{"Key Text":{"value":"Avoidance of glycerol"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Severe brain edema treated with glycerol-containing osmotic agents (the conventional treatment for hyperammonemia and brain edema) has resulted in continued deterioration and is contraindicated in those with CTLN2. Degradation of large amounts of glycerol and fructose generates NADH in the liver cytosol, which may disturb liver function and produce toxic substances.  Infusion of high concentration glucose may also exacerbate hyperammonemia. Mannitol infusion appears to be safer. A retrospective study of 3 patients with CTLN2 treated for brain edema at one institute and an additional 11 patients previously reported found that all 12 patients treated with 10% glycerol (with or without 20% mannitol) died due to rapidly deteriorating encephalopathy and brain edema while the 2 patients who received only 20% D-mannitol recovered with the disappearance of brain edema."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000546"}},{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA471","properties":{"Key Text":{"value":"Avoidance of alcohol"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Drinking alcohol can trigger the onset of CTLN2 because alcohol dehydrogenase (ADH) generates NADH in the cytosol of the liver."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA470","properties":{"Key Text":{"value":"Avoidance of acetaminophen and rabeprozole"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Acetaminophen and rabeprozole may trigger CTLN2."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Tier":{"value":"3"},"Notes":{"value":"In Japan, the frequency of homozygotes or compound heterozygotes for SLC25A13 pathogenic variants is calculated to be 1:17,000-21,000. Carrier or heterozygote rates have been estimated as 1:65-1:67. The estimated frequency in Korea is 1 in 50,000 and 1 in 17,000 in China with an estimated carrier frequency of 1:65 in China and 1:112 in Korea."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000546"}},{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}},"Penetrances":{"value":4,"items":[{"Penetrance":{"value":"ACPE553","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"No information on the penetrance of developing CTLN2 was identified."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}},{"Penetrance":{"value":"ACPE554","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"While the male-to-female ration of NICCD is roughly equal (73:80) the unequal male-to-female ratio of CTLN2 (2.4:1) suggests that among individuals with biallelic SLC25A13 variants, females are more resistant to the CTLN2 phenotype than males."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}}},{"Penetrance":{"value":"ACPE552","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Occasionally a parent of a child with NICCD may have two SLC25A13 pathogenic variants without severe symptoms of CTLN2, a finding in two of 48 fathers and one of 54 mothers tested in 163 Japanese families with NICCD."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]}}}},{"Penetrance":{"value":"ACPE555","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"One study of Japanese patients found that 17 of 19 patients (89%) with genetically confirmed CTLN2 had hepatic steatosis. Four patients (21%) had been diagnosed with nonalcoholic fatty liver disease before the appearance of neuropsychologic symptoms."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000546"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR229","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN250","properties":{"Key Text":{"value":"No significant correlation between SLC25A13 pathogenic variant types and decreased level of hepatic enzyme ASS activity/protein or age of onset in individuals with CTLN2 is observed."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI256","properties":{"Key Text":{"value":"Identified interventions include liver transplantation and/or dietary therapy, ongoing blood monitoring, and avoidance of possible triggers (e.g., medications and alcohol)."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC250","properties":{"Key Text":{"value":"More than 30% of individuals with CTLN2 have been misdiagnosed initially as having epileptic seizures and/or a psychological disorder (e.g., depression, schizophrenia); others may be diagnosed as having diseases such as hepatoma, pancreatitis, and hyperlipidemia."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000545"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2017-05-01"},"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"weaverm"}}]},"Notes":{"value":""}}},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Hepatic encephalopathy","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modification with arginine and sodium pyruvate 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encephalopathy","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modification with arginine and sodium pyruvate supplementation","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Liver failure","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplantation","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"0"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Hepatic encephalopathy","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modification with arginine and sodium pyruvate 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failure","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplantation","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"0"}}}}]}}}}]}}}}]}}},"Scorers":{"value":9,"items":[{"Scorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Hepatic encephalopathy","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"I just don't see the answer to this in the summary. Am I missing it?"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modification with arginine and sodium pyruvate supplementation","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"I based this on the GeneReview and generalized from other UCDs."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Liver failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"I just don't see the answer to this in the summary. Am I missing it?"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplantation","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Hepatic encephalopathy","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"I'm sure one can die in acute encephalopathic crises so I could be talked into a 3 but it would depend on how frequently this occurred, etc."}}},"Likelihood":{"value":"3D","properties":{"Notes":{"value":"This was hard to assess given the data presented. Since it's rare to have no symptoms and hepatic encephalopathy is a common manifestation of the disorder, I gave it a 3. But my confidence in this score is not high (thus my \"D\" for poor evidence). One side-note, I'm wondering if at some point we should separate out \"poor\" from \"controversial\" which are now lumped together under \"D\". They are very, very different things..."}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Dietary modification with arginine and sodium pyruvate supplementation","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Dietary modifications are one of our exemplars of a \"2\"."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Dietary modifications are one of our exemplars of a \"2\"."}}}}}},{"Intervention":{"value":"Arginine and sodium pyruvate adminitation","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Liver failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3D","properties":{"Notes":{"value":"See notes above. \"Liver failure\" is pretty non-specific."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplantation","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":"I'll bet I'm the only one with an evidence level of A given the Tier 3 designation. But how could the evidence be low that giving someone a new liver isn't highly effective in eliminating the problems associated with an in-born disease that primarily affects the liver?"}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Hepatic encephalopathy","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modification with arginine and sodium pyruvate supplementation","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"Could be convinced to go with 3 if diet modification is easy to adhere to."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Could be convinced to go with 3 if diet modification is easy to adhere to."}}}}}}]}}}},{"Outcome":{"value":"Liver failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplantation","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Depends on whether \"most successful therapy\" counts as a 2 or 3."}}},"Nature Of Intervention":{"value":"0","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Hepatic encephalopathy","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":"0C for both based on no estimates of penetrance and minimal evidence. I think that category fits better than E, non-systematically identified evidence, although that is also a possibility."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modification with arginine and sodium pyruvate supplementation","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Little evidence on actual effectiveness."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Liver failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplantation","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"0","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last 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transplantation","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Hepatic encephalopathy","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modification with arginine and sodium pyruvate supplementation","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"used Kimura et al paper"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Liver 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data"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modification with arginine and sodium pyruvate supplementation","properties":{"Effectiveness":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Liver failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2D","properties":{"Notes":{"value":"small study of liver pheno"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplantation","properties":{"Effectiveness":{"value":"3N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Hepatic encephalopathy","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Dietary modification with arginine and sodium pyruvate supplementation","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Liver failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplantation","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"OMIM pairs updated.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36128},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-11"},"ReleasedBy":{"value":"elizabeth.v.clarke@kpchr.org","properties":{"First Name":{"value":"Elizabeth"},"Last Name":{"value":"Clarke"}}}}}}}},
{"ActionabilityDocID":{"value":"AC119","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"CDC73","properties":{"HGNCId":{"value":"HGNC:16783"},"GeneOMIM":{"value":"607393"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"145000"}}]}}}}]},"Syndrome":{"value":"Hyperparathyroidism 2 - HPRT2","properties":{"OmimIDs":{"value":3,"items":[{"OmimID":{"value":"145000"}},{"OmimID":{"value":"145001"}},{"OmimID":{"value":"608266"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":""},"Acronyms":{"value":0,"items":[]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Title","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2016-12-29"},"Label":{"value":"Label"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium"}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph"}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound"}}]}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"The prevalence of hyperparathyroidism 2 (HPRT2; also known as hyperparathyroidism – jaw tumor syndrome) is not well established. Fewer than 300 cases from approximately 100 families have been reported to date. However, the variable penetrance and expressivity of the genes suggest that the real frequency may be underestimated."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}},{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"The primary finding of HPRT2 is primary hyperparathyroidism (pHPT) and is typically caused by a single parathyroid adenoma which is often cystic. A second parathyroid tumor may occur synchronously or metachronously months to decades after the first tumor. In 10-22% of cases, the pHPT is caused by parathyroid carcinoma. Individuals with pHPT may be asymptomatic or have mild manifestations, but in the case of parathyroid carcinoma severe hypercalcemic crises may occur. Clinical manifestations include nephrolithiasis, reduced bone mass, fatigue, muscle weakness, bone or joint pain, and constipation.  Ossifying fibromas of the mandible and/or maxilla may also manifest and, although benign, these tumors can be locally aggressive and may continue to enlarge if not treated. These tumors may be bilateral or multifocal, can recur, and can disrupt normal dentition, impair breathing, and be of significant cosmetic concern. Renal manifestations include kidney lesions (most commonly cysts), renal hamartomas, and (more rarely) Wilms tumor.  Renal cystic disease is variable and ranges from a few minor cysts to bilateral polycystic disease presenting with end-stage renal disease. Women with HPRT2 are at an increased risk for benign and malignant uterine tumors. Women with HPRT2 also have a higher rate of miscarriage and lower rate of fertility. \n\nTwo other CDC73-related disorders have been described: hyperparathyroidism 1 (HPRT1; also known as familial isolated hyperparathyroidism) and parathyroid carcinoma. HPRT1 is characterized by the presence of pHPT in the absence of other clinical features. Parathyroid carcinoma can include the following clinical manifestations: palpable neck mass, renal calculi, hoarseness, difficulty speaking or swallowing, muscle weakness, nausea/vomiting, altered mental status, and bone pain and/or pathologic fractures. Because of true variable expression, early identification of one but not all findings, or failure to identify all clinical features in HPRT2, it is more practical to consider CDC73-related disorders as a spectrum."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}},{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"In HPRT2, pHPT has been found in up to 95% of affected individuals, with onset typically in late adolescence or early adulthood and prevalence increasing with age. The median age of diagnosis of pHPT is 27 years (rage 12-58 years) with a prevalence that increases with age. The earliest reported age for pHPT is 7 years, parathyroid carcinoma is 20 years, and metastatic parathyroid carcinoma is 26 years.  However, onset may be delayed until the sixth decade, though some older healthy individuals with a pathogenic variant have been reported.  Multiglanular synchronous tumors at initial surgery occur in 20% of cases with a second tumor appearing metachronously in 24% of cases.   Lower penetrance of pHPT in females compared to males with HPRT2 has been reported. Uterine involvement is the second most common clinical feature and occurs in 57% of affected women. Ossifying fibromas occur in 30-40% individuals and usually are detectable before the third decade of life. Approximately 13-20% of individuals with HPRT2 have kidney lesions."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}},{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1073","properties":{"Key Text":{"value":"Evaluations at initial diagnosis"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with a CDC73-related disorder, the following are recommended at initial diagnosis:"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}},{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC252","properties":{"Recommendation":{"value":"• Evaluation for pHPT with measurement of concomitant intact parathyroid hormone levels and serum calcium concentration"},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]}}}},{"RecommendationID":{"value":"REC256","properties":{"Recommendation":{"value":"• Evaluation of standard end organ damage of pHPT"},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}}]}}}},{"RecommendationID":{"value":"REC255","properties":{"Recommendation":{"value":"• Baseline bone density of the lumbar spine, hips, and distal radius by dual-energy x-ray absorptiometry (DEXA) and 24-hour urine collection for calcium in individuals with evidence of pHPT"},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]}}}},{"RecommendationID":{"value":"REC251","properties":{"Recommendation":{"value":"• Evaluation for jaw tumors with panoramic jaw x-ray"},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}}]}}}},{"RecommendationID":{"value":"REC254","properties":{"Recommendation":{"value":"• Evaluation for renal lesions with renal ultrasound examination"},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}}]}}}},{"RecommendationID":{"value":"REC253","properties":{"Recommendation":{"value":"• Evaluation for uterine tumors with pelvic ultrasound examination, CT, or MR starting at reproductive age"},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}}]}}}},{"RecommendationID":{"value":"REC257","properties":{"Recommendation":{"value":"• Consultation with a medical genetics professional (e.g., medical geneticist, genetic counselor)."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1074","properties":{"Key Text":{"value":"Surgical management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"A recent consensus guideline recommended that patients at risk for hereditary pHPT be identified before surgery due to earlier onset, increased multiglandular involvement, and higher failure rate (i.e., persistent pHPT) after routine surgical treatment compared to sporadic pHPT, and should thus be treated differently. Total parathyroidectomy offers a simple surgical cure for pHPT, but results in permanent hypothyroidism and its associated morbidity. Thus, the surgical approach for treating hereditary pHPT is to obtain and maintain normocalcemia for the longest time possible, avoid hypocalcemia, minimize surgical morbidity, and facilitate future surgery for recurrent disease. Although the optimal surgical approach in CDC73-related pHPT has not yet been established and remains controversial, some consensus guidelines were proposed for more limited approaches."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}}]}}}},{"Patient Management":{"value":"ACPM1072","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Primary hyperparathyroidism during pregnancy may pose increased risks to the mother (symptomatic hypercalcemia) and to the fetus (intrauterine growth retardation, preterm delivery, intrauterine fetal demise, and/or postpartum neonatal hypocalcemia). Conservative observation may be appropriate for mild asymptomatic hypercalcemia, but for symptomatic primary hyperparathyroidism or evidence of adverse effects on the fetus, surgery (preferred in the second trimester) is required for definitive treatment. These women should be managed in conjunction with a maternal-fetal medicine specialist."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU582","properties":{"Key Text":{"value":"Regular screenings"},"Tier":{"value":"4"},"Recommendation Text":{"value":"There are currently no well-established surveillance guidelines for CDC73-related disorders. The following recommendations have been proposed:\n• Serum testing for biochemical evidence of pHPT [calcium, iPTH, and 25-(OH) vitamin D] annually\n• Consider periodic parathyroid ultrasound examination for the detection of non-functioning parathyroid carcinoma, which can develop on rare occasions\n• Dental panoramic x-ray with neck shielding at least every five years; dental providers should be notified of the diagnosis and the need for monitoring for osseous fibromas of the maxilla and mandible\n• Individuals who have undergone surgery for a jaw tumor require closer follow-up for possible tumor recurrence\n• Monitor for kidney lesions by renal ultrasound examination at least every five years, starting at the age of diagnosis\n• For women, starting at reproductive age, lifelong monitoring for uterine tumors with routine gynecologic care (including pelvic examination) and pelvic ultrasound examination in women with a menstrual disorder (particularly abnormal uterine bleeding or menorrhagia); care providers in obstetrics and gynecology should be notified of the risk of uterine tumors."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM391","properties":{"Key Text":{"value":"Genetic counseling and testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"First-degree relatives of a patient with a pathogenic variant should be identified and offered genetic counselling and appropriate genetic testing, and individuals who have inherited the mutation should be offered periodic biochemical screening, even if asymptomatic."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}}]}}}},{"Family Management":{"value":"ACFM392","properties":{"Key Text":{"value":"Regular screenings"},"Tier":{"value":"4"},"Recommendation Text":{"value":"The age at which genetic testing and surveillance should begin for at-risk relatives is also not well established, but the following recommendations have been proposed:\n• Testing and surveillance could be considered for pHPT and jaw tumors beginning at around age five to ten years, as this is the age of the youngest reported case of pHPT and is ten years younger than the earliest reported age of parathyroid carcinoma diagnosis\n• The age at onset of kidney lesions is not well described; renal ultrasound examination can be considered at the time of diagnosis\n• Uterine tumors have only been reported in adults; surveillance can begin at reproductive age."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA473","properties":{"Key Text":{"value":"Circumstances to avoid"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals with CDC73-related disorders should avoid:\n• Dehydration\n• Radiation exposure\n• Biopsy of extrathyroid tissue in the neck, which increases the risk of seeding of a possible parathyroid carcinoma."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE556","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"The main finding of HPRT2, pHPT, is found in almost 100% of CDC73 mutation carriers."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}}]}}}},{"Penetrance":{"value":"ACPE557","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Among affected individuals with HPRT2, the following outcomes have been reported:\n• Ossifying fibromas of the mandible or maxilla: 30-40%\n• Parathyroid cancer: 22%\n• Kidney lesions: 13-20%\n• Uterine involvement: 57%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}},{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN251","properties":{"Key Text":{"value":"HPRT2 has variable expression."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC026","properties":{"Recommendation":{"value":"The same pathogenic variant can cause all three phenotypes of CDC73-related disorders: HPT-JT, HPRT1, and parathyroid carcinoma."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]}}}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI257","properties":{"Key Text":{"value":"Interventions identified include imaging and biochemical surveillance and avoidance of dehydration, radiation, and certain biopsy technique which could be burdensome to the patient. In addition, surgical management of pHPT can result in permanent hypoparathroidism, laryngeal nerve injury, and the likelihood of repeat surgery due to recurrence."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000548"}},{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC251","properties":{"Key Text":{"value":"Interventions identified include imaging and biochemical surveillance and avoidance of dehydration, radiation, and certain biopsy technique which could be burdensome to the patient. In addition, surgical management of pHPT can result in permanent hypoparathroidism, laryngeal nerve injury, and the likelihood of repeat surgery due to recurrence."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000549"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Overall Score":{"value":"11CC"},"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Overall Score":{"value":"8CC"},"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Overall Score":{"value":"9CC"},"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]},"FinalScoreOfScorers":{"value":8,"items":[{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"sobreiran","properties":{"First Name":{"value":"Nara"},"Last Name":{"value":"Sobreira"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":8,"items":[{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"Considered 2 given that hypercalcemic crises can occur, however since those are rarer went with a 1."}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"Effectiveness is detecting chemical pHPT. The evidence level is problematic as there's likely strong evidence for detecting pHPT in general, but limited evidence in this disorder. Scored a C but could easily be convinced to raise this."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"Went with midpoint of 30-40%"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"Same issue for evidence here. It's not an issue for detection but probably more for the periodicity of the screening."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"Scored risk for ESRD here. Wilm's tumor would also score a 2."}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"Ditto."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"There's no question that we're very good at detecting and managing pHPT, in spite of some issues regarding the optimal surgical approach."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"This was a tough one; I'm assuming that detecting these when they are more operable is a good thing but I'm not sure about the evidence."}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Moderately effective is the best I could give this. It's pretty hard to intervene when you see cysts, for example. So a \"2\" is generous in my mind and I'd easily be talked into a \"1\""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"3N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"Not much evidence to do, but hard to imagine not monitoring these parameters"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"No data on effectiveness"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"sobreiran","properties":{"First Name":{"value":"Nara"},"Last Name":{"value":"Sobreira"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Morbidity from primary hyperparathyroidism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance of parathyroid hormone and calcium","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Complications of osseous fibromas","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with panoramic radiograph","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity from advanced renal lesions","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last 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lesions","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"1 or 2; small% will be advanced"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance with renal ultrasound","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"?data"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"OMIM pairs updated.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36130},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-11"},"ReleasedBy":{"value":"elizabeth.v.clarke@kpchr.org","properties":{"First Name":{"value":"Elizabeth"},"Last Name":{"value":"Clarke"}}}}}}}},
{"ActionabilityDocID":{"value":"AC121","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"PYGM","properties":{"HGNCId":{"value":"HGNC:9726"},"GeneOMIM":{"value":"608455"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"232600"}}]}}}}]},"Syndrome":{"value":"Glycogen Storage Disease V","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"232600"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"368"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"PYGM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-03-06"},"Label":{"value":"PYGM"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}},"Scorers Stage1":{"value":2,"items":[{"Scorer Stage1":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}},{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen"}}]}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"The prevalence of Glycogen Storage Disease Type V (GSDV), also known as McArdle disease, has been estimated at 1:100,000-170,000. Recent data based on exome sequencing indicates that the prevalence may be closer to 1:50,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000551"}},{"Reference":{"value":"/coll/reference_model/doc/RF000550"}},{"Reference":{"value":"/coll/reference_model/doc/RF000552"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Symptoms of GSDV are caused by the inability to produce the enzyme muscle glycogen phosphorylase, which is critical for glycolysis. The usual presentation of GSDV is exercise intolerance in the first few minutes of exercise which is relieved by rest. Symptoms are usually precipitated by isometric or sustained vigorous aerobic exercise. Manifestations may include stiffness of muscles, myalgia, fatigue, tachycardia, and severe muscle pain. If exercise continues at the same intensity, muscle spasms may occur which can lead to muscle damage. Fixed muscle weakness, generally of proximal muscles, occurs in 25% of affected individuals and is more likely to occur in individuals over age 40.  Other, less common, presentations of GSDV include: severe para-spinal wasting and weakness, severe obstructive hypertrophic cardiomyopathy, acute renal failure in the absence of exertion, hyper-CK-emia (elevations of serum creatine kinase (CK) activity) in infants and adolescents, and clumsiness in children.\n\nMost individuals learn to improve exercise tolerance through exploiting the “second wind” phenomenon where relief of myalgia and rapid fatigue occur after a few minutes of rest due to a metabolic shift to fatty acid oxidation. The ability to develop a metabolic second wind is increased in those who keep physical fit through aerobic exercise (e.g., walking). However, those who undergo sustained or strenuous exercise (e.g., lifting heavy weights or sprinting) carry a high risk of muscle damage."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000550"}},{"Reference":{"value":"/coll/reference_model/doc/RF000553"}},{"Reference":{"value":"/coll/reference_model/doc/RF000552"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Age of onset is frequently in the few decades of life but can vary, with some individuals manifesting progressive weakness starting in the sixth or seventh decade of life. However, many individuals remember painful symptoms from early childhood. The condition is relatively stable throughout life; however, a worsening of symptoms may occur in middle age accompanied by some muscle wasting. 50% have recurrent episodes of myoglobinuria following intense exercise that could eventually result in acute renal failure, although reported cases are rare. Renal failure is almost always reversible, but emergency treatment is required. Most individuals are able to have relatively normal lives through adjusting daily activities."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000550"}},{"Reference":{"value":"/coll/reference_model/doc/RF000553"}},{"Reference":{"value":"/coll/reference_model/doc/RF000552"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1076","properties":{"Key Text":{"value":"Initial evaluation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with GSDV the following evaluations are recommended:\n- Physical examination with emphasis on muscle strength/weakness\n- Basal serum CK activity"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000550"}}]}}}},{"Patient Management":{"value":"ACPM1077","properties":{"Key Text":{"value":"Training for appropriate exercise regimen"},"Tier":{"value":"3"},"Recommendation Text":{"value":"In some individuals, improvement in exercise and circulatory capacity has been reported following aerobic training, probably caused by the increased circulatory capacity, which facilitates delivery of blood-borne fuels. Therefore, it has been recommended that individuals engage in regular, moderate aerobic activity."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000550"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC259","properties":{"Recommendation":{"value":"In some individuals, improvement in exercise and circulatory capacity has been reported following aerobic training, probably caused by the increased circulatory capacity, which facilitates delivery of blood-borne fuels. Therefore, it has been recommended that individuals engage in regular, moderate aerobic activity."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000552"}}]}}}},{"RecommendationID":{"value":"REC258","properties":{"Recommendation":{"value":"Some observational studies have examined the effect of aerobic exercise.\n- 8 unrelated patients with GSDV underwent 14 weeks of exercise training on a stationary bike. Individuals showed increases in work capacity (50% increase in the first 6 minutes, 30% increase after “second wind”), oxygen uptake (14%), cardiac output (15%), and mitochondrial enzyme levels (citrate synthase:  80%, beta hydroxyacyl coenzyme A dehydrogenase: 62%). Patients did not experience pain or cramping. A “second wind” was present in patients before and after training.\n- 9 individuals with GSDV underwent an eight-month supervised aerobic exercise program of walking or cycling. Individuals showed increases in peak power output (25%), VO2peak (44%), and ventilary threshold (27%). CK levels were lower at the end of the training period, suggesting that training did not induce muscle damage. No adverse events were reported from training."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000550"}},{"Reference":{"value":"/coll/reference_model/doc/RF000552"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1075","properties":{"Key Text":{"value":"Pharmacological and nutritional therapies"},"Tier":{"value":"1"},"Recommendation Text":{"value":"A systematic review of pharmacological and nutritional therapies for GSDV identified 13 studies including a total of 85 patients, but there are no related recommendations for use of these therapies. Literature was limited by the small number of patients included in these studies (range: 1-19 patients) and a lack of replication of interventions. Overall, no benefit was found with: D-ribose, glucagon, verapamil, vitamin B6, branched chain amino acids, dantrolene sodium, and high-dose creatinine. Low quality of evidence suggested some benefit from the use of creatinine, oral sucrose, Ramipril, and a carbohydrate-rich diet in some measures; however, the significance of these clinical benefits is unclear."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000553"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU583","properties":{"Key Text":{"value":"Physical exam"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Appropriate surveillance includes annual routine physical examination and review of diet."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000550"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM393","properties":{"Key Text":{"value":"Family management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Early diagnosis of GSDV in relatives at risk may improve long-term outcome by heightened awareness of the need to avoid repetitive episodes of muscle damage that may lead to rhabdomyolysis and fixed weakness."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000550"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA477","properties":{"Key Text":{"value":"Static contractions"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Exercises that involve heavy static contractions or induce severe myalgia should be avoided. These may include:\n- Static muscle contractions (e.g., handgrip exercises)\n- Static muscle contractions or heavy loads on low muscle mass (e.g., weight lifting)\n- Dynamic exercises at a high-intensity level (e.g., competitive ball games)\n- Exercises with a high involvement of eccentric (lengthening) muscle contractions (e.g., jumps)\n- Very intense dynamic aerobic exercise (e.g., running, strenuous swimming, or cycling) except in individuals who are very fit and well habituated."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000550"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA475","properties":{"Key Text":{"value":"Sedentary lifestyle"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Individuals should avoid a totally sedentary life, which induces deconditioning."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000550"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA474","properties":{"Key Text":{"value":"General anesthetics"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Risk of acute muscle damage is reported with certain general anesthetics (usually muscle relaxants and inhaled anesthetics), although in practice, problems appear to be rare and GSDV does not appear to cause severe perioperative problem in routine anesthetics. Measures for preventing muscle ischemia and rhabdomyolysis should be taken in individuals with GSDV. One report of a 2 year old boy not previously recognized as having GSDV reported hyperthermia, pulmonary edema, and rhabdomyolysis following surgery for tetralogy of Fallot (patient had no prior surgeries). The patient died 10 days following surgery. While the clinicians believe that an adverse reaction to protamine was the likely cause of the adverse events, it is suggested that the presence of GSDV may have rendered the patient more susceptible to these adverse reactions."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000554"}},{"Reference":{"value":"/coll/reference_model/doc/RF000550"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA476","properties":{"Key Text":{"value":"Statins"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Clinicians should be cautious when recommending statins to individuals who have GSDV or are carriers for a PYGM pathogenic mutation due to a potentially increased risk of statin-induced myopathy. A study of 136 individuals with statin-induced myopathy identified 20-fold more PYGM heterozygotes than expected for the general population and 12-fold greater than the control group in the study (p=0.004)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000550"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Tier":{"value":"5"},"Notes":{"value":"Recent data based on exome sequencing indicates that the prevalence may be closer to 1:50,000 indicating that the disease may be underdiagnosed or the penetrance of some variants are overestimated."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000551"}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE558","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"No information on penetrance was identified for individuals detected based on genetic mutation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}},{"Penetrance":{"value":"ACPE559","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"5"},"Notes":{"value":"Cross-sectional data from a registry of all 239 patients diagnosed with GSDV in the Spanish National Health system found 99.5% of patients reported a history of acute crises of exercise intolerance. 50% of cases reported recurrent myoglobinuria. 86% of patients reported experiencing the “second wind phenomenon”."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000555"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR230","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN252","properties":{"Key Text":{"value":"There is considerable heterogeneity in the severity of symptoms, even in individuals who possess the same genetic mutation. This may be due the presence of modifying genes, differences in lifestyle, and aerobic capacity."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000553"}},{"Reference":{"value":"/coll/reference_model/doc/RF000552"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI258","properties":{"Key Text":{"value":"Potential interventions include aerobic exercise training, avoidance of static contractions, and caution with certain anesthetics and statins."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC252","properties":{"Key Text":{"value":"Many individuals remember painful symptoms from early childhood, but the disorder is rarely diagnosed before adulthood."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000550"}}]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2017-05-01"},"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"weaverm"}}]},"Notes":{"value":""}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Overall Score":{"value":"9NC"},"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":9,"items":[{"FinalScoreOfScorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed 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contractions","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last 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Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"1D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":9,"items":[{"Scorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3B","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"Seems sufficiently morbid to me to get a \"2\""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":"Of course, these were all people who had a diagnosis so it's little wonder they had symptoms! But since this has long been recognized as a Mendelian disorder it seems logical that the penetrance is quite high."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"The studies are small and limited and they didn't go on long enough to look at the incidence of acute crises so I couldn't give it a 3. I could probably be talked down to a 1."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"This probably reflects my own personal aversion to exercise more than anything else :)\nI'll bet Kristy gives it a \"3\"..."}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"Didn't quite seem to rise to a 2, but could be convinced that the fixed muscle weakness is sufficiently severe for a 2."}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"We don't know in the setting of genotypically identified individuals."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":"Went with the Cochrane Review statement, as it was a higher tier and the small studies didn't include a control group."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"I'm comfortable with the moderate effectiveness, but the evidence level is variable. I assume the tier 1 is based on the Cochrane systematic review. I'd be comfortable with either A or C"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"Hard to know if this is minimal or moderate improvement; I've been conservative in my score of a 1. Similarly with evidence level."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"Was b/w 1 and 2"}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"1.5 - depends on exercise"}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":"just exercise intolerance"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"1D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle damage, and fixed contractions","properties":{"Severity":{"value":"0","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Training for an appropriate exercise regimen","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"OMIM pairs updated.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36132},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-11"},"ReleasedBy":{"value":"elizabeth.v.clarke@kpchr.org","properties":{"First Name":{"value":"Elizabeth"},"Last Name":{"value":"Clarke"}}}}}}}},
{"ActionabilityDocID":{"value":"AC122","properties":{"Status":{"value":"Released - Under Revision"},"Genes":{"value":6,"items":[{"Gene":{"value":"MUT","properties":{"HGNCId":{"value":"HGNC:7526"},"GeneOMIM":{"value":"609058"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"251000"}}]}}}},{"Gene":{"value":"MMAA","properties":{"HGNCId":{"value":"HGNC:18871"},"GeneOMIM":{"value":"607481"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"251100"}}]}}}},{"Gene":{"value":"MMAB","properties":{"HGNCId":{"value":"HGNC:19331"},"GeneOMIM":{"value":"607568"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"251110"}}]}}}},{"Gene":{"value":"MMADHC","properties":{"HGNCId":{"value":"HGNC:25221"},"GeneOMIM":{"value":"611935"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"277410"}}]}}}},{"Gene":{"value":"MCEE","properties":{"HGNCId":{"value":"HGNC:16732"},"GeneOMIM":{"value":"608419"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"251120"}}]}}}},{"Gene":{"value":"MMACHC","properties":{"HGNCId":{"value":"HGNC:24525"},"GeneOMIM":{"value":"609831"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"277400"}}]}}}}]},"Syndrome":{"value":"Methylmalonic Academia","properties":{"OmimIDs":{"value":6,"items":[{"OmimID":{"value":"251000"}},{"OmimID":{"value":"251100"}},{"OmimID":{"value":"251110"}},{"OmimID":{"value":"277410"}},{"OmimID":{"value":"251120"}},{"OmimID":{"value":"277400"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":"Inborn error of metabolism associated with elevated methylmalonic acid (MMA) in the blood and urine without associated hyperhomocysteinemia or homocystinuria, resulting from the failure to convert methymalonyl-CoA into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix. \\n\\nCaused by a complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 and mut- enzymatic subtypes, respectively), a defect in the transport or synthesis of its cofactor adenosylcobalamin (cblA, cblB, or cblD variant type 2), or a deficiency of the enzyme methylmalonyl-CoA epimerase. \\n\\nOnset ranges from the neonatal period to adulthood. All phenotypes demonstrate periods of relative health and intermittent metabolic decompensation, usually associated with infections and stress.\\n\\nThe atypical and \"benign\"/adult form is associated with mildly increased urinar excretion of methylmalonate, though it is uncertain whether some of these individuals would develop symptoms"},"Acronyms":{"value":2,"items":[{"Acronym":{"value":"Methylmalonic aciduria"}},{"Acronym":{"value":"MA"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":5,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Methylmalonic acidemia","properties":{"NumberOfHits":{"value":5},"Date":{"value":"2015-08-18"},"Label":{"value":"OMIM1"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"GeneReview","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Isolated Methylmalonic 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aciduria","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-08-18"},"Label":{"value":"NGC2"}}}},{"SearchString":{"value":"MUT","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-08-18"},"Label":{"value":"NGC3"}}}},{"SearchString":{"value":"MMMA","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-08-18"},"Label":{"value":"NGC4"}}}},{"SearchString":{"value":"MMAB","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-08-18"},"Label":{"value":"NGC5"}}}},{"SearchString":{"value":"MMADHC","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-08-18"},"Label":{"value":"NGC6"}}}},{"SearchString":{"value":"MCEE","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-08-18"},"Label":{"value":"NGC7"}}}}]},"Notes":{"value":""}}}},{"Source":{"value":"PUBMED","properties":{"SearchStrings":{"value":2,"items":[{"SearchString":{"value":"\"Methylmalonic aciduria cblB type\" [Supplementary Concept] OR \"Methylmalonic aciduria cblA type\" [Supplementary Concept] OR \"Methylmalonic Aciduria and Homocystinuria, CblD Type\" [Supplementary Concept] OR \"Methylmalonic Aciduria due to Methylmalonyl-CoA Mutase Deficiency\" [Supplementary Concept] OR \"Methylmalonic acidemia\" [Supplementary Concept","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2015-08-18"},"Label":{"value":"PUBMED1"}}}},{"SearchString":{"value":"((((\"Methylmalonyl-CoA Mutase\"[Mesh]) OR \"MMAA protein, human\" [Supplementary Concept]) OR \"cob(I)alamin adenosyltransferase\" [Supplementary Concept]) OR \"MMADHC protein, human\" [Supplementary Concept]) OR \"methylmalonyl-coenzyme A racemase\" [Supplementary Concept]","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2015-08-18"},"Label":{"value":"PUBMED2"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"No"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}},"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"genbadmin","properties":{"First Name":{"value":"Genboree"},"Last Name":{"value":"Administrator Account"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"No"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity from methylmalonic aciduria","properties":{"Interventions":{"value":5,"items":[{"Intervention":{"value":"Protein restriction (Vitamin B12 responsive)"}},{"Intervention":{"value":"Monitor kidney function (Vitamin B12 responsive)"}},{"Intervention":{"value":"Vitamin B12 (Vitamin B12 responsive)"}},{"Intervention":{"value":"Protein restriction (Vitamin B12 non - responsive)"}},{"Intervention":{"value":"Monitor kidney function (Vitamin B12 non - responsive)"}}]}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Notes":{"value":"Prevalence of methylmalonic aciduria (MMA) has been estimated between 1/50,000 to 1/100,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000345"}},{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"MMA is an inborn error of vitamin B12 metabolism characterized by gastrointestinal and neurometabolic manifestations resulting from decreased function of the mitochondrial enzyme methylmalonyl-CoA mutase. Clinical signs, which typically present neonatally or during infancy, include lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and muscle hypotonia, as well as developmental delay, intellectual disability, hepatomegaly and coma. Longterm consequences of the disorder include neurological damage due to metabolic stroke affecting the brain stem, and end stage renal failure. The adult or “benign” form of MMA is associated with a mildly increased urinary excretion of methylmalonate, but it is uncertain if some of these individuals will develop symptoms. This form of MA is not well understood, though patients are typically viewed as stable, but may be prone to acute metabolic decompensation."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000345"}},{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Onset ranges from the neonatal period to adulthood. The most common MMA phenotype presents during infancy where infants are normal at birth, but rapidly develop clinical manifestations. All phenotypes demonstrate periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. Survival expectancy depends on the MMA subtype."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1083","properties":{"Key Text":{"value":"Establish extent of disease"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease in an individual diagnosed with isolated MMA, the following evaluations are recommended:\\n- serum chemistry panel (Na , K , CI , glucose, urea, creatinine, AST, ALT, alkaline phosphatase, bilirubin [T/U], triglycerides, and cholesterol)\\n- complete blood count with differential\\n- arterial or venous blood gas\\n- plasma ammonium concentration\\n- formal urinalysis\\n- quantitative plasma amino acids\\n- urine organic acid analysis by gas chromatography and mass spectrometry (GC-MS)\\n- if possible, measurement of plasma concentrations of methylmalonic acid, methylcitrate, free and total carnitine, and an acylcarnitine profile to document propionylcarnitine (C3 species) concentration."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]}}}},{"Patient Management":{"value":"ACPM1081","properties":{"Key Text":{"value":"Nutritional management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Nutritional management should include a low-protein, high-calorie diet."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]}}}},{"Patient Management":{"value":"ACPM1078","properties":{"Key Text":{"value":"Hydroxocobalamin injections"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Patients who are vitamin B12 responsive, should be administered hydroxocobalamin injections every day to every other day. This regimen should be adjusted for the patient’s age and weight."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]}}}},{"Patient Management":{"value":"ACPM1079","properties":{"Key Text":{"value":"Carnitine"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Carnitine can be given daily as a dietary supplement to increase intracellular CoA pools and enhance the excretion of propionylcarnitine."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]}}}},{"Patient Management":{"value":"ACPM1080","properties":{"Key Text":{"value":"Antibiotics"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Antibiotics can be used to reduce the production of proprionate from gut flora, though the recommended types, dosage, frequency may vary"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]}}}},{"Patient Management":{"value":"ACPM1082","properties":{"Key Text":{"value":"Medic Alert bracelets"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Medic Alert bracelets allow for easily accessed detailed emergency treatment protocols to\\nfacilitate care in the event of an episode"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU584","properties":{"Key Text":{"value":""},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"Information on surveillance was not identified."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM394","properties":{"Key Text":{"value":"Biochemical testing"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Siblings of patients should be evaluated using biochemical testing. Genetic testing is possible when the mutation is known"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA478","properties":{"Key Text":{"value":"Avoid fasting"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Patients are recommended to avoid fasting and increased dietary protein and to regulate their stress."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Tier":{"value":"4"},"Notes":{"value":"Virtually all cases are attributed to a mutation in MUT, MMA, MMAB, MCEE, or MMADHC. Thus the prevalence of genetic mutations should be similar to prevalence estimates for methylmalonic aciduria (between 1/50,000 to 1/100,000)."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE560","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"Information on penetrance was not available."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR231","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information on relative risk was not available."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN253","properties":{"Key Text":{"value":"Clinical presentation of methylmalonic aciduria can vary and may present with severe manifestations during the neonatal period or as an atypical or “benign” form with onset during adulthood with mild clinical outcomes."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI259","properties":{"Key Text":{"value":"Identified interventions include Medic Alert bracelets, B12 administration, avoidance of fasting and increased dietary protein, and stress regulation."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC253","properties":{"Key Text":{"value":"Without newborn screening, an individual with the adult onset form would likely escape detection prior to their first episode."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000333"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity from methylmalonic aciduria","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3D"},"Interventions":{"value":5,"items":[{"Intervention":{"value":"Protein restriction (Vitamin B12 responsive)","properties":{"Overall Score":{"value":"8DC"},"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Monitor kidney function (Vitamin B12 responsive)","properties":{"Overall Score":{"value":"10DD"},"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Vitamin B12 (Vitamin B12 responsive)","properties":{"Overall Score":{"value":"10DC"},"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Protein restriction (Vitamin B12 non - responsive)","properties":{"Overall Score":{"value":"8DC"},"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Monitor kidney function (Vitamin B12 non - responsive)","properties":{"Overall Score":{"value":"10DD"},"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]},"FinalScoreOfScorers":{"value":1,"items":[{"FinalScoreOfScorer":{"value":"genbadmin","properties":{"First Name":{"value":"Genboree"},"Last Name":{"value":"Administrator Account"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity from methylmalonic aciduria","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":5,"items":[{"Intervention":{"value":"Protein restriction (Vitamin B12 responsive)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Monitor kidney function (Vitamin B12 responsive)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Vitamin B12 (Vitamin B12 responsive)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Protein restriction (Vitamin B12 non - responsive)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Monitor kidney function (Vitamin B12 non - responsive)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}}]}}}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"Name of the outcome changed: Reduced Morbidity => Morbidity from methylmalonic aciduria\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36135},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-03-21"},"ReleasedBy":{"value":"genbadmin","properties":{"First Name":{"value":"Genboree"},"Last Name":{"value":"Administrator Account"}}}}}}}},
{"ActionabilityDocID":{"value":"AC124","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"NF1","properties":{"HGNCId":{"value":"HGNC:7765"},"GeneOMIM":{"value":"613113"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"162200"}}]}}}}]},"Syndrome":{"value":"Neurofibromatosis type 1","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"162200"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"636"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-03-27"},"Label":{"value":"OMIM"}}}}]},"Notes":{"value":""}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes"}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance"}}]}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 5000"},"Notes":{"value":"Neurofibromatosis type 1 (NF1) occurs with a birth incidence of 1 in 2,500-3,000 and a prevalence of 1 in 3,500-5,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000561"}},{"Reference":{"value":"/coll/reference_model/doc/RF000562"}},{"Reference":{"value":"/coll/reference_model/doc/RF000564"}},{"Reference":{"value":"/coll/reference_model/doc/RF000563"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Characteristics symptoms of NF1 include: multiple café-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas (benign peripheral nerve sheath tumors), iris Lisch nodules (hamartomas), and characteristics bony dysplasia of the long bones and sphenoid wing. Most individuals have normal intelligence, but learning disabilities are present in at least 50%. Less common but potentially more serious manifestations can include: other forms of tumors (e.g., plexiform neurofibromas, malignant peripheral nerve sheath tumors), ocular (e.g., optic gliomas), cognitive (e.g. intellectual disability), neurologic (e.g., seizures, migraines), musculoskeletal (e.g., scoliosis), and vascular/cardiac (e.g., hypertension) findings. \nWomen with NF1 have a substantially increased risk of developing breast cancer before age 50 years with estimated risk at least three times greater than the general population. People with NF1 may also be at increased risk for many other common cancers."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000565"}},{"Reference":{"value":"/coll/reference_model/doc/RF000561"}},{"Reference":{"value":"/coll/reference_model/doc/RF000562"}},{"Reference":{"value":"/coll/reference_model/doc/RF000167"}},{"Reference":{"value":"/coll/reference_model/doc/RF000564"}},{"Reference":{"value":"/coll/reference_model/doc/RF000563"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Approximately 90% of individuals with NF1 will have two or more diagnostic criteria by age 6, 97% by age 8, and all do so by 20 years of age. The most common presenting feature is multiple café-au-lait spots. Many individuals with NF1 develop only cutaneous manifestations of the disease and Lisch nodules, but the frequency of more serious complications increases with age. Bony manifestations are congenital, and café-au-lait spots are present at birth and increase in number the first few years of life. Discrete cutaneous and subcutaneous neurofibromas are rare before late childhood. The total number of neurofibromas in adults vary from a few to thousands, with more developing throughout life, though the rate of appearance may vary from year to year. Many women experience a rapid increase in the number and size of neurofibromas during pregnancy. Plexiform neurofibromas generally grow slowly over years, but rapid growth can occur in benign lesions, especially in early childhood. Most are asymptomatic; however, when symptomatic, plexiform neurofibromas can cause disfigurement and may compromise function or even jeopardize life. Malignant peripheral nerve sheath tumors tend to occur at a much younger age in people with NF1, often in adolescence or early adulthood. Optic gliomas, which may lead to blindness, are generally present before age six with loss of visual acuity or proptosis, but may not become symptomatic until later in childhood or adulthood. Symptomatic optic gliomas progress slowly, and may even regress. \nThe significant risk of breast cancer appears to begin at age 30 and drop after age 50 where risk is not significantly different from that of the general population.\nThe median life expectancy of individuals with NF1 is approximately 8-15 years lower than the general population with early causes of death including malignancy and vasculopathy. In a study of US death certificates, mean and median ages of death were estimated as 54.4 and 59 years respectively. Cosmetic, medical, behavioral, and social features of the disease all may compromise the quality of life in people with NF1."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000565"}},{"Reference":{"value":"/coll/reference_model/doc/RF000566"}},{"Reference":{"value":"/coll/reference_model/doc/RF000561"}},{"Reference":{"value":"/coll/reference_model/doc/RF000562"}},{"Reference":{"value":"/coll/reference_model/doc/RF000167"}},{"Reference":{"value":"/coll/reference_model/doc/RF000564"}},{"Reference":{"value":"/coll/reference_model/doc/RF000563"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1085","properties":{"Key Text":{"value":"Initial investigation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extend of disease and needs in an individual diagnosed with NF1, the following evaluations are recommended: \n- Personal medical history with particular attention to the features of NF1\n- Physical examination with particular attention to the skin, skeleton, cardiovascular system, and neurologic systems\n- Ophthalmologic evaluation including slit lamp examination of the irides\n- Other studies as indicated on the basis of clinically apparent signs or symptoms\n- Medical genetics consultation"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000564"}}]}}}},{"Patient Management":{"value":"ACPM1084","properties":{"Key Text":{"value":"Review of symptoms"},"Tier":{"value":"2"},"Recommendation Text":{"value":"There is no medical treatment that can prevent or reverse the characteristic lesions. The mainstay of management is age specific monitoring of disease manifestations and patient education to allow early detection of treatable complications (e.g., removal of malignant peripheral nerve sheath tumors) and prompt institution of therapy.  Management is often performed under the aegis of a specialized \"Neurofibromatosis Clinic\", where considerable expertise representing multiple medical disciplines can be gathered. NF1 individuals need to be encouraged to seek review of any unusual symptoms and ask if they are related to NF1. Young adults aged 16-25 years are at a vulnerable stage of life and require education about NF1 and its possible complications. Counseling about disease inheritance and psychological support are advised, particularly as neurofibromas often start to develop in late adolescence."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000561"}},{"Reference":{"value":"/coll/reference_model/doc/RF000562"}}]}}}},{"Patient Management":{"value":"ACPM1086","properties":{"Key Text":{"value":"Literacy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"If present, cognitive impairment remains stable in adulthood. Adults should be asked about their literacy and numeracy as impairment of these skills reduces clinic attendance and understanding of information about their condition. Referral to adult literacy classes might be appropriate in some instances. Clinic visits should be followed where possible by a telephone call to ascertain that the individual understands his/her care plan."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000562"}}]}}}},{"Patient Management":{"value":"ACPM1087","properties":{"Key Text":{"value":"Prenatal Care"},"Tier":{"value":"2"},"Recommendation Text":{"value":"When caring for pregnant women, close liaison between the obstetrician and neurofibromatosis clinician is important due to the potential for neurofibromas to grow in size and number. Hypertension requires care evaluation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000562"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU585","properties":{"Key Text":{"value":"NF1 clinic"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Adults should be offered the opportunity of attending a specialist NF1 clinic, typically run by geneticists and neurologists, on an annual basis.  Monitoring after the mid-twenties depends on patient preference and disease severity. Adults with mild disease have a much lower risk of complications. If they elect not to attend a specialist NF1 clinic, they should be fully conversant with the problems that they might encounter. The minimum requirement for an asymptomatic adult is to be aware of unusual symptoms, particularly the clinical features of malignant peripheral nerve sheath tumors and of spinal cord compression, and blood pressure measurement. Treatment of essential hypertension is the same as in the general population."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000561"}},{"Reference":{"value":"/coll/reference_model/doc/RF000562"}}]}}}},{"Surveillance":{"value":"ACSU587","properties":{"Key Text":{"value":"Breast cancer screening"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Women should be offered annual mammogram starting at age 30 and could consider breast MRI with contrast from ages 30-50 years.  At this time there are no data to suggest an increase in breast cancer risk after age 50. A population based study in Finland of 1,404 patients with NF1 showed a significant association between NF1 and breast cancer risk (SIR: 3.04, 95% CI: 2.06-4.31; p<0.001). The highest excess incidence was noted in women under age 40 (SIR: 11.10, 95% CI: 5.56-19.50; p<0.001). Increased risk was also noted in England (SIR: 3.5, 95% CI: 1.9-5.9), with higher risks in women under 50 (SIR: 4.9, 95% CI: 2.4-8.8). The cumulative risk of developing breast cancer was estimated at 8.4% by age 50. Case-control analysis of women from England show that relative risk estimates are higher for women ages 30 to 39 (RR: 6.5, 95% CI: 2.6-13.5) and ages 40 to 49 (RR: 4.4, 95% CI: 2.5-7.0) but then drops for women ages 50 to 59 (RR: 2.6, 95% CI: 1.5-4.2) and continue to drop as age increases (RR: 1.9, 95% CI: 1.0-3.3 for ages 60 to 69; RR: 0.8, 95% CI: 0.2-2.2 for ages 70 to 79). There is no data regarding the benefit of risk-reducing mastectomy for women with NF1 mutations; therefore, risk reducing surgery is not recommended for these patients but may be considered based on family history."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast Cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000565"}}]}}}},{"Surveillance":{"value":"ACSU586","properties":{"Key Text":{"value":"Breast cancer screening"},"Tier":{"value":"1"},"Recommendation Text":{"value":"No studies on the effectiveness of screening for breast cancer in women with NF1 mutations were identified.  One guideline summarizes that low quality evidence suggests a disease specific survival benefit with mammographic surveillance in women aged less than 50 years with a family history of breast cancer. First, an observational study indicated a decreased risk of death from breast cancer when diagnosed during mammographic surveillance (lead time adjusted HR 0.24 [95% CI 0.09 to 0.66]). Modeling data predicts a decrease in 10 year breast cancer mortality death in those undergoing screening RR 0.80 (95% CI 0.66 to 0.96). A retrospective study showed a decreased rate of all-cause mortality in BRCA1/2 carriers diagnosed with breast cancer during an intensive mammographic surveillance program (HR 0.44 [95% CI 0.25 to 0.77])."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast Cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000517"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM395","properties":{"Key Text":{"value":"Genetic counseling"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Genetic counseling should be offered to all first degree relatives of an individual with NF1. When possible the parents and siblings should be examined for signs and symptoms of NF1. At least a three generation pedigree should be collected to identify additional family members who may be affected with NF1."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000561"}},{"Reference":{"value":"/coll/reference_model/doc/RF000562"}},{"Reference":{"value":"/coll/reference_model/doc/RF000167"}},{"Reference":{"value":"/coll/reference_model/doc/RF000563"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA479","properties":{"Key Text":{"value":"Radiotherapy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Radiotherapy is contraindicated because of risk of malignancy."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000562"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 10000"},"Tier":{"value":"3"},"Notes":{"value":"The mutation rate for NF1 (~1:10,000) is among the highest known for any gene in humans. Half of affected individuals have NF1 as a result of a de novo mutation. Given that all cases of NF1 are associated with mutations in NF1 it is expected that the prevalence of the mutation would be similar to the prevalence of the condition."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000564"}}]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE561","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Penetrance is virtually complete after childhood."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000564"}}]}}}},{"Penetrance":{"value":"ACPE562","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"Frequency of onset of major clinical manifestations:\n- Cafe´-au-lait patches: >99% \n- Skin-fold freckling: 85% \n- Lisch nodules: 90–95%\n- Cutaneous neurofibromas: >99%\n- Plexiform neurofibromas: 30%(visible) – 50%(on imaging) \n- Malignant peripheral nerve sheath tumor: 2–5% (8–13% lifetime risk)\n- Scoliosis: 10%\n- Pseudarthrosis of tibia: 2%\n- Renal artery stenosis: 2%\n- Pheochromocytoma: 2%\n- Severe cognitive impairment (IQ <70): 4–8%\n- Learning problems: 30–60%\n- Epilepsy: 6–7%\n- Optic pathway glioma: 15% (only 5% symptomatic)\n- Cerebral gliomas: 2–3%\n- Sphenoid wing dysplasia: <1\n- Aqueduct stenosis: 1.5%"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000562"}}]}}}},{"Penetrance":{"value":"ACPE563","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"The cumulative risk of developing breast cancer was estimated at 8.4% by age 50."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast Cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000565"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR232","properties":{"Key Text":{"value":">3"},"Notes":{"value":"Among one cohort the relative risk of malignant neoplasms or benign central nervous system tumors was estimated at 4.0. A second cohort identified a relative risk of developing malignant peripheral nerve sheath tumors of 113."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000566"}}]},"Tier":{"value":"3"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN254","properties":{"Key Text":{"value":"NF1 is characterized by extreme clinical variability, not only between unrelated individuals and among affected individuals within a single family but even within a single person with NF1 at different times in life."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000561"}},{"Reference":{"value":"/coll/reference_model/doc/RF000564"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI260","properties":{"Key Text":{"value":"Recommendations for management of individuals with NF1 include increased pregnancy monitoring, measurement of hypertension, and enhanced breast cancer surveillance."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC254","properties":{"Key Text":{"value":"Clinical management of persons with NF is complicated by a wide range of variability of expression, often impeding accurate diagnosis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000561"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC030","properties":{"Recommendation":{"value":"Approximately 90% of individuals with NF1 will have two or more diagnostic criteria by age 6, 97% by age 8, and all do so by 20 years of age."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000563"}}]}}}},{"RecommendationID":{"value":"REC029","properties":{"Recommendation":{"value":"Occasionally, a parent of an affected individual has been found to have a segmental/mosaic form of NF1 with few health problems."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000562"}}]}}}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"1970-01-01"},"Scorers Present":{"value":6,"items":[{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"bieseckerl"}},{"Scorer":{"value":"williamsm"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"weaverm"}}]},"Notes":{"value":""}}},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Overall Score":{"value":"7CD"},"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Overall Score":{"value":"9CB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":9,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2A"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":9,"items":[{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"I'm being generous...not much to suggest this is particularly effective for PNS tumors regarding benefitting outcomes. So I could be talked down to a 1 w/o problem"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"I gave it a \"2\" BUT, I'm concerned about the legitimacy of this association. See the recent large study by Couch et al. in JAMA Oncology\ndoi:10.1001/jamaoncol.2017.0424\n\nI think that this kind of thing is going to be played out again and again as we begin to collect better evidence that calls into questions some of these gene/disease associations."}}},"Likelihood":{"value":"2D","properties":{"Notes":{"value":"Again, see my prior note. I'm not at all confident this association is real. So I gave it a low evidence level; I'm sure I'll be an outlier..."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"See prior note. I knocked down the evidence a notch but wonder about the whole scoring endeavor of this association."}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Can't remember if this has been a 2 or a 3 for other conditions."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"Can't remember if this has been a 2 or a 3 for other conditions."}}}}}}]}}}}]}}}},{"Scorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"Unsure whether to use the 2-5% risk or the 8-13%, but since we are supposed to focus on adults, I guess the latter?"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"I dont understand what the qualifier \"for educational purposes\" means, so I will ignore that. Maybe it means patient education?"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Quite a range of RR for screening. Difficult to know what adjective that qualifies as."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"Scored prevalence of MPNST specifically."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"Scored prevalence of breast cancer specifically."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"No evidence on effectiveness in spite of Tier 2 recommendation for annual NF1 clinic attendance"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Used the Tier 1 reference to the decreased all-cause mortality in BRCA1/2 & dropped evidence level for extrapolation."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"no evidence that participating in a NF1 clinic improves malignant peripheral nerve sheath tumor outcome"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"used BRCA1 surveillance at 2A to downgrade evidence level for extrapolation to 2B"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"0N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"1D","properties":{"Notes":{"value":"no data"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Malignant peripheral nerve sheath tumors","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Consultation with a provider experienced with NF1 for educational purposes","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast Cancer","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"OMIM pairs updated.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36138},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-11"},"ReleasedBy":{"value":"elizabeth.v.clarke@kpchr.org","properties":{"First Name":{"value":"Elizabeth"},"Last Name":{"value":"Clarke"}}}}}}}},
{"ActionabilityDocID":{"value":"AC126","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"ACADVL","properties":{"HGNCId":{"value":"HGNC:92"},"GeneOMIM":{"value":"609575"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"201475"}}]}}}}]},"Syndrome":{"value":"Very Long Chain Actyl-CoA Dehydrogenase Deficiency (ACADVLD)","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"201475"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"26793"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-03-08"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle cramps, and exercise intolerance","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Multidisciplinary care","properties":{"FullName":{"value":"Multidisciplinary care (includes initial evaluation with echocardiography, dietary modification with MCT supplementation as appropriate, and exercise guidance)"}}}}]},"FullName":{"value":"Enter value here..."}}}},{"Outcome":{"value":"Perinatal or delivery complications","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management"}}]}}}},{"Outcome":{"value":"Surgical complications","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk surgical and anesthesia management"}}]}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Notes":{"value":"Based on newborn screening data, the incidence of the deficiency of very long-chain acyl-coA dehydrogenase (ACADVLD) has been estimated from 1/30,000 to 1/95,000. Prevalence estimates range from 1/100,000 to 9/100,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000571"}},{"Reference":{"value":"/coll/reference_model/doc/RF000570"}},{"Reference":{"value":"/coll/reference_model/doc/RF000569"}},{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"ACADVLD is an inborn error of mitochondrial long-chain fatty acid (LCFA) oxidation, which results in impaired energy production from exogenous and endogenous fatty acids. ACADVLD is associated with three phenotypes. The severe, early-onset form has high mortality and typically presents in the first months of life with cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. The intermediate form typically presents in infancy or early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy, and is associated with a lower mortality than the severe form. The later-onset form, probably the most common phenotype, presents with intermittent rhabdomyolysis, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptoms, though some patients may have a previous history of hypoglycemia."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000573"}},{"Reference":{"value":"/coll/reference_model/doc/RF000571"}},{"Reference":{"value":"/coll/reference_model/doc/RF000570"}},{"Reference":{"value":"/coll/reference_model/doc/RF000568"}},{"Reference":{"value":"/coll/reference_model/doc/RF000572"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"While ACADVLD can be detected through newborn screening, there is a paucity of data regarding which individuals are at risk for neonatal or childhood symptoms. The later-onset myopathic form typically presents in later childhood or adulthood. Episodes are usually triggered by exercise, fasting, cold/heat and/or stress but viral infection can also precipitate/exacerbate this presentation. In rare cases it can lead to renal failure and can be fatal."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000571"}},{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1091","properties":{"Key Text":{"value":"Evaluations at Initial Diagnosis"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with ACADVLD, the following evaluations are recommended:\n• Measurement of baseline plasma (serum) creatine kinase (CK) concentration\n• Measurement of baseline liver transaminases\n• Cardiac echocardiography\n• Electrocardiogram\n• Clinical genetics consultation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}},{"Patient Management":{"value":"ACPM1088","properties":{"Key Text":{"value":"Emergency Treatment"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Emergency treatment aims to prevent mobilization of fat by providing ample glucose, enterally or intravenously. In adult patients, early signs of metabolic decompensation are predominated by muscle symptoms. Hypoglycemia only occurs at a relatively late stage. The aim of emergency treatment should always be to intervene while blood glucose is normal.  It is advised that individuals undertake a regimen of high glucose drinks at the first sign of feeling unwell or have loss of appetite."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000574"}},{"Reference":{"value":"/coll/reference_model/doc/RF000575"}}]}}}},{"Patient Management":{"value":"ACPM1093","properties":{"Key Text":{"value":"Dietary Modifications"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Most dietary recommendations are focused on infants and children and are based on case reports and expert opinion due to lack of evidence-based protocols. Individuals with late-onset ACADVLD older than 12 months are recommended to have some sort of dietary modification. Specifically, an age-appropriate ‘‘heart-healthy” diet supplemented with medium chain triglycerides (MCT) has been recommended. For those patients who have symptomatic myopathy, a diet with more stringent LCFA restriction may be considered. However, for asymptomatic patients, the role of LCFA consumption in the development of later-onset myopathy is not known and there is some concern that a highly restricted or less palatable diet could contribute to catabolism or essential fatty acid deficiency."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000570"}},{"Reference":{"value":"/coll/reference_model/doc/RF000576"}}]}}}},{"Patient Management":{"value":"ACPM1094","properties":{"Key Text":{"value":"MCT Administration"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Administration of MCT prior to exercise has demonstrated benefit in older individuals with LCFA defects who have exercise intolerance. However, one report of 2 adult men with ACADVLD deficiency with exercise intolerance did not respond to intravenous glucose or MCT."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000573"}},{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}},{"Patient Management":{"value":"ACPM1092","properties":{"Key Text":{"value":"Exercise Modification"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Severe exercise (e.g., military training) has unmasked symptoms in previously asymptomatic adults, emphasizing that exercise should be guided by the individual’s tolerance level."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}},{"Patient Management":{"value":"ACPM1090","properties":{"Key Text":{"value":"Surgical Management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Surgical procedures in patients with metabolic disorders require specific perioperative and anesthetic measures based on the nature of the disorder.  During surgery, prolonged fasting, perioperative stress, and certain anesthetics can lead to metabolic derangements. Using two children, symptomatic and diagnosed during infancy with ACADVLD, as an illustration of the unpredictability of perioperative response, where one patient deteriorated with perioperative precautions and one patient did well without any precautions, some specific perioperative precautions have been advised:\n1. Undergo age and weight appropriate glucose infusion perioperatively\n2. Undergo pre- (during) and postoperative monitoring of glucose and CK\n3. Prevent perioperative stress by providing adequate premedication\n4. Avoid volatile anesthetics\n5. Avoid anesthetics containing high dose of long chain fatty acids like propofol and etomidate."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000572"}}]}}}},{"Patient Management":{"value":"ACPM1089","properties":{"Key Text":{"value":"Pregnancy Management"},"Tier":{"value":"3"},"Recommendation Text":{"value":"ACADVLD is a therapeutic challenge during pregnancy given the risk of metabolic decompensation during catabolic states, such as labor and early postpartum period. One case report indicated that placental and fetal LCFA oxidation may temporize or even improve maternal LCFA oxidation during pregnancy. The multidisciplinary care plan implemented for this patient (vaginal delivery, spontaneous birth, avoidance of inhaled anesthetics, availability of high-carbohydrate liquids throughout labor and postpartum period, and monitoring of renal function) resulted in an uncomplicated delivery and postpartum course with return of symptoms around 8 weeks postpartum. It was recommended that cesarean delivery in ACADVLD should be reserved for obstetrical indications or clear maternal or fetal benefit."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM396","properties":{"Key Text":{"value":"Genetic Testing"},"Tier":{"value":"4"},"Recommendation Text":{"value":"It is appropriate to evaluate the older and younger sibs of a proband with ACADVLD in order to identify as early as possible those who would benefit from institution of treatment and preventive measures. If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA483","properties":{"Key Text":{"value":"Fasting"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals with ACADVLD should avoid fasting"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA484","properties":{"Key Text":{"value":"Myocardial Irritation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Patients should avoid myocardial irritation (e.g., cardiac catheterization)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA480","properties":{"Key Text":{"value":"Dehydration"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Patients should avoid dehydration due to risk for acute tubular necrosis"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA482","properties":{"Key Text":{"value":"High Fat or Carbohydrate-Restricted Diet for Weight Reduction"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Patients should avoid a high-fat diet, including ketogenic or carbohydrate-restricted diets, for the purpose of weight loss. Careful weight reduction without side effects has been shown in 2 patients with adult-onset LCFA defects (1 with ACADVLD and 1 with carnitine palmitoyl-CoA transferase 2) by restricting LCFAs and calories, supplementing with calories provided through MCT, and limiting overnight catabolism with uncooked cornstarch. Any weight loss should be performed under the guidance of a metabolic dietician."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA481","properties":{"Key Text":{"value":"Exercise and Cold/Heat Exposure"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Patients should limit exercise and cold/heat exposure."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000571"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Tier":{"value":"Not provided"},"Notes":{"value":"Information on the prevalence of genetic variants associated with ACADVLD was not available."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC063","properties":{"Recommendation":{"value":"However, the prevalence of homozygotes should be similar to the prevalence of ACADVLD detected during newborn screening, which can identify asymptomatic individuals. Based on newborn screening data, the incidence of ACADVLD has been estimated from 1/95,000 to 1/30,000."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000569"}},{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}},{"RecommendationID":{"value":"REC062","properties":{"Recommendation":{"value":"Using the ACADVLD prevalence estimate of 1/31,000 based on newborn screening data, the carrier frequency has been estimated as 1/90."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000577"}}]}}}}]}}},"Penetrances":{"value":4,"items":[{"Penetrance":{"value":"ACPE565","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"No information on penetrance of signs and symptoms in adults identified based on genetic status was identified."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}},{"Penetrance":{"value":"ACPE566","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Severe forms are suspected to be fully penetrant. However, since the later-onset forms may have vague or intermittent symptoms, it is possible that some individuals will have no symptoms during their lifetime."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}},{"Penetrance":{"value":"ACPE567","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"A retrospective analysis of outcomes of 52 individuals diagnosed with ACADVLD by newborn screening in the US aged 1-18 years found that most individuals remained asymptomatic during the observed periods. Of the 52 individuals, cardiomyopathy was diagnosed in 2 (4%), 14 (27%) had elevated serum kinase (usually diagnosed between ages 1-3), and 11 (21%) developed rhabdomyolysis. A report of 22 patients identified by newborn screening in Australia followed for a median of 104 months on a low fat diet found no episodes of encephalopathy or hypoglycemia, but 3 (14%) cases had muscle pain with or without rhabdomyolysis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000573"}}]}}}},{"Penetrance":{"value":"ACPE564","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Among 13 clinically diagnosed patients (age of onset: birth to 13 years; median age at examination: 30.5 years) all patients were found to have exercise intolerance and recurrent rhabdomyolysis episodes generally triggered by strenuous exercise, fasting, cold, or fever (median age at onset: 10 years)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN255","properties":{"Key Text":{"value":"There is a strong genotype-phenotype correlation in ACADVLD, with severe disease associated with no residual enzyme activity (often resulting from null variants) and milder childhood and adult forms are often associated with residual enzyme activity (often resulting from pathogenic missense variants)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000570"}},{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI261","properties":{"Key Text":{"value":"Interventions identified in this report include dietary modifications, MCT supplementation (typically taken as a liquid), adjustment to exercise regimens, and extra precautions during surgical procedures."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC255","properties":{"Key Text":{"value":"Patients with ACADVLD were traditionally diagnosed after developing symptoms of the disorder. However, expanded newborn screening now provides pre-symptomatic diagnosis in infants, typically through elevation of C14:1 acylcarnitine and other acylcarnitines."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000570"}},{"Reference":{"value":"/coll/reference_model/doc/RF000576"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC032","properties":{"Recommendation":{"value":"However, complete ascertainment by newborn screening is not assured. Newborn screening data have affirmed that acylcarnitine analysis during periods of physiologic wellness often fails to identify affected individuals who have the milder phenotypes. In addition, many children ascertained by newborn screening are asymptomatic, suggesting that these individuals may have gone undiagnosed prior to population-based screening."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}},{"RecommendationID":{"value":"REC031","properties":{"Recommendation":{"value":"Two individuals, both previously asymptomatic, were diagnosed following episodes during military training which required airlift rescue."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000568"}}]}}}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle cramps, and exercise 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Evidence is sparse."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"All of these seemed relatively innocuous and I'm taking my cue from the discussion recently in which it was appropriately pointed out that some dietary modifications are easier than others. Please pass the chips."}}}}}}]}}}},{"Outcome":{"value":"Perinatal or delivery complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"O for unknown"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":"Poor, anecdotal evidence. But certainly seems prudent"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Surgical complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"O for unknown"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk surgical and anesthesia management","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle cramps, and exercise intolerance","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"The evidence is conflicting here; either 2 or 3."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Multidisciplinary care","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Perinatal or delivery complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Surgical complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"There is no mention of the likelihood of surgical complications."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk surgical and anesthesia management","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Status":{"value":"Incomplete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle cramps, and exercise intolerance","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Multidisciplinary care","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Perinatal or delivery complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"1D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Surgical complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"I don't see anything in your notes about surgical complications."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk surgical and anesthesia management","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle cramps, and exercise intolerance","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"I scored 2 as Rhabdomyolysis, while rare, can be associated with major morbidity and rarely death. NB Rhabdomyolysis is spelled wrong above"}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"I scored 2, as the studies were in younger individuals, so I presumed the adults would likely be lower. The retrospective study is probably the best data we have, but it's pretty weak."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Multidisciplinary care","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Perinatal or delivery complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"I think the text should be metabolic decompensation, not dispensation."}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Surgical complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk surgical and anesthesia management","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle cramps, and exercise intolerance","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3D","properties":{"Notes":{"value":"Dropped level of evidence from C because the data were from patients with newborn or childhood onset."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Multidisciplinary care","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"Could differ based on how broadly defined multi-D care is (include diet & exercise modification?)"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Would consider how we've scored dietary medications before, though this is broader because it includes other interventions that could lead to cumulative burden"}}}}}}]}}}},{"Outcome":{"value":"Perinatal or delivery complications","properties":{"Severity":{"value":"Not Scored","properties":{"Notes":{"value":"No data specific to this outcome"}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"Just 1 case reported noted here"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Could use some more detail about what's involved"}}}}}}]}}}},{"Outcome":{"value":"Surgical complications","properties":{"Severity":{"value":"Not Scored","properties":{"Notes":{"value":"No data specific to this outcome"}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk surgical and anesthesia management","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"Not enough data (2 cases, each with different outcomes) to go on"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle cramps, and exercise intolerance","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Multidisciplinary care","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Perinatal or delivery complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"unknown - no data here"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":"This seems reasonable but no data to support recommendation."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Surgical complications","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":"malignant hyperthermia"}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"unknown - no data here"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk surgical and anesthesia management","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"Extrapolating from RYR1"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle cramps, and exercise intolerance","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"scoring for later onset, not infantile which might include sudden death."}}},"Likelihood":{"value":"2D","properties":{"Notes":{"value":"poor evidence as everything based on people with established diagnosis. Looking under the lamppost only"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Multidisciplinary care","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Perinatal or delivery complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"did not see info in the clinical features but if baseline scored a 2, perinatal and operative can't be less."}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":"saw no info on this"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"common sense recommendations but don't see evidence presented that this improves outcomes"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Surgical complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"did no see info in the clinical features but if baseline scored a 2, perinatal and operative can't be less."}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":"saw no info on this"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk surgical and anesthesia management","properties":{"Effectiveness":{"value":"0N","properties":{"Notes":{"value":"these are common sense recommendations but don't see any evidence to indicate improved outcomes"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Rhabdomyolysis, muscle cramps, and exercise intolerance","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"1.5"}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"maybe 2; Assume this is for late onset."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Multidisciplinary care","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"data?"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Perinatal or delivery complications","properties":{"Severity":{"value":"0","properties":{"Notes":{"value":"no info"}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"based on what?"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Surgical complications","properties":{"Severity":{"value":"0","properties":{"Notes":{"value":"no info - assume this relates to dehydration and fasting, possibly adverse response?"}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk surgical and anesthesia management","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"data?"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"OMIM pairs updated.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36140},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-11"},"ReleasedBy":{"value":"elizabeth.v.clarke@kpchr.org","properties":{"First Name":{"value":"Elizabeth"},"Last Name":{"value":"Clarke"}}}}}}}},
{"ActionabilityDocID":{"value":"AC127","properties":{"Status":{"value":"Released"},"Genes":{"value":2,"items":[{"Gene":{"value":"ATM","properties":{"HGNCId":{"value":"HGNC:795"},"GeneOMIM":{"value":"607585"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"114480"}}]}}}},{"Gene":{"value":"CHEK2","properties":{"HGNCId":{"value":"HGNC:16627"},"GeneOMIM":{"value":"604373"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"114480"}}]}}}}]},"Syndrome":{"value":"Breast Cancer","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"114480"}}]},"OrphanetIDs":{"value":0,"items":[]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-09-19"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Breast Cancer (ATM)","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"FullName":{"value":"Chemoprevention"}}}},{"Intervention":{"value":"Surveillance","properties":{"FullName":{"value":"Surveillance"}}}}]},"FullName":{"value":"Breast Cancer (ATM)"}}}},{"Outcome":{"value":"Breast cancer (CHEK2)","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"FullName":{"value":"Chemoprevention"}}}},{"Intervention":{"value":"Surveillance","properties":{"FullName":{"value":"Surveillance"}}}}]},"FullName":{"value":"Breast cancer (CHEK2)"}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Notes":{"value":"For women, lifetime risk estimates indicate that 12.3% will develop breast cancer and 2.8% will die from it. Among a sample of women with non-metastatic breast cancer 1% had an ATM pathogenic variant, and 8.5% of women with early-onset breast cancer were found to have an ATM pathogenic variant.  Among familial breast cancer families without a BRCA1/2 pathogenic variant, CHEK2 pathogenic variants have been detected in 5% of cases."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000578"}},{"Reference":{"value":"/coll/reference_model/doc/RF000511"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"ATM encodes the ATM protein, which is involved in cell cycle control and DNA repair. CHEK2 codes for the CHEK2 protein which acts at a tumor suppressor in blocking cell proliferation and initiating DNA repair.  ATM and CHEK2 pathogenic variants are associated with an increased risk of breast cancer."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000578"}},{"Reference":{"value":"/coll/reference_model/doc/RF000579"}},{"Reference":{"value":"/coll/reference_model/doc/RF000581"}},{"Reference":{"value":"/coll/reference_model/doc/RF000580"}},{"Reference":{"value":"/coll/reference_model/doc/RF000629"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"The presence of an ATM pathogenic variant has been linked to reduced overall survival in individuals with breast cancer (HR: 5.6; 95% CI: 2.6 to 12.0). ATM mutation carriers (heterozygotes) have been found to have a reduced life expectancy of 7-8 years less than family members who are non-carriers, with higher relative risks of mortality including cancer mortality. The relative risk for developing breast cancer for females with heterozygous ATM pathogenic variants is estimated to be 3.0 (95% CI: 2.1-4.5), with higher risks for those under the ages of 45-55. Variables that appear to affect breast cancer risk in ATM heterozygotes include age, position within the pedigree, and previous exposure to radiation, age at first childbirth, smoking, and specific ATM pathogenic variant. \n\nThe presence of a CHEK2 pathogenic variant has been linked to reduced overall survival in individuals with breast cancer (HR: 6.9; 95% CI: 3.1 to 15.0).Most studies of breast cancer risk in CHEK2 heterozygotes have involved specific variants.  Case-control studies indicate that the 1100delC variant (NM_007194.3(CHEK2):c.1100delC (p.Thr367Metfs)) is associated with increased risk for breast cancer, even in women unselected for family history (OR=2.34; 95% CI: 1.72–3.20; p<0.001), and a significantly increased risk of developing ER-positive breast cancer (OR=2.55; 95% CI: 2.10–3.10; p<0.001).  Results from a meta-analysis showed that the missense variant I157T (NM_007194.3(CHEK2):c.470T>C (p.Ile157Thr)) is associated with increased risk for breast cancer (OR=1.58; 95% CI: 1.42–1.75; p<0.001)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000578"}},{"Reference":{"value":"/coll/reference_model/doc/RF000579"}},{"Reference":{"value":"/coll/reference_model/doc/RF000580"}},{"Reference":{"value":"/coll/reference_model/doc/RF000629"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1096","properties":{"Key Text":{"value":"Chemoprevention"},"Tier":{"value":"1"},"Recommendation Text":{"value":"While no chemoprevention recommendations were identified for patients with ATM or CHEK2 pathogenic variants specifically, guidelines based on lifetime risk levels similar to those associated with ATM or CHEK2 pathogenic variants state that healthcare professionals within a specialist genetics clinic should discuss and give written information on the absolute risks and benefits of all options for chemoprevention to women at high risk or moderate risk of breast cancer.  No direct evidence on the effectiveness of chemoprevention in patients with ATM or CHEK2 pathogenic variants was detected. Evidence cited in guidelines was based on patients defined as high-risk based on a family history of breast, ovarian or related (prostate/pancreatic cancer) or with a BRCA1, BRCA2, and/or TP53 pathogenic variant. \n\nAmong these patients:\n- High quality evidence from two randomized trials suggests the incidence of breast cancer is lower in patients given tamoxifen than in those given a placebo (RR=0.65; 95% CI: 0.56-0.74). Longer term follow-up from one of these trials has subsequently been published; this study found that over a median of 16 years, there was a significant reduction in the occurrence of all breast cancers in the tamoxifen group (HR=0.71; 95% CI: 0.60 to 0.83; p<0.0001). However, no significant difference was found in breast-cancer specific mortality (OR=1.19; 95% CI: 0.68-2.10; p=0.8). \n\n- Low quality evidence from a single randomized trial suggests the incidence of breast cancer is lower in patients given exemestane compared with those given a placebo (HR=0.35; 95% CI: 0.18-0.70)"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast Cancer (ATM)"}},{"Outcome":{"value":"Breast cancer (CHEK2)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000517"}}]}}}},{"Patient Management":{"value":"ACPM1097","properties":{"Key Text":{"value":"Mastectomy"},"Tier":{"value":"1"},"Recommendation Text":{"value":"There are mixed recommendations for whether women should be offered risk-reducing mastectomy. One guideline states that women with an ATM pathogenic variant do not rise to the level of risk that would justify surgery."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast Cancer (ATM)"}},{"Outcome":{"value":"Breast cancer (CHEK2)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000580"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC260","properties":{"Recommendation":{"value":"A second guideline recommends that women with a ATM pathogenic variant could consider risk-reducing mastectomy based on their family history. For women with a CHEK2 pathogenic variant, the evidence is insufficient for risk-reducing mastectomy, women should be managed based on family history."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000578"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1095","properties":{"Key Text":{"value":"Mastectomy"},"Tier":{"value":"1"},"Recommendation Text":{"value":"No direct evidence on the effectiveness of risk-reducing surgery in patients with ATM or CHEK2 pathogenic variants was identified. Findings from 2 observational studies and 3 decision analysis studies suggest that risk-reducing subcutaneous/total mastectomy has a beneficial effect in terms of significantly reducing the risk of breast cancer in women with a family history of breast cancer, or with BRCA1 and BRCA2 pathogenic variants. One of the observational studies found that risk-reducing mastectomy was also associated with a reduction in breast cancer mortality in women with a family history of breast cancer. Among the two observational studies, one found no cases of invasive breast cancer among women who had undergone bilateral total mastectomy over 3 years (compared to 8/63 patients undergoing surveillance only). The second study showed a reduction in the risk of breast cancer of 89.5% in moderate-risk women who had undergone mastectomy and a reduction of 90-94% among high-risk women. The risk reduction for death among women undergoing mastectomy was 100% among moderate-risk women, and 81-94% among high-risk women."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast Cancer (ATM)"}},{"Outcome":{"value":"Breast cancer (CHEK2)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000517"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU589","properties":{"Key Text":{"value":"Surveillance"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Females heterozygous for an ATM pathogenic variant are advised to have earlier surveillance for breast cancer starting at age 40. The modality of screening varies by guideline, with one guideline recommending screening with annual mammography from 40 to 50 years of age followed by screening from age 50-75 in the general population screening program."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast Cancer (ATM)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000580"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC042","properties":{"Recommendation":{"value":"A second guideline recommended annual mammography starting at age 40 and breast MRI with contrast may be considered."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000578"}}]}}}},{"RecommendationID":{"value":"REC043","properties":{"Recommendation":{"value":"Female carriers of the ATM 7271T-G missense mutation (NM_000051.3(ATM):c.7271T>G (p.Val2424Gly)) are advised to have an annual MRI starting at the age of 25 combined with annual mammography from age 30 onwards (as routinely offered to all BRCA1/2 mutation carriers that are at similar risk)."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000580"}}]}}}}]}}}},{"Surveillance":{"value":"ACSU588","properties":{"Key Text":{"value":"Surveillance"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Heterozygous female carriers of a CHEK2 pathogenic variant are advised to undergo screening with annual mammography starting at age 40 and may consider screening with breast MRI."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast cancer (CHEK2)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000578"}}]}}}},{"Surveillance":{"value":"ACSU590","properties":{"Key Text":{"value":"Surveillance"},"Tier":{"value":"1"},"Recommendation Text":{"value":"No direct evidence on the effectiveness of breast cancer surveillance in patients with ATM or CHEK2 pathogenic variants was identified.  Evidence cited in guidelines was based on patients with a BRCA1/2 pathogenic variant or a family history of breast cancer. One guideline summarizes that low quality evidence suggests a disease-specific survival benefit with mammographic surveillance in women aged less than 50 years with a family history of breast cancer. First, an observational study found that death from breast cancer was less likely in women aged less than 50 years with family history whose breast cancer was diagnosed during mammographic surveillance compared to a control group of unscreened women of similar age who developed breast cancer (lead time adjusted HR=0.24; 95% CI: 0.09-0.66]). Second, a study modelled death from breast cancer in a mammographic surveillance study in women with a family history aged less than 50 years and a control group from another study, using prognostic features at diagnosis and underlying risk. Projected ten-year death from breast cancer was lower in the mammographic surveillance group than in the control group of unscreened women of similar age (RR=0.80; 95% CI: 0.66-0.96). Third, a retrospective study found that death from any cause was less likely in BRCA1/2 mutation carriers aged between 28 and 77 years diagnosed with breast cancer during an intensive mammographic surveillance program than in those diagnosed outside this program (HR=0.44; 95% CI: 0.25-0.77])."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast Cancer (ATM)"}},{"Outcome":{"value":"Breast cancer (CHEK2)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000517"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM397","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"1"},"Recommendation Text":{"value":"While no recommendations were identified for family members of individuals carrying an ATM or CHEK2 pathogenic variant, it is recommended that family members at risk of carrying a BRCA1/2 pathogenic variant should undergo genetic testing to determine their genetic risk. These recommendations may similarly apply to women at elevated risk due to other pathogenic variants."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000511"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA485","properties":{"Key Text":{"value":""},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":""},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"Information on the prevalence of ATM or CHEK2 pathogenic variants in the general population was not identified."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE569","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"1"},"Notes":{"value":"The penetrance of breast cancer in individuals with a pathogenic variant in ATM is estimated to be 6% (95% CI: 4.6-7.4%) by age 60 and 33 to 38% (95% CI: 24.6-40.4%) by age 80. Based on published relative risks, the lifetime risk may vary between 24 and 55%. For those under age 50, the risk is estimated to be 16% and may vary between 11 and 19%. The lifetime risk for those with an ATM 7271T-G missense mutation is 69%, which is similar to the lifetime risk for BRCA1/2 mutation carriers."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast Cancer (ATM)"}},{"Outcome":{"value":"Breast cancer (CHEK2)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000581"}},{"Reference":{"value":"/coll/reference_model/doc/RF000580"}}]}}}},{"Penetrance":{"value":"ACPE570","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"1"},"Notes":{"value":"A rough estimate of the lifetime risk (based on ORs from case-control studies aggregated with the risk in women in the general population) found that among those with familial breast cancer, women heterozygous for the CHEK2 1100delC variant have a cumulative breast cancer risk of 37% (95% CI: 26-56%) by age 70."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast cancer (CHEK2)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000579"}}]}}}},{"Penetrance":{"value":"ACPE568","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"The estimated risk of breast cancer by age 80 for those with a CHEK2 pathogenic variant is 29%, and estimates of cumulative lifetime risk for those with a family history of breast cancer range from 28% to 37%."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Breast cancer (CHEK2)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000578"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR234","properties":{"Key Text":{"value":">3"},"Notes":{"value":"A meta-analysis of four cohort studies of breast cancer for females with a heterozygous ATM pathogenic variant found a pooled relative risk of 3.0 (95% CI: 2.1-4.5). For women under age 45-55 the pooled relative risk was 7.0 (95% CI: 4.1-11.7)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000580"}}]},"Tier":{"value":"1"}}}},{"Relative Risk":{"value":"RR235","properties":{"Key Text":{"value":">3"},"Notes":{"value":"Among those with a familial breast cancer, women heterozygous for the CHEK2 1100delC variant have a relative risk of breast cancer of 4.8 (95% CI: 3.3-7.2)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000579"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC014","properties":{"Recommendation":{"value":"Among men with the CHEK2 1100delC variant, a 10-fold increase in breast cancer risk has been estimated."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000582"}}]}}}}]},"Tier":{"value":"1"}}}},{"Relative Risk":{"value":"RR233","properties":{"Key Text":{"value":">3"},"Notes":{"value":"The estimated relative risk of breast cancer for those with a CHEK2 truncating mutation is 3.0 (90% CI: 2.6-3.5)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000578"}}]},"Tier":{"value":"3"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN256","properties":{"Key Text":{"value":"No information identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI262","properties":{"Key Text":{"value":"The interventions identified in this report include screening tests, prophylactic surgery to remove target organs, and medications with potential side effects."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000517"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC256","properties":{"Key Text":{"value":"Given that women with  ATM or CHEK2 pathogenic variants have an increased risk of breast cancer at younger ages than the general population it is possible that cases could be missed by current screening programs."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2017-10-30"},"Scorers Present":{"value":5,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}}]},"Notes":{"value":""}}},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Breast Cancer (ATM)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Overall Score":{"value":"8AB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance","properties":{"Overall Score":{"value":"9AB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast cancer (CHEK2)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Overall 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Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Breast cancer (CHEK2)","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Breast Cancer (ATM)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2A"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2B"},"Nature Of 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Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Breast Cancer (ATM)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":"I'm on the fence here as the risks are hovering around the 40% cutoff. I could live with either a 2 or 3. Interesting that the penetrance of the one variant is so much higher."}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Need to make sure this is concordant with BRCA"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"Need to make sure this is concordant with BRCA"}}}}}},{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":"Need to be sure that the effectiveness for surveillance is consistent with BRCA"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast cancer (CHEK2)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":"More comfortable with a 2 for CHEK2"}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Breast Cancer (ATM)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":"No difference in mortality tempered my enthusiasm, thus my \"minimally effective\" score."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"The hazards associated with tamoxifen are not trivial and include DVT/PE."}}}}}},{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":"Mammography is already a fairly poor screening modality. I could be persuaded to bump my score up to a \"2\" b/o MRI..."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast cancer (CHEK2)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"I knocked down the efficacy score since it is all extrapolated from BRCA carriers..."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Breast Cancer (ATM)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":"Assuming BRCA1/2 information is relevant to ATM/CHEK2"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast cancer (CHEK2)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":"Assuming BRCA1/2 information is relevant to ATM/CHEK2"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Breast Cancer (ATM)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":"No doubt chemoprevention good in most familial breasst cancer but no evidence in these gene carriers.  They could be the fails"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast cancer (CHEK2)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Breast Cancer (ATM)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"dropped evidence level due to extrapolation from increased-risk setting"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast cancer (CHEK2)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Breast Cancer 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estimate\""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Chemoprevention","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Extrapolating from BRCA1 & BRCA2"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Breast Cancer 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Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.1","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36142},"ReasonCode":{"value":"Q0","properties":{"Reason":{"value":"Initial Release"}}},"Date":{"value":"2017-10-30"},"ReleasedBy":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"}}}}}}}},
{"ActionabilityDocID":{"value":"AC128","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"GCH1","properties":{"HGNCId":{"value":"HGNC:4193"},"GeneOMIM":{"value":"600225"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"128230"}}]}}}}]},"Syndrome":{"value":"Dopa-Responsive Dystonia","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"128230"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"98808"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-04-04"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuromuscular dysfunction","properties":{"Interventions":{"value":3,"items":[{"Intervention":{"value":"Regular examinations and surveillance by a movement disorder specialist"}},{"Intervention":{"value":"Levodopa therapy"}},{"Intervention":{"value":"Avoidance of oral contraceptives"}}]},"FullName":{"value":"Enter value here..."}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"GCH1-deficient dopa-responsive dystonia (DRD) is a rare disorder. It is observed worldwide with no increased prevalence in any ethnic group. Prevalence estimates range from 0.5 to 9 per million."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000558"}},{"Reference":{"value":"/coll/reference_model/doc/RF000587"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"DRD typically presents with gait disturbance caused by dystonia in the leg, most commonly due to flexion-inversion of the foot. Occasionally, initial symptoms are arm dystonia, postural tremor of the hand, slowness of movements, or cervical dystonia resulting in stumbling and falling. Brisk deep-tendon reflexes in the legs, ankle clonus, and/or striatal toe (dystonic extension of the big toe) may be present.  Rapid fatiguing with repetitive motor tasks (e.g., finger tapping or foot tapping) is often observed. Later in the course of disease, some, especially those with later onset in adolescence or adulthood, develop parkinsonism. Without treatment, adults may suffer from limb contractures. Diurnal fluctuation of symptoms (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep) are also characteristic, though variable, and often attenuate with age and disease progression. Some individuals demonstrate only exercise-induced exacerbation or manifestation of dystonia. In general, intellectual, cerebellar, sensory, and autonomic disturbances do not occur. In rare instances, anxiety, depression, obsessive-compulsive disorder, and/or sleep disturbances have been reported.\n\nThe clinical phenotype has been extended to include adult-onset “benign” parkinsonism, various types of focal dystonia, DRD simulating cerebral palsy or spastic paraplegia, and spontaneous remission of dystonia and/or parkinsonism (sometimes with a relapse in the later course of illness). Individuals with adult-onset “benign” parkinsonism manifest no dystonia prior to the onset of parkinsonism in mid- or late adulthood."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000558"}},{"Reference":{"value":"/coll/reference_model/doc/RF000587"}},{"Reference":{"value":"/coll/reference_model/doc/RF000557"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"DRD typically presents in childhood, with an average age of onset of approximately 6 years (range 1-12 years) following normal early motor development.  Though age of onset has been reported as late as 54 years. Patients with a later disease onset have a milder phenotype and disease progression is slower. In general, gradual progression to generalized dystonia is observed in those with childhood onset. Individuals with adolescent onset seldom develop severe generalized dystonia; such individuals may become more symptomatic in mid-adulthood due to development of overt parkinsonism. A predominance of clinically affected females is observed, with a female-to-male ratio estimated from 2:1 to 6:1. Women may also have a younger age at onset than men with more frequent onset of dystonia in the lower limbs. There is no decrease in life expectancy."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000558"}},{"Reference":{"value":"/coll/reference_model/doc/RF000587"}},{"Reference":{"value":"/coll/reference_model/doc/RF000557"}},{"Reference":{"value":"/coll/reference_model/doc/RF000560"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1099","properties":{"Key Text":{"value":"Evaluations following diagnosis"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with DRD, a neurologic examination to assess the severity of motor disturbances and a clinical genetics consultation are recommended."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000558"}}]}}}},{"Patient Management":{"value":"ACPM1098","properties":{"Key Text":{"value":"Levodopa"},"Tier":{"value":"3"},"Recommendation Text":{"value":"All individuals with DRD, including those with adult-onset “benign” parkinsonism, demonstrate a dramatic and sustained complete or near-complete response of symptoms to relatively low doses of levodopa. Even individuals who have been untreated for more than 50 years (e.g., persons initially diagnosed with cerebral palsy) can show a remarkable response to levodopa. Appropriate levodopa therapy can reverse symptoms and signs. Motor benefit can be recognized immediately or within a few days of starting levodopa therapy; full benefit occurs within several days to a few months. Treatment is lifelong."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000558"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC261","properties":{"Recommendation":{"value":"There is some evidence that residual symptoms may still occur following the initiation of levodopa. A literature review of 352 symptomatic cases found that, among patients with available clinical information, residual motor symptoms were observed with 32% having remaining dystonia and 16% having residual parkinsonism. However, the authors note that these findings should be interpreted with caution as multiple biases are likely present in the literature. The summarized studies were not population-based and within the clinic samples there may be a selective reporting of atypical or severe cases. In addition, the residual motor signs also included subtle motor signs that did not necessarily interfere with the patients’ activities of daily life, but were detectable on neurologic examination."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000557"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1100","properties":{"Key Text":{"value":"Correct diagnosis"},"Tier":{"value":"5"},"Recommendation Text":{"value":"There is a marked delay in diagnosis of DRD, which could have consequences on the disability of patients. A literature review of 352 symptomatic cases reported a long delay in diagnosis, where the mean age of onset was 11.6 (SD=13.4) years and the average delay in diagnosis was 13.5 (SD=13.3) years. Complications related to a delay in diagnosis (i.e., contractures, secondary orthopedic deformities, and unnecessary surgical procedures) were identified among 8% of cases; however clinical information was not available for all patients."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000557"}}]}}}},{"Patient Management":{"value":"ACPM1101","properties":{"Key Text":{"value":"Anesthesia management"},"Tier":{"value":"3"},"Recommendation Text":{"value":"There are no definite recommendations for general or regional anesthesia. Due to lack of experience with this exceptionally rare disease, the patient should be monitored at intensive or intermediate care unit post-operatively. The delayed intake of dopamine and any kind of stress could cause an amplification of the symptoms. Levodopa treatment should strictly be continued, and side effects should be considered and monitored. Stress should be strictly prevented with anxiolytic medications. Succinylcholine should be avoided in immobilized (e.g., wheelchair-bound) patients due to the risk of hyperkalemic cardiac arrest and rhabdomyolysis. Monitoring of the neuromuscular blockade is strictly recommended if any neuromuscular blocking agent is used. The temperature should be monitored as usual."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000588"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU591","properties":{"Key Text":{"value":"Examinations by movement disorder specialist"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Examination by a movement disorder specialist at least several times yearly is recommended."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000558"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM398","properties":{"Key Text":{"value":"Genetic counseling and testing"},"Tier":{"value":"4"},"Recommendation Text":{"value":"It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment. If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives; however, molecular genetic testing cannot predict the occurrence of symptoms, or if they do occur, the age of onset, severity and type of symptoms, or rate of disease progression."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000558"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA486","properties":{"Key Text":{"value":"Oral contraceptives"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Exacerbation of symptoms after taking oral contraceptives (OC) has been reported in some women with DRD. One case report described onset of tremor following OC commencement. Tremor improved significantly when OC was discontinued and recurred when it was recommenced. A second report also reported marked exacerbation of dystonia following OC use in one woman. A third study of 19 women indicated that of the 13 who reported taking OC, 3 reported marked worsening of symptoms during use."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000558"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Tier":{"value":"Not provided"},"Notes":{"value":"The prevalence of pathogenic variants in GCH1 should be similar to the prevalence of GCH1-deficient DRD, which has been estimated from 0.5 per million (Tier 3) to 9 per million (Tier 4). However, given reduced penetrance particularly in males, the prevalence of individuals with symptomatic DRD may be lower."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000558"}},{"Reference":{"value":"/coll/reference_model/doc/RF000587"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE571","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Penetrance in individuals with DRD has been reported to be higher in females than in males. Estimates in females range from 87-100% while estimates in males range from 35-55% when defined by symptoms of dystonia with a positive responsive to levodopa."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000558"}}]}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN257","properties":{"Key Text":{"value":"Wide intra- and interfamilial variations in expressivity have been reported in DRD."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000558"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI263","properties":{"Key Text":{"value":"Interventions identified in this report include neurological exams, regular evaluations with a movement disorder specialist, and the administration of levodopa. At the initiation of levodopa therapy, some individuals with DRD develop dyskinesias, which subside following dose reduction and do not reappear when the dose is slowly increased later.  Under optimal doses, individuals with DRD on long-term levodopa treatment do not develop either motor response fluctuations (wearing-off and on-off phenomena) or dopa-induced dyskinesias."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000558"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC257","properties":{"Key Text":{"value":"There is a marked delay in diagnosis of DRD, which could have consequences on the disability of patients. A literature review of 352 symptomatic cases reported a long delay in diagnosis, where the average delay in diagnosis was 13.5 (SD=13.3) years."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000557"}}]},"Tier":{"value":"5"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2017-06-19"},"Scorers Present":{"value":1,"items":[{"Scorer":{"value":"leekristy"}}]},"Notes":{"value":""}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuromuscular dysfunction","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Regular examinations and surveillance by a movement disorder specialist","properties":{"Overall Score":{"value":"8CD"},"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Levodopa therapy","properties":{"Overall Score":{"value":"11CC"},"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of oral contraceptives","properties":{"Overall Score":{"value":"9CC"},"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":5,"items":[{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuromuscular dysfunction","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Regular examinations and surveillance by a movement disorder specialist","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Levodopa therapy","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of oral contraceptives","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuromuscular dysfunction","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Regular examinations and surveillance by a movement disorder specialist","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Levodopa therapy","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of oral contraceptives","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuromuscular dysfunction","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Regular examinations and surveillance by a movement disorder specialist","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Levodopa therapy","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of oral contraceptives","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuromuscular dysfunction","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Regular examinations and surveillance by a movement disorder specialist","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Levodopa therapy","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of oral contraceptives","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuromuscular dysfunction","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Regular examinations and surveillance by a movement disorder specialist","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Levodopa therapy","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of oral contraceptives","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}}]}}},"Scorers":{"value":5,"items":[{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuromuscular dysfunction","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Regular examinations and surveillance by a movement disorder specialist","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"looks like just a recommendation at this point"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Levodopa therapy","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of oral contraceptives","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuromuscular dysfunction","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Regular examinations and surveillance by a movement disorder specialist","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Levodopa therapy","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of oral contraceptives","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuromuscular dysfunction","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Regular examinations and surveillance by a movement disorder specialist","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Levodopa therapy","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of oral contraceptives","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuromuscular dysfunction","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Regular examinations and surveillance by a movement disorder specialist","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Levodopa therapy","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of oral contraceptives","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neuromuscular dysfunction","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Regular examinations and surveillance by a movement disorder specialist","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Levodopa therapy","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of oral contraceptives","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"OMIM pairs updated.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36144},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-11"},"ReleasedBy":{"value":"elizabeth.v.clarke@kpchr.org","properties":{"First Name":{"value":"Elizabeth"},"Last Name":{"value":"Clarke"}}}}}}}},
{"ActionabilityDocID":{"value":"AC129","properties":{"Status":{"value":"Released"},"Genes":{"value":5,"items":[{"Gene":{"value":"PMP22","properties":{"HGNCId":{"value":"HGNC:9118"},"GeneOMIM":{"value":"601097"},"SyndromeOMIMs":{"value":2,"items":[{"OMIM":{"value":"118220"}},{"OMIM":{"value":"118300"}}]}}}},{"Gene":{"value":"MPZ","properties":{"HGNCId":{"value":"HGNC:7225"},"GeneOMIM":{"value":"159440"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"118200"}}]}}}},{"Gene":{"value":"LITAF","properties":{"HGNCId":{"value":"HGNC:16841"},"GeneOMIM":{"value":"603795"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"601098"}}]}}}},{"Gene":{"value":"EGR2","properties":{"HGNCId":{"value":"HGNC:3239"},"GeneOMIM":{"value":"129010"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"607678"}}]}}}},{"Gene":{"value":"NEFL","properties":{"HGNCId":{"value":"HGNC:7739"},"GeneOMIM":{"value":"162280"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"607734"}}]}}}}]},"Syndrome":{"value":"Charcot - Marie - Tooth Disease, Type 1","properties":{"OmimIDs":{"value":6,"items":[{"OmimID":{"value":"118200"}},{"OmimID":{"value":"118220"}},{"OmimID":{"value":"601098"}},{"OmimID":{"value":"607678"}},{"OmimID":{"value":"118300"}},{"OmimID":{"value":"607734"}}]},"OrphanetIDs":{"value":0,"items":[]},"Overview":{"value":""},"Acronyms":{"value":0,"items":[]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-12-20"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":2,"items":[{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}}},{"Scorer Stage1":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations"}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine"}}]}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 5000"},"Notes":{"value":"Charcot-Marie-Tooth (CMT) hereditary neuropathy is the most common genetic cause of neuropathy. Estimates of the prevalence of CMT range from 9.7/100,000 in Serbia to 82.3/100,000 in Norway. The prevalence of CMT type 1 (CMT1) has been estimated from 15:100,000-20:100,000. The prevalence of CMT1A (the most common subtype) is approximately 10:100,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}},{"Reference":{"value":"/coll/reference_model/doc/RF000737"}},{"Reference":{"value":"/coll/reference_model/doc/RF000728"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"The CMT1 subtypes, identified solely by molecular findings, are often clinically indistinguishable.\n\nThe classic phenotype of CMT1 is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity. It is usually slowly progressive and often associated with pes cavus foot deformity (high instep) and bilateral foot drop.  Clinical severity is variable, ranging from extremely mild disease that goes unrecognized by patient or physician, to considerable weakness and disability, with fewer than 5% of individuals becoming wheelchair dependent. The typical presenting symptom of CMT1 is weakness of the feet and ankles. The typical affected adult has bilateral foot drop, symmetric atrophy of muscles below the knee (stork leg appearance), atrophy of intrinsic hand muscles, and absent tendon reflexes in both upper and lower extremities. The proximal muscles usually remain strong. Variable scoliosis may develop during adolescence. \n\nMild to moderate sensory deficits of position, vibration, and pain/temperature commonly occur in the feet, but many affected individuals are unaware of this symptom. Pain, especially in the feet, is reported by 20%-30% of individuals. The pain is often musculoskeletal in origin but may be neuropathic in some cases. \n\nOther observed findings in CMT1 individuals include: vestibular impairment, sleep apnea, restless leg syndrome, episodic pressure palsies, impotence, hip dysplasia, pulmonary insufficiency, deafness or early hearing loss, and lower-limb muscle atrophy and fatty infiltration."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}},{"Reference":{"value":"/coll/reference_model/doc/RF000181"}},{"Reference":{"value":"/coll/reference_model/doc/RF000590"}},{"Reference":{"value":"/coll/reference_model/doc/RF000737"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Individuals with CMT1 usually become symptomatic between ages of five and 25; age of onset ranges from infancy (resulting in delayed walking) to the fourth and subsequent decades. Affected individuals experience long plateau periods without obvious deterioration.  The disease does not decrease life span.\n\nWomen have been reported to have earlier onset of symptoms (8.6 versus 14 years) and higher deterioration of quality of life compared to affected men."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}},{"Reference":{"value":"/coll/reference_model/doc/RF000181"}},{"Reference":{"value":"/coll/reference_model/doc/RF000590"}},{"Reference":{"value":"/coll/reference_model/doc/RF000737"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1103","properties":{"Key Text":{"value":"Initial evaluation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with CMT1, the following evaluations are recommended: physical examination, nerve conduction velocity (NCV), family history, and medical genetic consultation"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}}]}}}},{"Patient Management":{"value":"ACPM1102","properties":{"Key Text":{"value":"Treatment of CMT"},"Tier":{"value":"4"},"Recommendation Text":{"value":"No treatment reverses or slows the natural progression of CMT. Treatment of CMT1 is symptomatic and involves evaluation and management by a multidisciplinary team that includes neurologists, physiatrist, orthopedic surgeons, and physical and occupational therapists. These treatments may include: ankle/foot orthoses; orthopedic surgery; forearm crutches/canes/wheelchairs; exercise as tolerated; serial night casting to help increase ankle flexibility; treatment of musculoskeletal pain with acetaminophen or NSAIDS; treatment of neuropathic pain with tricycle antidepressants or drugs such as carbamazepine or gabapentin; and career and employment counseling. Daily heel cord stretching exercises to prevent Achilles’ tendon shortening are desirable."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}},{"Reference":{"value":"/coll/reference_model/doc/RF000737"}}]}}}},{"Patient Management":{"value":"ACPM1104","properties":{"Key Text":{"value":"Exercise Interventions"},"Tier":{"value":"1"},"Recommendation Text":{"value":"A systematic review of exercise interventions for individuals with CMT identified 9 studies of 134 individuals with CMT (3 randomized trials, 5 quasi-experimental, 1 case report). This review found that although benefits appear to be gained from exercise in strength and function in some studies, most outcomes reported were not statistically significant. The authors concluded that the optimal exercise modality and intensity for people with CMT, the clinical relevance of the changes observed, and the safety of exercise in these patients is still unclear. A review of four RCTs (149 patients with neuromuscular disease) found no benefit of any studied intervention (night splits, prednisone, orthopedic surgery) for sustainably increasing ankle range of motion."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000729"}},{"Reference":{"value":"/coll/reference_model/doc/RF000730"}}]}}}},{"Patient Management":{"value":"ACPM1105","properties":{"Key Text":{"value":"Preoperative management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Preoperative assessment for co-morbidities and autonomic denervation is recommended. During surgical positioning, transport and mobilization, cautious positioning and protection of pressure points is recommended to avoid nerve compression. Neuromuscular block monitoring during surgery is also recommended."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000590"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU592","properties":{"Key Text":{"value":"Regular evaluation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals should be evaluated regularly by a team comprising physiatrists, neurologists, and physical and occupational therapists to determine neurologic status and functional disability."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}}]}}}},{"Surveillance":{"value":"ACSU593","properties":{"Key Text":{"value":"Pressure sore evaluation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals should undergo regular foot examination for pressure sores."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM399","properties":{"Key Text":{"value":"Genetic counseling"},"Tier":{"value":"4"},"Recommendation Text":{"value":"It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of being affected."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA489","properties":{"Key Text":{"value":"Obesity"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Obesity should be avoided because it makes walking more difficult."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}},{"Reference":{"value":"/coll/reference_model/doc/RF000738"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA490","properties":{"Key Text":{"value":"Avoidance of Vincristine and Paclitaxel"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Over 30 medications have been identified as toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. Vincristine and paclitaxel (chemotherapeutic agents) pose a definite high risk of nerve damage and should be avoided by all patients with CMT, including those who are asymptomatic."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA487","properties":{"Key Text":{"value":"Avoidance of succinylcholine"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Avoiding succinylcholine, a muscle relaxant used for anesthesia, is recommended."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000590"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA488","properties":{"Key Text":{"value":"Avoidance of medications"},"Tier":{"value":"5"},"Recommendation Text":{"value":"A review of case reports addressing CMT and toxic medication effects identified 22 reports (30 patients) addressing vincristine toxicity. 18 of 30 patients developed marked sensory symptoms or new onset weakness, with some developing dysarthria and dysphagia. Nearly all reports describe eventual improvement, but frequently not to baseline levels. These cases occurred in both adults (15) and children (15). Most individuals having a reaction were previously unsuspected or undiagnosed with CMT (26 of 30) and were only recognized following administration of vincristine; however, 10 cases, in retrospect, had overt clinical signs or a close relative with known CMT.  A review of the CMT North American Database (including 209 individuals) identified 19 medications associated with clinical worsening. The majority of cases reviewed did not have information on genotype of CMT subtype; however, of those cases with identified subtypes the vast majority were CMT1A."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000732"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Information on the prevalence of pathogenic variants associated with CMT1 was not identified. However, the prevalence of CMT type 1 (CMT1) has been estimated from 15:100,000-20:100,000.  The estimated proportion of CMT1 cases related to each subtype include: CMT1A (70%-80%; PMP22), CMT1B (6%-10%; MPZ), CMT1C (1%-2%; LITAF), CMT1D (<2%; EGR2), CMT1E (<5%; PMP22), and CMT2E/1F (<5%; NEFL)."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE572","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Penetrance of CMT1 is usually nearly 100%, but the wide range in age onset and severity may\\nresult in under-recognition of individuals with mild or late-onset disease."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}},{"Reference":{"value":"/coll/reference_model/doc/RF000737"}},{"Reference":{"value":"/coll/reference_model/doc/RF000738"}}]}}}},{"Penetrance":{"value":"ACPE573","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"A study of 109 persons (mean age 22 years; range 1-60 years) from completely ascertained sibships from 15 unrelated families, concluded that penetrance (as indicated by physical examination and nerve conduction) was 28% complete in the first decade and essentially complete by the middle of the third decade.  However, this study was conducted prior to the introduction of genetic testing and was based on an assumption that 50% of sibships should be affected. Overall 48% of individuals were found to be affected (44% affected with probands excluded). The average age of onset was 12.2 years with a standard deviation of 7.3. The mean age at time of diagnosis was 18.3 years (range 3 to 54 years)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000181"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR236","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information regarding relative risk was not identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN258","properties":{"Key Text":{"value":"Inter- and intra-familial phenotypic variability is common."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000181"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI264","properties":{"Key Text":{"value":"Potential interventions include examinations (physical exam, electrophysiological, ophthalmologic, family history, genetics consultation), physical therapy/stretching, and avoidance of certain medications."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC258","properties":{"Key Text":{"value":"Mild disease may go unrecognized by the affected individual and physician."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2018-02-05"},"Scorers Present":{"value":6,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"srego"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"weaverm"}}]},"Notes":{"value":"Medical evaluations were scored as ineffective  because all treatment is symptomatic."}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Overall Score":{"value":"IN"},"Effectiveness":{"value":"IN","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Overall Score":{"value":"9CC"},"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":8,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"INC"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"IN"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"INA"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"INC"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":8,"items":[{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"Tough call between a 1 and a 2. For most people it's pretty minor but since it can be quite debilitating (albeit in a minority of cases) I went with a 2 for severity."}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"INC","properties":{"Notes":{"value":"I suspect I'll be an outlier here but I think this quote from the summary says it all: \"Treatment of CMT1 is symptomatic\""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":"I won't score this since I rated it as ineffective and we decided early on that a score of IN precluded any scoring in this category so as not to inflate scores inappropriately"}}}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"3N","properties":{"Notes":{"value":"Certainly exposure to these agents is problematic and it's particularly worrisome that \"Most individuals having a reaction were previously unsuspected or undiagnosed with CMT (26 of 30)\"\nWe run into the issue here of \"penetrance\" in that most people will never be exposed to these agents. Shouldn't we have a score for penetrance of that particular intervention/outcome that takes this into account?\nI wish we'd had something to score about surgical positioning since this is a problem with CMT patients and most people end up getting surgery so the \"penetrance\" could be high for problems along those lines."}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"only one study on penetrance cited and no genetic testing done in that study."}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"IN","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"IN","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"INA","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Am thinking mostly of the burden of forgoing chemo agents that would typically be first-line, or thought to be most effective."}}}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of Vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"2.0.1","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36146},"ReasonCode":{"value":"Q4","properties":{"Reason":{"value":"Scoring pairs updated <strong>with</strong> major updates in the report"}}},"Date":{"value":"2018-02-05"},"ReleasedBy":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"}}}}}}}},
{"ActionabilityDocID":{"value":"AC131","properties":{"Status":{"value":"Released"},"Genes":{"value":3,"items":[{"Gene":{"value":"KCNQ1","properties":{"HGNCId":{"value":"HGNC:6294"},"GeneOMIM":{"value":"607542"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"192500"}}]}}}},{"Gene":{"value":"KCNH2","properties":{"HGNCId":{"value":"HGNC:6251"},"GeneOMIM":{"value":"152427"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"613688"}}]}}}},{"Gene":{"value":"SCN5A","properties":{"HGNCId":{"value":"HGNC:10593"},"GeneOMIM":{"value":"600163"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"603830"}}]}}}}]},"Syndrome":{"value":"Romano-Ward Long QT Syndrome","properties":{"OmimIDs":{"value":3,"items":[{"OmimID":{"value":"192500"}},{"OmimID":{"value":"613688"}},{"OmimID":{"value":"603830"}}]},"OrphanetIDs":{"value":0,"items":[]}}},"Stage 1":{"value":null,"properties":{}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death (KCNQ1, KCNH2)","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Beta blockers"}},{"Intervention":{"value":"ICD implantation"}}]}}}},{"Outcome":{"value":"Sudden cardiac death (SCN5A)","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Beta blockers"}},{"Intervention":{"value":"ICD implantation"}}]}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 5000"},"Notes":{"value":"Long QT Syndrome (LQTS) has prevalence estimates ranging from 1/2000 to 1/7000"},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000591"}},{"Reference":{"value":"/coll/reference_model/doc/RF000327"}},{"Reference":{"value":"/coll/reference_model/doc/RF000334"}},{"Reference":{"value":"/coll/reference_model/doc/RF000233"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"LQTS is an electrophysiological disorder characterized by QT interval prolongation and torsade de pointes (TdP) ventricular tachycardia in the absence of structural heart disease. TdP is typically self-terminating, resulting in a syncopal event, which is the most common symptom in LQTS. TdP can degenerate into a malignant ventricular arrhythmia which may result in cardiac arrest or sudden cardiac death (SCD). The precipitating conditions associated with arrhythmic events are, to a large extent, gene-specific with most arrhythmic events occurring during physical or emotional stress in LQT1 (KCNQ1); at rest, during emotional stress , and with sudden noises in LQT2 (KCNH2); and at rest or during sleep in LQT3 (SCN5A)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000591"}},{"Reference":{"value":"/coll/reference_model/doc/RF000327"}},{"Reference":{"value":"/coll/reference_model/doc/RF000334"}},{"Reference":{"value":"/coll/reference_model/doc/RF000234"}},{"Reference":{"value":"/coll/reference_model/doc/RF000005"}},{"Reference":{"value":"/coll/reference_model/doc/RF000235"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"The mean age for the first manifestation of LQTS is 12 years, but can range from the first year of life to as late as the fifth or sixth decade. Subsequent cardiac events may occur from infancy through middle age, but are most common from the pre-teen years through the 20s. After age 40, cardiac events are uncommon for most genotypes. Among untreated patients, the natural history typically involves several syncopal events, eventually leading to SCD. For some, SCD is the first manifestation of the disease.\n\nPrognosis in LQTS is often determined by the genetic defect, QT duration, gender, and prior events. LQT3 patients have the highest risk, compared to LQT1 and LQT2. A normal QT interval provides a good prognosis, while a QT interval exceeding 500ms provides the highest risk of symptoms. Males have a poorer prognosis than females in adulthood, though the reverse is true in childhood. A family history of SCD has not been shown to be a risk factor for SCD. However, patients who have been resuscitated from SCD have an especially poor prognosis, with a relative risk of 12.9 of experiencing another cardiac arrest. Risk of SCD is also increased during the immediate post-partum period, particularly in women with LQT2."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000591"}},{"Reference":{"value":"/coll/reference_model/doc/RF000327"}},{"Reference":{"value":"/coll/reference_model/doc/RF000334"}},{"Reference":{"value":"/coll/reference_model/doc/RF000234"}},{"Reference":{"value":"/coll/reference_model/doc/RF000005"}},{"Reference":{"value":"/coll/reference_model/doc/RF000235"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1107","properties":{"Key Text":{"value":"Beta blockers"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Beta blockade should be initiated in those who have had symptoms, those with a definite long QT interval, and in those with a positive genetic diagnosis but a normal QT interval. In a study of LQT1 (n=549) and LQT2 (n=422) patients from an international registry, reduction of risk of cardiac arrest or SCD was 23% in LQT1 adult males, 34% in LQT1 adult females, 46% in LQT2 adult males and 71% in LQT2 adult females."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000591"}},{"Reference":{"value":"/coll/reference_model/doc/RF000234"}},{"Reference":{"value":"/coll/reference_model/doc/RF000235"}},{"Reference":{"value":"/coll/reference_model/doc/RF000006"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC262","properties":{"Recommendation":{"value":"Evidence regarding the effectiveness of beta blockers in patients with LQT3 is variable. One primary study reported that beta-blockers had statistically significant effects in preventing cardiac events in patients with LQT1 (HR=0.29, p<0.001) and LQT2 (HR=0.47, p=0.01) but not in patients with LQT3 (HR=1.67, p=0.44); sample size was particularly small for the LQT3 subset and lacked power. A second primary study reported that beta-blocker therapy significantly reduced the risk of cardiac arrest and sudden cardiac death in a large group of LQT3 patients (HR=0.34, p=0.02), but detailed information on study design and results were lacking."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000592"}},{"Reference":{"value":"/coll/reference_model/doc/RF000237"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1108","properties":{"Key Text":{"value":"ICD"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Implantation with an implantable cardioverter defibrillator (ICD) along with continued use of beta blockers can be effective in reducing SCD in LQTS patients. ICD implantation is recommended for high risk LQTS patients, such as those with a previous cardiac arrest, those who experience syncope and/or ventricular tachycardia while receiving beta blockers, and those with LQT2 and LQT3 which are associated with a high risk of cardiac arrest. In one study of high-risk LQT patients, 1.3% mortality was reported in ICD-treated (n=73) vs. 16 % in untreated (n=161) patients, but the difference was not significant at p=0.07. Two additional smaller studies of patients with ICD treatment reported no mortality over an average 3 year follow-up. Cohort studies have reported appropriate ICD therapy rates from 37-65% and inappropriate therapy rates from 11-33%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000234"}},{"Reference":{"value":"/coll/reference_model/doc/RF000005"}}]}}}},{"Patient Management":{"value":"ACPM1106","properties":{"Key Text":{"value":"Left cardiac sympathetic neural denervation"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Left cardiac sympathetic neural denervation (LCSD) may be considered for LQTS patients with syncope, TdP, or cardiac arrest while receiving beta blockers. No primary studies were cited; the level of evidence was rated as, “limited population risk strata evaluated” and “conflicting evidence from single randomized trial or non-randomized studies.”"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000234"}}]}}}}]},"Surveillances":{"value":null,"items":[]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM400","properties":{"Key Text":{"value":"ECG"},"Tier":{"value":"2"},"Recommendation Text":{"value":"First degree relatives of patients with LQTS should undergo an ECG to determine QT interval and genetic testing for certainty of mutation status."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000591"}}]}}}},{"Family Management":{"value":"ACFM401","properties":{"Key Text":{"value":"General recommendations"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Family members who have not been excluded for LQTS should avoid medications contra- indicated in LQTS, beta blockers should be proposed, and sensible limitations should be placed on sporting activities."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000591"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA495","properties":{"Key Text":{"value":"Sports activity"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with LQTS are recommended to avoid competitive sports activity, specifically those with LQT1 and those who have experienced cardiac events during exercise. However, among 60 LQTS athletes who did not follow recommendations in one study, only 1 experienced a sporting-related event: a 9-year-old boy with LQT1, extreme QT prolongation, a history of aborted cardiac arrest and non-compliance with beta-blockers."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000591"}},{"Reference":{"value":"/coll/reference_model/doc/RF000234"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA493","properties":{"Key Text":{"value":"Drugs known to prolong the QT interval"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with LQTS should avoid drugs known to prolong the QT interval, cause TdP, or deplete potassium and magnesium."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000591"}},{"Reference":{"value":"/coll/reference_model/doc/RF000234"}},{"Reference":{"value":"/coll/reference_model/doc/RF000235"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA491","properties":{"Key Text":{"value":"Avoid or limit swimming and diving"},"Tier":{"value":"2"},"Recommendation Text":{"value":"LQT1 patients and other LQTS patients who have experienced exercise-induced syncope should avoid or limit swimming and diving."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000591"}},{"Reference":{"value":"/coll/reference_model/doc/RF000234"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA494","properties":{"Key Text":{"value":"Acoustic stimuli"},"Tier":{"value":"2"},"Recommendation Text":{"value":"LQT2 patients and other LQTS patients who have experienced auditory-evoked cardiac events should avoid exposure to acoustic stimuli especially during sleep (e.g. avoidance of telephone and alarm clock on the night stand)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000234"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA492","properties":{"Key Text":{"value":"Electrolyte abnormalities"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with LQTS should avoid or rapidly correct any electrolyte abnormalities that may occur during diarrhea, vomiting, metabolic conditions, or imbalanced diets for weight loss."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000235"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Mutations in KCNQ1, KCNH2, and SCN5A (all gain of function for SCN5A) make up almost 100% of patients with genetically confirmed autosomal dominant LQTS. Note that only about 75% of clinically diagnosed patients will have a detectable mutation"},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000327"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE574","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Among all patients with LQTS, approximately 50% or fewer have symptoms, usually one to a few syncopal spells, while the remaining approximately 50% or more never show symptoms. Across LQTS subtypes, the penetrance of syncopal events varies: 63% in LQT1, 46% in LQT2, and 18% in LQT3. The incidence of SCD is 6-8% among all individuals with LQTS, which does not differ across subtypes."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000327"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC072","properties":{"Recommendation":{"value":"An evaluation of 647 patients reported that the incidence of a first cardiac event (defined as syncope, cardiac arrest, or SCD) before the age of 40 was lower among patients with LQT1 (30%) compared to patients with LQT2 (46%) and LQT3 (42%). Looking at just cardiac arrest or SCD, the incidence was still lower in LQT1 (37/386 or 10%) compared to LQT2 (41/206 or 20%) and LQT3 (9/55 or 16%)"},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000238"}}]}}}}]}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN259","properties":{"Key Text":{"value":"The number of syncopal events in symptomatic patients with LQTS ranges from 1 to hundreds, indicating variable expressivity"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000327"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI265","properties":{"Key Text":{"value":"The identified interventions include implantation of an ICD, which would involve invasive surgery and device maintenance, potentially starting at a young age. In addition, the use of ICD therapy carriers a risk for psychological consequences due to fear of being shocked, particularly among patients who have experienced a shock. Lifetime treatment with beta blockers may have side effects."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC259","properties":{"Key Text":{"value":"LQTS is typically diagnosed with ECG, a screening procedure not typically recommended for asymptomatic adults with apparently low risk of coronary heart disease. Additionally, up to one- third of asymptomatic gene mutation carriers have results within the normal range. It is likely that this disorder could go unrecognized and present in a patient as TdP and cardiac arrest, potentially resulting in SCD."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000327"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death (KCNQ1, KCNH2)","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Beta blockers","properties":{"Overall Score":{"value":"10CB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"ICD implantation","properties":{"Overall Score":{"value":"9CA"},"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Sudden cardiac death (SCN5A)","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Beta blockers","properties":{"Overall Score":{"value":"8CD"},"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"ICD implantation","properties":{"Overall Score":{"value":"9CA"},"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":0,"items":[]}}}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36149},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-11"},"ReleasedBy":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"}}}}}}}},
{"ActionabilityDocID":{"value":"AC132","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"COL3A1","properties":{"HGNCId":{"value":"HGNC:2201"},"GeneOMIM":{"value":"120180"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"130050"}}]}}}}]},"Syndrome":{"value":"Ehlers-Danlos Syndrome Type IV","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"130050"}}]},"OrphanetIDs":{"value":0,"items":[]}}},"Stage 1":{"value":null,"properties":{}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Vascular or organ rupture or perforation","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoidance of invasive procedures"}}]}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"There are no good current estimates of the prevalence of Ehlers-Danlos Syndrome (EDS) type IV in any population because a large proportion of cases remain undiagnosed. A minimum prevalence of about 1:200,000 can be estimated by extrapolating from the number of known individuals with genetic testing, biochemical, or pedigree-confirmed diagnoses in the United States.\n\nEDS type IV appears to constitute approximately 5-10% of all EDS cases."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}},{"Reference":{"value":"/coll/reference_model/doc/RF000452"}},{"Reference":{"value":"/coll/reference_model/doc/RF000453"}},{"Reference":{"value":"/coll/reference_model/doc/RF000454"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"EDS type IV, or vascular EDS, is characterized by thin, translucent skin; easy bruising; characteristic facial appearance (in some individuals); and arterial, intestinal, and/or uterine fragility. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in the majority of adults identified to have EDS type IV. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, but also may occur spontaneously.\n\nThe vascular complications may affect all anatomical areas; spontaneous rupture of the aorta and medium-to-large size vessels are the most frequent complications reported. There is also a high risk of recurrent perforation in the sigmoid colon."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}},{"Reference":{"value":"/coll/reference_model/doc/RF000452"}},{"Reference":{"value":"/coll/reference_model/doc/RF000453"}},{"Reference":{"value":"/coll/reference_model/doc/RF000454"}},{"Reference":{"value":"/coll/reference_model/doc/RF000455"}},{"Reference":{"value":"/coll/reference_model/doc/RF000074"}},{"Reference":{"value":"/coll/reference_model/doc/RF000047"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"The overall mortality of EDS type IV is 90% by the age of 50 because of spontaneous rupture of vessels and internal organs.\n\nThe median survival for individuals with EDS type IV is 48 years.\n\nVascular fragility is dominant in the third and fourth decade.\n\nPregnancy increases the likelihood of a uterine or vascular rupture. Pregnancy for women with EDS type IV confers as much as a 12% risk for death from peripartum arterial rupture or uterine rupture."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}},{"Reference":{"value":"/coll/reference_model/doc/RF000452"}},{"Reference":{"value":"/coll/reference_model/doc/RF000453"}},{"Reference":{"value":"/coll/reference_model/doc/RF000047"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1113","properties":{"Key Text":{"value":""},"Tier":{"value":"4"},"Recommendation Text":{"value":"Information on the effectiveness of the patient management recommendation(s) below was not provided.\n\nCurrently, no consensus exists regarding the appropriate extent of evaluation at the time of initial diagnosis. Approach to a vascular evaluation depends on the age of the individual and the circumstances in which the diagnosis is made."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}}]}}}},{"Patient Management":{"value":"ACPM1112","properties":{"Key Text":{"value":""},"Tier":{"value":"1"},"Recommendation Text":{"value":"Invasive procedures (treatment, diagnostic, etc.) should be avoided, except in life-threatening situations."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000452"}}]}}}},{"Patient Management":{"value":"ACPM1109","properties":{"Key Text":{"value":""},"Tier":{"value":"4"},"Recommendation Text":{"value":"Affected individuals are instructed to seek immediate medical attention for sudden, unexplained pain."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}}]}}}},{"Patient Management":{"value":"ACPM1110","properties":{"Key Text":{"value":""},"Tier":{"value":"4"},"Recommendation Text":{"value":"Educating pregnant women with EDS type IV as to possible complications, and frequent surveillance in a high-risk obstetrical program is recommended. Pregnancy for women with EDS type IV has as much as a 12% risk for death from peripartum arterial or uterine rupture."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}}]}}}},{"Patient Management":{"value":"ACPM1111","properties":{"Key Text":{"value":""},"Tier":{"value":"4"},"Recommendation Text":{"value":"A MedicAlert bracelet should be worn."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU594","properties":{"Key Text":{"value":"Screening"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"There are no published data that assess the efficacy of screening strategies to identify the regions in the arterial vasculature at highest risk."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM402","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Genetic testing is recommended for at-risk family members; management is the same as for individuals identified through clinical findings."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA497","properties":{"Key Text":{"value":""},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals with EDS type IV should not engage in any competitive athletic activity."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000452"}},{"Reference":{"value":"/coll/reference_model/doc/RF000074"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA496","properties":{"Key Text":{"value":""},"Tier":{"value":"1"},"Recommendation Text":{"value":"Unless the procedure is considered absolutely life-saving, surgery and all other invasive procedures should be avoided whenever possible."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000452"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC055","properties":{"Recommendation":{"value":"Examples of invasive procedures: \n\n-  Diagnostic colonoscopy should not be performed in patients with EDS type IV."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000452"}}]}}}},{"RecommendationID":{"value":"REC054","properties":{"Recommendation":{"value":"-  Arteriograms are not recommended."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}}]}}}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Tier":{"value":"4"},"Notes":{"value":"The prevalence of individuals with mutations in COL3A1 is estimated to range from 1:50,000 to 1:200,000."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE575","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Penetrance appears to be close to 100% with missense or exon-skipping mutations; the age at which the mutation becomes penetrant may vary"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR237","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"NA"},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN260","properties":{"Key Text":{"value":"There is high variability in disease expression, highlighted by the fact that clinical diagnosis is based on any two of four possible major diagnostic criteria, and that two or more of thirteen possible minor diagnostic criteria are supportive but not sufficient for diagnosis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}}]},"Tier":{"value":"4"}}}},{"Expressivity Note":{"value":"EN261","properties":{"Key Text":{"value":"A subpopulation of individuals with EDS type IV (3-4%) have haploinsufficiency mutations; improved outcomes are reported in this group, including a 15-year delay in onset of complications, similarly improved life expectancy, and paucity of both obstetric and bowel complications."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI266","properties":{"Key Text":{"value":"Management could result in significant alterations to lifestyle choices (pregnancy, participation in sports) and medical treatment/screening"},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC260","properties":{"Key Text":{"value":"Because many families with EDS type IV are identified only after a severe complication or death, it is likely that individuals/families with COL3A1 mutations with a mild phenotype do not come to medical attention and, therefore, go undetected"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000593"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Vascular or organ rupture or perforation","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoidance of invasive procedures","properties":{"Overall Score":{"value":"10CA"},"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":0,"items":[]}}}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36151},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-10"},"ReleasedBy":{"value":"hunterj","properties":{"First Name":{"value":"Jessica"},"Last Name":{"value":"Hunter"}}}}}}}},
{"ActionabilityDocID":{"value":"AC133","properties":{"Status":{"value":"Released"},"Genes":{"value":2,"items":[{"Gene":{"value":"BRCA1","properties":{"HGNCId":{"value":"HGNC:1100"},"GeneOMIM":{"value":"113705"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"604370"}}]}}}},{"Gene":{"value":"BRCA2","properties":{"HGNCId":{"value":"HGNC:1101"},"GeneOMIM":{"value":"600185"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"612555"}}]}}}}]},"Syndrome":{"value":"Hereditary Breast and Ovarian Cancer","properties":{"OmimIDs":{"value":2,"items":[{"OmimID":{"value":"604370"}},{"OmimID":{"value":"612555"}}]},"OrphanetIDs":{"value":0,"items":[]}}},"Stage 1":{"value":null,"properties":{}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Breast Cancer (BRCA1)","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance"}},{"Intervention":{"value":"Mastectomy"}}]}}}},{"Outcome":{"value":"Ovarian Cancer (BRCA1)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy"}}]}}}},{"Outcome":{"value":"Breast Cancer (BRCA2)","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance"}},{"Intervention":{"value":"Mastectomy"}}]}}}},{"Outcome":{"value":"Ovarian Cancer (BRCA2)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy"}}]}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Notes":{"value":"For women, lifetime risk estimates indicate that 12.3% will develop breast cancer and 2.8% will die from it, while 1.4% will develop ovarian cancer and 1% will die from it. Among these breast and ovarian cancer cases, BRCA mutations have a prevalence of 3% and 10%, respectively."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000594"}},{"Reference":{"value":"/coll/reference_model/doc/RF000595"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"BRCA1 and BRCA2 mutations are associated with increased risks of breast, ovarian, fallopian tube, and primary peritoneal cancers in women. These mutations are also associated with breast cancer and, to a lesser extent, prostate cancer, in males. Both sexes may also be at an increased risk of pancreatic cancer. BRCA mutations are associated with a strong family history of breast and ovarian cancers and are found more frequently in the Ashkenazi Jewish population."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000594"}},{"Reference":{"value":"/coll/reference_model/doc/RF000202"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"BRCA-related breast and ovarian cancers occur at a younger age, typically prior to age 50, and breast cancers are more likely to be “triple-negative” (i.e. estrogen and progesterone receptor and HER2 negative). Compared to non-carriers with breast cancer, BRCA1 mutation carriers have significantly decreased overall survival rates both in the short- and long-term, though similar association was not detected for BRCA2 mutation carriers."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000594"}},{"Reference":{"value":"/coll/reference_model/doc/RF000202"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1115","properties":{"Key Text":{"value":"Chemoprevention"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Chemoprevention medications (e.g. tamoxifen, raloxifene) have been shown to reduce the incidence of breast cancer in high-risk women in the general population, but their effectiveness has not been assessed in the context of BRCA mutations."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000594"}},{"Reference":{"value":"/coll/reference_model/doc/RF000203"}},{"Reference":{"value":"/coll/reference_model/doc/RF000204"}}]}}}},{"Patient Management":{"value":"ACPM1114","properties":{"Key Text":{"value":"Prophylactic surgery"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Prophylactic surgery (e.g. bilateral mastectomy or salpingo-oophorectomy) has been shown to substantially reduce the risk for breast or ovarian cancer in both high-risk women and those who are BRCA mutation carriers. Breast cancer risk was reduced by 85-100% with mastectomy and by 37% to 100% with oophorectomy. Ovarian cancer risk was reduced by 69-100% with oophorectomy. Breast cancer-specific mortality was reduced by 81-100% after mastectomy and all-cause mortality was reduced by 55-100% after oophorectomy."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000594"}},{"Reference":{"value":"/coll/reference_model/doc/RF000203"}},{"Reference":{"value":"/coll/reference_model/doc/RF000205"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU597","properties":{"Key Text":{"value":"Breast cancer screening"},"Tier":{"value":"1"},"Recommendation Text":{"value":"More frequent and intensive breast cancer screening, including clinical breast exams, mammography, and MRI starting at age 25. 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The age at onset of breast cancer is typically prior to age 50, before the start of typical surveillance among average risk populations. Ovarian cancer is typically metastatic when diagnosed, thus risk-reducing BSO bilateral salpingo-oophorectomy is currently the only effective strategy to reduce the risk of dying from ovarian cancer."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000594"}},{"Reference":{"value":"/coll/reference_model/doc/RF000203"}}]},"Tier":{"value":"1"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Breast Cancer (BRCA1)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance","properties":{"Overall Score":{"value":"10AA"},"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Mastectomy","properties":{"Overall Score":{"value":"9AA"},"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Ovarian Cancer (BRCA1)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Overall Score":{"value":"8AA"},"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Breast Cancer (BRCA2)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance","properties":{"Overall Score":{"value":"10AA"},"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Mastectomy","properties":{"Overall Score":{"value":"9AA"},"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Ovarian Cancer (BRCA2)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Overall Score":{"value":"8AA"},"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":0,"items":[]}}}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36153},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-04-09"},"ReleasedBy":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"}}}}}}}},
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Abdominal aortic aneurysms and cerebral and peripheral artery aneurysms have been observed in patients."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000596"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"In the absence of surgical repair of the ascending aorta, affected individuals typically have progressive enlargement of the ascending aorta leading to an acute aortic dissection or, in rare cases, aortic rupture. The age of onset and presentation of the aortic disease are highly variable, as are the other vascular diseases and features. The mean age of onset of familial TAAD is earlier than for non-familial TAAD. Aortic dissections have occurred in children with FTAAD as young as 12 years. Predisposition to FTAAD is not known to be increased in any ethnic or racial group. Pregnant women are at increased risk for complications such as rapid aortic root enlargement and aortic dissection or rupture during pregnancy, delivery, or the post-partum period."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000596"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1119","properties":{"Key Text":{"value":"Prophylactic surgical repair of the aorta"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with mutations in MYH11, SMAD3, and ACTA2 and at >4.2 cm for patients with mutations in TGFBR1 or TGFBR2 mutations. Earlier repair can be considered in patients with a family history of aortic dissection, growth of the aorta at 1 cm/year, or aortic regurgitation. Timely repair of aortic aneurysms prolongs survival and approaches that of age-matched controls in patients with Marfan syndrome; however, evidence on effectiveness was not provided for patients with FTAAD."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000050"}},{"Reference":{"value":"/coll/reference_model/doc/RF000047"}},{"Reference":{"value":"/coll/reference_model/doc/RF000049"}}]}}}},{"Patient Management":{"value":"ACPM1118","properties":{"Key Text":{"value":"Beta adrenergic-blocking agents"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Beta adrenergic-blocking agents are recommended to reduce aortic dilation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000049"}}]}}}},{"Patient Management":{"value":"ACPM1116","properties":{"Key Text":{"value":""},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals with TGFBR1 or -2 a mutation should be taught the signs and symptoms of aortic dissection and should consider wearing a medical alert bracelet."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000049"}}]}}}},{"Patient Management":{"value":"ACPM1117","properties":{"Key Text":{"value":"Management of hypertension"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Hypertension should be aggressively treated and controlled."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000596"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU600","properties":{"Key Text":{"value":"Aortic imaging"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should undergo complete aortic imaging at initial diagnosis and 6 months later to determine the rate of aortic enlargement followed by imaging annually or every 6 months for those with a >4.5 com diameter, a significant rate of growth, or aortic regurgitation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000050"}},{"Reference":{"value":"/coll/reference_model/doc/RF000047"}},{"Reference":{"value":"/coll/reference_model/doc/RF000049"}}]}}}},{"Surveillance":{"value":"ACSU599","properties":{"Key Text":{"value":"Cerebrovascular imaging"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Cerebrovascular imaging to assess for cerebrovascular disease and cardiac evaluation to assess for coronary artery disease should be considered in individuals with an ACTA2 mutation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000596"}}]}}}},{"Surveillance":{"value":"ACSU598","properties":{"Key Text":{"value":"Pregnancy and postpartum monitoring"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Pregnant women with a known aortic root or ascending thoracic dilatation should be monitored during pregnancy and postpartum by a cardiologist and a high-risk obstetrician, and undergo monthly or bimonthly echocardiographic assessment of the ascending aorta. It is recommended that pregnant women found to have dilatation of the aortic arch, descending thoracic aorta, or the abdominal aorta undergo MRI or transesophageal echocardiogram."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000596"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM404","properties":{"Key Text":{"value":"Aortic imaging"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Aortic imaging is recommended for first-degree relatives of patients with thoracic aneurysm and/or dissection to identify those with asymptomatic disease."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000047"}}]}}}},{"Family Management":{"value":"ACFM406","properties":{"Key Text":{"value":"Imaging"},"Tier":{"value":"1"},"Recommendation Text":{"value":"If one or more first-degree relatives are found to 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the potential for bodily collision."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000074"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA499","properties":{"Key Text":{"value":""},"Tier":{"value":"4"},"Recommendation Text":{"value":"Patients should avoid isometric exercise that could lead to significant blows to the chest as these could accelerate aortic root dilatation or cause dissection/rupture."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000596"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"Information regarding the prevalence of genetic mutations associated with FTAAD was unavailable."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE577","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"FTAAD displays incomplete penetrance, primarily in women."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000047"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR239","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information regarding relative risk was unavailable."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity 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catastrophic acute aortic dissection occurs."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000596"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Clinically significant aortic aneurysm","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Aortic surveillance","properties":{"Overall Score":{"value":"11DC"},"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Aortic dilation 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{"ActionabilityDocID":{"value":"AC135","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"PROC","properties":{"HGNCId":{"value":"HGNC:9451"},"GeneOMIM":{"value":"612283"},"SyndromeOMIMs":{"value":2,"items":[{"OMIM":{"value":"176860"}},{"OMIM":{"value":"612304"}}]}}}}]},"Syndrome":{"value":"Thrombophilia due to protein C deficiency","properties":{"OmimIDs":{"value":2,"items":[{"OmimID":{"value":"176860"}},{"OmimID":{"value":"612304"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"745"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-05-09"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"hunterj","properties":{"First Name":{"value":"Jessica"},"Last Name":{"value":"Hunter"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"No"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)"}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women"}}]}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 500"},"Notes":{"value":"Partial protein C (PROC) deficiency (heterozygous forms) is present in 0.2-0.5% of the general population and 3% of patients with thrombosis. Prevalence of severe PROC deficiency (homozygous or compound heterozygous forms) is estimated as 1/500,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000598"}},{"Reference":{"value":"/coll/reference_model/doc/RF000599"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"PROC deficiency is associated with reduced or absent levels of PROC activity, where PROC is a natural inhibitor of coagulation. Partial PROC deficiency (heterozygous forms) is associated with an increased risk of venous thromboembolism (VTE). VTE most commonly occurs in the form of a deep vein thrombosis (DVT) of the lower limbs with or without pulmonary embolism (PE). Cerebral venous thrombosis (CVT) may occur as well. Beyond the acute sequelae, VTE may result in chronic conditions, including post-thrombotic syndrome, venous insufficiency, and pulmonary hypertension.\\n\\nPatients with severe PROC deficiency (homozygous or compound heterozygous forms with undetectable PROC levels) typically manifest several hours to days after birth and may develop purpura fulminans, a life-threatening condition involving severe clotting throughout the body and causing necrosis of tissues. Prognosis is severe for these patients.  Patients with homozygous or compound heterozygous PROC deficiency with low but detectable PROC levels have milder symptoms similar to those of heterozygous individuals."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000598"}},{"Reference":{"value":"/coll/reference_model/doc/RF000599"}},{"Reference":{"value":"/coll/reference_model/doc/RF000600"}},{"Reference":{"value":"/coll/reference_model/doc/RF000458"}},{"Reference":{"value":"/coll/reference_model/doc/RF000601"}},{"Reference":{"value":"/coll/reference_model/doc/RF000602"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Heterozygotes are usually asymptomatic until adulthood. VTE events are mainly provoked by other risk factors such as surgery, pregnancy, immobilization, or exogenous hormone use. Additional risk factors for VTE include a first-degree relative with an VTE event before age 50, personal history of VTE, obesity, and certain comorbidities (e.g., cancer, heart or respiratory failure). The annual VTE incidence is 1-2% for PROC deficiency.  In general, prognosis is good for heterozygous patients, though mortality may result from PE. With adequate treatment and monitoring, the risk of VTE is markedly reduced. Men and women are equally affected.\\n\\nWomen with PROC deficiency are at an increased risk of VTE during pregnancy, with an estimated VTE risk of 0.1-0.8% per pregnancy without a prior VTE and 4-17% with a prior VTE. Among those with a family history of VTE, the risk in pregnancy has been reported as 2-7%. However, it is currently controversial whether there is an association between inherited thrombophilias and pregnancy complications such as uteroplacental thrombosis that can lead to adverse pregnancy outcomes such as fetal loss, preeclampsia, fetal growth restriction, and placental abruption."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000598"}},{"Reference":{"value":"/coll/reference_model/doc/RF000599"}},{"Reference":{"value":"/coll/reference_model/doc/RF000600"}},{"Reference":{"value":"/coll/reference_model/doc/RF000603"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1121","properties":{"Key Text":{"value":"Antithrombotic prophylaxis for stroke"},"Tier":{"value":"2"},"Recommendation Text":{"value":"There is very little evidence to guide management of asymptomatic people with hereditary thrombophilias (including PROC deficiency) for the primary prevention of stroke. Evidence that most VTE events occurred during periods of high risk periods (such as surgery, trauma, or pregnancy) suggest that antithrombotic prophylaxis would likely be effective. However, the effect of this prophylaxis on the incidence of stroke or transient ischemic attack is unknown."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000604"}}]}}}},{"Patient Management":{"value":"ACPM1120","properties":{"Key Text":{"value":"Anticoagulation following CVT"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Following a CVT or cerebral venous and sinus thrombosis (CVST), there is an increased risk of recurrence (estimated from 2-5%; adjusted HR=4.71, 95% CI: 1.34-16.5) and recurrence tends to occur within the first year of the index CVT. The recurrent event is more often a VTE than a CVT. Indefinite anticoagulation may be considered in patients with PROC deficiency at the first CVT or CVST. However, there are no secondary-prevention trials of duration of anticoagulation in adults with CVT and guidelines are based solely on observational data."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000458"}}]}}}},{"Patient Management":{"value":"ACPM1122","properties":{"Key Text":{"value":"Perioperative VTE prophylaxis"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Perioperative VTE prophylaxis is recommended for patients with PROC deficiency undergoing gynecological surgery. Prophylaxis may include low-dose unfractionated heparin (UFH) or low molecular weight heparin (LMWH) with or without intermittent pneumatic compression devices or graduated compression stockings. Continuing prophylaxis may be considered for 2-4 weeks after discharge. Data from two randomized trials and a large retrospective series in the general population have found that the incidence of VTE in patients undergoing prophylaxis following gynecologic surgery with one of the above modalities was 1-6.5% compared with 15-40% reported in an untreated population."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000598"}}]}}}},{"Patient Management":{"value":"ACPM1123","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Based on the increased risk of VTE, all pregnant women with an inherited thrombophilia should be referred to a local expert and undergo individualized risk assessment which may modify pregnancy management decisions. The decision to treat with thromboprophylaxis, anticoagulation therapy, or no pharmacological treatment is influenced by VTE history, severity of inherited thrombophilia, and additional risk factors (e.g., cesarean delivery, prolonged immobility, obesity, and family history of VTE). Thromboprophylaxis may include LMWH or UFH. Surveillance includes clinical vigilance and appropriate objective investigation of women with symptoms suspicious of VTE.\n•  Women without a prior VTE are recommended to undergo antepartum and postpartum surveillance without thromboprophylaxis. Guidelines differ on whether postpartum thromboprophylaxis is recommended among all women or only in the presence of other risk factors (e.g., family history of VTE).\n•  Women with a prior VTE who are not receiving long-term anticoagulation therapy may undergo either antepartum surveillance without anticoagulation therapy or with prophylactic or intermediate-dose LMWH/UFH, but are recommended postpartum thromboprophylaxis.\n•  Pneumatic compression boots or elastic stockings should be considered during the intrapartum period until the patient is ambulatory postpartum.\n•  LMWH is estimated to reduce the risk of VTE from 20 VTEs per 1000 to 13 fewer VTEs per 1000 among individuals with PROC deficiency. However, evidence about the relative effects of treatment is taken from a meta-analysis of thromboprophylaxis in patients undergoing hip arthroplasty and is rated by the guideline authors to be of low quality due to the indirectness of the population and imprecision in the baseline risk estimates for women with thrombophilias."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000600"}},{"Reference":{"value":"/coll/reference_model/doc/RF000267"}},{"Reference":{"value":"/coll/reference_model/doc/RF000605"}},{"Reference":{"value":"/coll/reference_model/doc/RF000606"}},{"Reference":{"value":"/coll/reference_model/doc/RF000607"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM407","properties":{"Key Text":{"value":"Identification of asymptomatic family members"},"Tier":{"value":"4"},"Recommendation Text":{"value":"There is no evidence that identification of thrombophilia in asymptomatic family members reduces risk of VTE."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000608"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA501","properties":{"Key Text":{"value":"Estrogen containing prescription drugs"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Thrombophilic disorders (including PROC deficiency) are contraindications for the use of estrogen containing prescription drugs approved for the prevention of postmenopausal osteoporosis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000609"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":"In most cases PROC deficiency is transmitted in an autosomal dominant manner; however, autosomal recessive PROC deficiency may also occur, resulting in very low levels of active PROC."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000601"}},{"Reference":{"value":"/coll/reference_model/doc/RF000602"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"The prevalence of mutations associated with PROC deficiency were not identified."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE578","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"PROC deficiency is associated with a reduced penetrance of VTE and specific estimates are not available. In general, individuals are at an annual risk of 0.4-1.0 VTEs (%/year)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000608"}}]}}}},{"Penetrance":{"value":"ACPE579","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Women with PROC deficiency have a VTE risk of is estimated as 0.1-0.8% per pregnancy without a prior VTE and 4-17% with a prior VTE compared to a background VTE incidence of ~0.1%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000496"}}]}}}},{"Penetrance":{"value":"ACPE580","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Although individuals with a PROC deficiency have a greater relative risk of VTE during pregnancy (estimated from case-control odds ratios), given the background incidence of VTE during pregnancy ~1/1000 deliveries, the absolute risk of in women without a prior event or family history remains low (0.7%; 95% CI: 0.3-1.5%)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000267"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR240","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"The risk of VTE has been estimated from a meta-analysis of case-control and cohort studies which estimated both an increased risk of first VTE (OR=7.5; 95% CI: 3.2-17.5) and VTE recurrence (OR=2.9; 95% CI: 1.4-6.0) associated with PROC deficiency compared to controls."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000603"}}]},"Tier":{"value":"1"}}}},{"Relative Risk":{"value":"RR241","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"PROC deficiency was not found to be associated with recurrent fetal loss (pooled OR: 1.6; 95% CI: 0.2–10.5) or non-recurrent fetal loss (pooled OR: 1.4, 95% CI: 1.0-2.1)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000611"}}]},"Tier":{"value":"1"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN264","properties":{"Key Text":{"value":"There is not a clear correlation between residual enzyme activity and clinical thrombosis. Clinical variability among individuals with homozygous PROC deficiency, including relatives, suggested that other factors need to interact for full clinical penetrance of the defect."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000602"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI269","properties":{"Key Text":{"value":"The primary intervention proposed for patients with PROC deficiency is the use of injectable heparin in situations of stress that may increase the risk of VTE. Neither UFH nor LMWH crosses the placenta and both are considered safe in pregnancy. During pregnancy, both UFH and LMWH have shorter half-lives and lower peak plasma concentrations, usually necessitating higher doses and more frequent administration in order to maintain effective concentrations. However, bleeding complications can arise from administration of UFH or LMWH, and this complication should be considered before initiating anticoagulation therapy. UFH, which is associated with increased bruising at the injection sites, also has been associated with other skin reactions and serious allergic reactions."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000600"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC263","properties":{"Key Text":{"value":"Screening for PROC deficiency is not routinely recommended. VTE may be the first manifestation of the disease."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000598"}},{"Reference":{"value":"/coll/reference_model/doc/RF000600"}},{"Reference":{"value":"/coll/reference_model/doc/RF000458"}},{"Reference":{"value":"/coll/reference_model/doc/RF000606"}},{"Reference":{"value":"/coll/reference_model/doc/RF000607"}},{"Reference":{"value":"/coll/reference_model/doc/RF000612"}}]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2017-08-07"},"Scorers Present":{"value":6,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"bieseckerl"}},{"Scorer":{"value":"odanielj"}}]},"Notes":{"value":""}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Overall Score":{"value":"8CB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Overall Score":{"value":"8CB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":9,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2B"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"ronakypatel","properties":{"First Name":{"value":"Ronak"},"Last Name":{"value":"Patel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}}]}}},"Scorers":{"value":8,"items":[{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"As with PS, this can present with sudden death due to PE but I think it's unusual enough that I went with a \"2\""}}},"Likelihood":{"value":"2B","properties":{"Notes":{"value":"The slightly higher rates of VTE with PC could edge it up into the \"3\" range but that's at the extreme so I settled on a \"2\"."}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Like with PS, I knocked down the quality of the data since I'm extrapolating from the GYN references."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"I am scoring only for adults with presumed heterozygous deficiency"}}},"Likelihood":{"value":"2D","properties":{"Notes":{"value":"same logic as before based n Bell et al., \nAnd don't we mean increased risk/penetrance not reduced"}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"Could go with 3 due to PE risk"}}},"Likelihood":{"value":"0B","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0B","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"Again scored for possibility of PE \"possible death\""}}},"Likelihood":{"value":"2B","properties":{"Notes":{"value":"Not at all sure what \"annual risk of 0.4 - 1.0 VTEs\" means. Does that mean a 40-100% risk of a VTE each year???\nPicked higher of tier 2 or 3 for evidence"}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.1.1","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36157},"ReasonCode":{"value":"Q3","properties":{"Reason":{"value":"Scoring pairs updated <strong>without</strong> major updates in the report"}}},"Date":{"value":"2018-02-08"},"ReleasedBy":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"}}}}}}}},
{"ActionabilityDocID":{"value":"AC136","properties":{"Status":{"value":"Released"},"Genes":{"value":3,"items":[{"Gene":{"value":"RAD51C","properties":{"HGNCId":{"value":"HGNC:9820"},"GeneOMIM":{"value":"602774"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"613399"}}]}}}},{"Gene":{"value":"RAD51D","properties":{"HGNCId":{"value":"HGNC:9823"},"GeneOMIM":{"value":"602954"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"614291"}}]}}}},{"Gene":{"value":"BRIP1","properties":{"HGNCId":{"value":"HGNC:20473"},"GeneOMIM":{"value":"605882"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"114480"}}]}}}}]},"Syndrome":{"value":"Ovarian cancer","properties":{"OmimIDs":{"value":3,"items":[{"OmimID":{"value":"613399"}},{"OmimID":{"value":"614291"}},{"OmimID":{"value":"114480"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"213517"}}]},"Overview":{"value":""},"Acronyms":{"value":0,"items":[]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-03-17"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"hunterj","properties":{"First Name":{"value":"Jessica"},"Last Name":{"value":"Hunter"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy"}}]}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"The prevalence of familial breast-ovarian cancer associated with heterozygous germline pathogenic variants in the RAD51C, RAD51D, or BRIP1  genes in the general population is not clear.  A recent review estimated that altogether, RAD51C pathogenic variants have been identified in 29 breast or ovarian cancer probands with a family history of ovarian cancer, with an overall prevalence of 0.84%. A study of 1915 women with ovarian cancer with available germline DNA, unselected for age or family history, reported a frequency of 0.6% of RAD51C and RAD51D and 1.4% of BRIP1 pathogenic variants."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000613"}},{"Reference":{"value":"/coll/reference_model/doc/RF000614"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Pathogenic variants in RAD51C , RAD51D, and BRIP1 are associated with an increased risk of ovarian cancer. However, there is currently insufficient evidence for the risk of breast cancer associated with these genes."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000616"}},{"Reference":{"value":"/coll/reference_model/doc/RF000617"}},{"Reference":{"value":"/coll/reference_model/doc/RF000618"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"A study of 6 unrelated German pedigrees indicated that the mean age of onset of ovarian cancer associated with RAD51C was 60 years, 8 years younger than the mean age of onset of ovarian cancer of 68 years in the general population. A US-based study of 1915 women with ovarian cancer with available germline DNA, unselected for age or family history, reported mean ages of onset of 64, 54, and 65.5 for individuals with pathogenic variants in RAD51C, RAD51D, and BRIP1, respectively. Individuals in the same study without an identified mutation had a median age of onset of 62 years."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000614"}},{"Reference":{"value":"/coll/reference_model/doc/RF000616"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1124","properties":{"Key Text":{"value":"Oophorectomy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Based on estimates from available studies, the lifetime risk of ovarian cancer in carriers of pathogenic variants in RAD51C, RAD51D , and BRIP1 appears to be sufficient to justify consideration of risk-reducing salpingo-oophorectomy (RRSO). However, the current evidence is insufficient to make a firm recommendation as to the optimal age for RRSO.  The argument has been made that RRSO should not be considered until a woman’s expected lifetime risk of developing ovarian cancer exceeds 2.6%, the expected lifetime risk of a woman with a BRCA-negative family history of ovarian cancer.  The cumulative risk for developing ovarian cancer does not approach 2.6% until ages  60 to 64 for RAD51C, ages 50 to 54 for RAD51D, and ages 50 to 55 years for BRIP1. However, some women may have additive risk factors and delaying the discussion of RRSO until these age ranges may miss some cases of early-onset ovarian cancer. Therefore, based on the current, limited evidence base, it has been recommended for carriers of RAD51C, RAD51D, and BRIP1 pathogenic variants that a discussion about RRSO should be held around age 45–50 years or earlier based on a specific family history of an earlier onset ovarian cancer."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000617"}},{"Reference":{"value":"/coll/reference_model/doc/RF000619"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC263","properties":{"Recommendation":{"value":"Evidence on the effectiveness of reducing risk of ovarian cancer following RRSO in patients with pathogenic variants in RAD51C, RAD51C, and BRIP1  was not available. However, studies in women who are at high risk, including those with BRCA1 an BRCA2 mutations, show a reduction in risk of ovarian cancer by 69-100%."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000203"}},{"Reference":{"value":"/coll/reference_model/doc/RF000620"}}]}}}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU601","properties":{"Key Text":{"value":"Ovarian cancer surveillance"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Screening for ovarian cancer in high risk groups, including carriers of pathogenic variants in RAD51C and RAD51D, should only be offered in the context of a research study."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000619"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC044","properties":{"Recommendation":{"value":"A similar recommendation was not identified for BRIP1."},"Tier":{"value":"Not provided"},"References":{"value":null,"items":[]}}}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"The prevalence of pathogenic mutations associated with an increased risk of ovarian cancer in RAD51C, RAD51D, and BRIP1 in the general population is unknown."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE581","properties":{"Key Text":{"value":"1-4 %"},"Tier":{"value":"3"},"Notes":{"value":"The cumulative risk of developing ovarian cancer in carriers of a RAD51C pathogenic variant approaches 2.6% around ages 60 to 64 years, with the cumulative risk between the ages of 55 to 59 being 1.5%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000617"}}]}}}},{"Penetrance":{"value":"ACPE582","properties":{"Key Text":{"value":"1-4 %"},"Tier":{"value":"3"},"Notes":{"value":"For RAD51D, carriers approach a cumulative risk of 2.6% around age 50 to 54."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000617"}}]}}}},{"Penetrance":{"value":"ACPE583","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"The cumulative lifetime risk of developing ovarian cancer by age 80 in carriers of BRIP1 pathogenic variants is estimated to be 5.8%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000617"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR242","properties":{"Key Text":{"value":">3"},"Notes":{"value":"The relative risk of ovarian cancer for RAD51C and RAD51D has been estimated as 5.88 (95% CI: 2.91–11.88) and 6.30 (95% CI: 2.86–13.85), respectively. However, literature related to risk of ovarian cancer and BRIP1 is odds ratios estimated from case-control studies, which are likely similar to relative risks given the rarity of this outcome in the general population: 8.13 (95% CI: 4.74-13.95) to 11.22 (95% CI: 3.22–34.10)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000616"}},{"Reference":{"value":"/coll/reference_model/doc/RF000617"}},{"Reference":{"value":"/coll/reference_model/doc/RF000618"}},{"Reference":{"value":"/coll/reference_model/doc/RF000621"}}]},"Tier":{"value":"3"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN265","properties":{"Key Text":{"value":"There may be the presence of additive risk factors that may increase the risk of early onset ovarian cancer."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000617"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI270","properties":{"Key Text":{"value":"In women with BRCA1 and/or BRCA2 mutations who underwent an RRSO, 5% of women with a personal history of breast cancer expirenced a surgical complication. In a second study  women with BRCA1 and/or BRCA2 mutations who underwent surgery at a mean age of 47 (47% with a personal history of breast cancer), most women reported worsening of vasomotor symptoms, and decreased sexual functioning after surgery. Guidelines state that the decision to carry out RRSO should not be made lightly, given the impact of premature menopause."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000617"}},{"Reference":{"value":"/coll/reference_model/doc/RF000203"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC264","properties":{"Key Text":{"value":"There are currently no ovarian cancer surveillance in the general population.  Ovarian cancer is typically metastatic when diagnosed, thus RRSO is the only effective strategy to reduce the risk of dying from ovarian cancer."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000203"}},{"Reference":{"value":"/coll/reference_model/doc/RF000620"}}]},"Tier":{"value":"1"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"1C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Overall Score":{"value":"7CB"},"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":8,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"1C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"1"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"1"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"1C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"1"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"1C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"1"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"1C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"1"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"1C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}}]}}},"Scorers":{"value":8,"items":[{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"Obviously tough because we have varying penetrances for the three genes. But I went with the higher BRIP1 associated risk. I could be talked down to a \"1\", especially since I suspect most of our penetrance figures for almost everything are inflated..."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"I reduced the evidence level simply because we're extrapolating."}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":"This obviously really depends heavily on when it is done. Since the general guidelines are not to wait until menopause, I knocked it down to a 1 given that this is a non-trivial intervention. But it also shows the problems with our scoring system...ovarian cancer is so bad and so undetectable...and oophorectomy is so effective that I hate to knock this down in its total points."}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"obviously an issue to have cutoffs that don't match available data. making assumptions about ongoing risks for RAD genes"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"3D","properties":{"Notes":{"value":"extrapolating from BRCA literature only.\nNot sure where to include salpingo origin of ovarian cancer in management considerations here"}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"For the BRIP1 penetrance data"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"Dropped the evidence level due to extrapolation - could consider scoring it lower due to lower ovarian cancer penetrance (and therefore lower absolute risk reduction)"}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":"Was considering 2, but dropped to 1 due to most women being pre-menopausal at recommended oophorectomy age (40-50)"}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"I scored this 2 based on BRIP1. I don't know if we should do this separately and lump RAD51C and RAD51D"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"Should be the same as scored for BRCA 1/2."}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":"Again, same as BRCA 1/2"}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"1C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"1C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"downgraded evidence level for extrapolation"}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"I scored this as 2 reasoning that the marginal risk of 5.8% includes the baseline risk. Not sure if that is what we do, but this seemed reasonable as the other two penetrances are in the 1-4 range."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"I scored this as 1, generalizing from BRCA1/2 and downgraded the evidence level since it is a generalization. But to be honest I can't remember if we are to downgrade the score or the evidence level."}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Ovarian cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Oophorectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.1","properties":{"Notes":{"value":"First stable release.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36159},"ReasonCode":{"value":"Q0","properties":{"Reason":{"value":"Initial Release"}}},"Date":{"value":"2017-10-06"},"ReleasedBy":{"value":"ronakypatel","properties":{"First Name":{"value":"Ronak"},"Last Name":{"value":"Patel"}}}}}}}},
{"ActionabilityDocID":{"value":"AC137","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"PROS1","properties":{"HGNCId":{"value":"HGNC:9456"},"GeneOMIM":{"value":"176880"},"SyndromeOMIMs":{"value":2,"items":[{"OMIM":{"value":"612336"}},{"OMIM":{"value":"176880"}}]}}}}]},"Syndrome":{"value":"Thrombophilia due to protein S deficiency","properties":{"OmimIDs":{"value":2,"items":[{"OmimID":{"value":"612336"}},{"OmimID":{"value":"176880"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"743"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-06-12"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"FullName":{"value":"Enter value here..."}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"FullName":{"value":"Enter value here..."}}}}]},"FullName":{"value":"Venous thromboembolism"}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Notes":{"value":"Partial protein S deficiency (heterozygous form) is present in 0.03-1% of the general population, and has been detected in 3.2% of patients with thrombosis. Prevalence of severe protein S deficiency (homozygous or compound heterozygous form) is unknown but is probably comparable to that of severe protein C deficiency which is estimated at 1/500,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000603"}},{"Reference":{"value":"/coll/reference_model/doc/RF000598"}},{"Reference":{"value":"/coll/reference_model/doc/RF000622"}},{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000608"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Protein S is a vitamin K-dependent plasma protein that inhibits blood clotting. Protein S deficiency generally has two causes, a silenced gene or a mutation that results in reduced free protein S antigen levels and activity. Individuals heterozygous for protein S deficiency are at increased risk for recurrent venous thromboembolism (VTE). Deep vein thrombosis (DVT) of the lower limbs with or without pulmonary embolism (PE) is the most common manifestation of the disease.  Beyond the acute sequelae, VTE may result in chronic conditions, including post-thrombotic syndrome, venous insufficiency, and pulmonary hypertension. Arterial thrombosis may also occur. Diagnosis of protein S deficiency is generally defined based on the presence of protein S antigen levels and anticoagulant activity rather than molecular testing. Although the deficiencies of the natural anticoagulants (including protein S) are usually labeled as high-risk thrombophilias, this perception may be based on older studies that focused on women with a history of recurrent VTE.\n\nAutosomal recessive thrombophilia due to protein S deficiency is very rare severe hematologic disorder resulting in thrombosis and secondary hemorrhage usually beginning in early infancy. Some individuals develop neonatal purpura fulminans (a life-threatening condition involving severe clotting throughout the body and causing necrosis of tissues), multifocal thrombosis, or intracranial hemorrhage several hours or days after birth, whereas others have recurrent thromboses later in childhood. Severe retinopathy of prematurity may also occur."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000598"}},{"Reference":{"value":"/coll/reference_model/doc/RF000622"}},{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000269"}},{"Reference":{"value":"/coll/reference_model/doc/RF000624"}},{"Reference":{"value":"/coll/reference_model/doc/RF000623"}},{"Reference":{"value":"/coll/reference_model/doc/RF000625"}},{"Reference":{"value":"/coll/reference_model/doc/RF000267"}},{"Reference":{"value":"/coll/reference_model/doc/RF000600"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Heterozygous patients are usually asymptomatic until adulthood. Most inherited factors that influence coagulability do not result in clot formation until the onset of a precipitation event, such as pregnancy, surgery, immobilization, or exogenous hormone use.  Prognosis is good for heterozygous patients. With adequate treatment and monitoring, the risk of thromboembolic disease is markedly reduced. Mortality may result from pulmonary embolism. The reported annual VTE incidence is 0.7-2.0% for individuals with protein S deficiency. \n\nThere is a 0.1% risk of VTE per pregnancy in women without a history of previous VTE. For those with a previous VTE the risk per pregnancy is 0-22%. Among those with a family history VTE, the risk in pregnancy has been reported as 6-7%.  It is currently controversial whether there is an association between inherited thrombophilias and uteroplacental thrombosis that lead to adverse pregnancy outcomes such as fetal loss, preeclampsia, fetal growth restriction, and placental abruption. Most of the available studies are small case-control and cohort studies assembled in heterogenous populations, and are frequently contradictory, and display potential reporting bias."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000603"}},{"Reference":{"value":"/coll/reference_model/doc/RF000598"}},{"Reference":{"value":"/coll/reference_model/doc/RF000622"}},{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000604"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1126","properties":{"Key Text":{"value":"Prevention of stroke"},"Tier":{"value":"2"},"Recommendation Text":{"value":"There is very little evidence to guide the management of asymptomatic people with hereditary thrombophilias (including protein S deficiency) for the primary prevention of stroke. Evidence that most VTE events occur during periods of high risk (such as surgery, trauma, or pregnancy) suggest that antithrombotic prophylaxis therapy during these periods would likely be effective. However, the effect of prophylaxis on the incidence of stroke or transient ischemic attack in these patients is unknown."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Venous thromboembolism"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000604"}}]}}}},{"Patient Management":{"value":"ACPM1125","properties":{"Key Text":{"value":"Anticoagulation following CVT"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Following a cerebral venous thrombosis (CVT) or cerebral venous and sinus thrombosis (CVST) individuals with protein S deficiency should be considered for indefinite anticoagulation. In individuals with thrombophilia (including protein S deficiency) have an increased risk of VTE (2-5%; adjusted HR, 4.71; 95% CI: 1.34-16.5) following an index CVT.  The recurrent event is more often a VTE than recurrent CVT. However, overall recurrence rates are low, there are no secondary prevention trials of duration of anticoagulation in adults with CVT or CVST; therefore, guidelines are based on solely on observational data."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Venous thromboembolism"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000626"}},{"Reference":{"value":"/coll/reference_model/doc/RF000458"}}]}}}},{"Patient Management":{"value":"ACPM1127","properties":{"Key Text":{"value":"Perioperative VTE"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Perioperative VTE prophylaxis should be prescribed prior to gynecologic surgery for all patients who have deficiencies of protein S. Prophylaxis may include low-dose unfractionated heparin (UFH) or low molecular weight heparin (LMWH) with or without intermittent pneumatic compression devices or graduated compression stockings. Continuing prophylaxis may be considered for 2-4 weeks after discharge.  Data from two randomized trials and a large retrospective series in the general population have found that the incidence of VTE in patients undergoing prophylaxis following gynecologic surgery with one of the above modalities was 1-6.5% compared with 15-40% reported in the an untreated population."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Venous thromboembolism"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000598"}}]}}}},{"Patient Management":{"value":"ACPM1128","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Based on the increased risk of VTE, all pregnant women with an inherited thrombophilia should be referred to a local expert and undergo individualized risk assessment which may modify pregnancy management decisions. The decision to treat with thromboprophylaxis, anticoagulation therapy, or no pharmacological treatment is influenced by VTE history, severity of inherited thrombophilia, and additional risk factors (e.g., cesarean delivery, prolonged immobility, obesity, and family history of VTE). Thromboprophylaxis may include LMWH or UFH. Surveillance includes clinical vigilance and appropriate objective investigation of women with symptoms suspicious of VTE.\n\n-Women without a prior VTE are recommended to undergo antepartum and postpartum surveillance without thromboprophylaxis. Guidelines differ on whether postpartum thromboprophylaxis is recommended among all women or only in the presence of other risk factors (e.g., family history of VTE).\n- Women with a prior VTE who are not receiving long-term anticoagulation therapy may undergo either antepartum surveillance without anticoagulation therapy or with prophylactic or intermediate-dose LMWH/UFH, but are recommended postpartum thromboprophylaxis.\n- Pneumatic compression boots or elastic stockings should be considered during the intrapartum period until the patient is ambulatory postpartum. LMWH during pregnancy is estimated to reduce the number of VTE events from 20 per 1,000 women to 7 per 1,000 women (95% CI: 4 to 14 per 1,000) in women with protein S deficiency and a positive family history of VTE, with no significant increase in bleeding events. However, evidence about the relative effects of treatment is taken from a meta-analysis of thromboprophylaxis in patients undergoing hip arthroplasty and is rated by the guideline authors to be of low quality due to the indirectness of the population and imprecision in the baseline risk estimates for women with thrombophilias."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Venous thromboembolism"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000600"}},{"Reference":{"value":"/coll/reference_model/doc/RF000627"}},{"Reference":{"value":"/coll/reference_model/doc/RF000628"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU602","properties":{"Key Text":{"value":"No recommendations related to surveillance were identified."},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":""},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM408","properties":{"Key Text":{"value":"Identification of family members"},"Tier":{"value":"4"},"Recommendation Text":{"value":"There is no evidence that identification of thrombophilia in asymptomatic family members reduces risk of VTE."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000608"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA502","properties":{"Key Text":{"value":"Estrogen"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Thrombophilic disorders (including protein S deficiency) are contraindications for the use of estrogen containing prescription drugs approved for the prevention of postmenopausal osteoporosis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000609"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":"In most cases Protein S deficiency is transmitted in an autosomal dominant manner; however, autosomal recessive Protein S deficiency may also occur, resulting in very low levels of active Protein S."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000624"}},{"Reference":{"value":"/coll/reference_model/doc/RF000623"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"The prevalence of mutations associated with protein S deficiency were not identified."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE584","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Protein S deficiency is associated with a reduced penetrance of VTE and specific estimates are not available. In general, individuals are at an annual risk of 0.28-0.4 VTEs (%/year)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Venous thromboembolism"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000608"}}]}}}},{"Penetrance":{"value":"ACPE585","properties":{"Key Text":{"value":"< 1 %"},"Tier":{"value":"3"},"Notes":{"value":"For women with a protein S free antigen level <5% the risk for a first VTE in pregnancy is 0.1%, for women who have previously had a VTE risk ranges from 0-22%. Among those with a positive family history the risk is 6-7%."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Venous thromboembolism"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000496"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC073","properties":{"Recommendation":{"value":"Although individuals with a protein S deficiency have a greater relative risk of VTE during pregnancy (estimated from case-control odds ratios), given the background incidence of VTE during pregnancy ~1/1000 deliveries, the absolute risk of in women without a prior event or family history remains low (0.5%; 95% CI: 0.2-1%)."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000458"}}]}}}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR243","properties":{"Key Text":{"value":">3"},"Notes":{"value":"The risk of VTE has been estimated from meta-analyses of case-control and cohort studies. In six cohort studies the risk of VTE was found to be higher in protein S deficient patients (defined by laboratory measures of protein S plasma levels) as compared to those with normal PS levels (24.7% vs. 3.34%; OR: 12.1; 95% CI: 4.2-34.00; p<0.000001). Risk of VTE recurrence was not found to be significant (p=0.08)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000603"}}]},"Tier":{"value":"1"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN266","properties":{"Key Text":{"value":"Family studies have identified that family members (even those with low laboratory measures of protein S) remain asymptomatic. Suggesting that additional factors may be necessary to precipitate thrombosis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000624"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI271","properties":{"Key Text":{"value":"The primary intervention proposed for patients with protein S deficiency is the use of injectable heparin in situations of stress that may increase the risk of thrombosis. During pregnancy, both UFH and LMWH have shorter half-lives and lower peak plasma concentrations, usually necessitating higher doses and more frequent administration. Bleeding complications can arise from administration of heparin and this complication should be considered before initiating anticoagulation therapy. UFH is associated with increased bruising at injection sites, and has also been associated with other skin reactions and serious allergic reactions."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000600"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC265","properties":{"Key Text":{"value":"Given that it is not generally recommended to screen for inherited thrombophilias in clinical settings. It is likely that protein S deficiency would not be detected during general clinical care."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000598"}},{"Reference":{"value":"/coll/reference_model/doc/RF000496"}},{"Reference":{"value":"/coll/reference_model/doc/RF000600"}},{"Reference":{"value":"/coll/reference_model/doc/RF000458"}},{"Reference":{"value":"/coll/reference_model/doc/RF000627"}},{"Reference":{"value":"/coll/reference_model/doc/RF000628"}}]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2017-08-07"},"Scorers Present":{"value":6,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"bieseckerl"}},{"Scorer":{"value":"odanielj"}}]},"Notes":{"value":""}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Overall Score":{"value":"8CB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Overall Score":{"value":"8CB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":8,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"0B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}}]}}},"Scorers":{"value":8,"items":[{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"It was modestly tempting to score this as a \"3\" since these folks occasionally present with a pulmonary embolus and sudden death by that mechanism. But I think it's much more common to present with DVT so I gave it a 2."}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"Annual risk of ,28-.4, times, say, 40 years would give us a 2."}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Risks of bleeding are non-trivial but don't knock it all the way down to a 1 in my mind."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Risks of bleeding are non-trivial but don't knock it all the way down to a 1 in my mind."}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"I extrapolated from the GYN literature that was cited and therefore knocked the evidence level down a grade..."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Again, the risks of bleeding are non-trivial but don't knock it all the way down to a 1 in my mind."}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"in an adult having testing, it should be heterozygous only."}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"Could be convinced to go with 3 due to PE risk."}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"On fence between 1 and 2"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"On fence between 1 and 2"}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Based on data from patients undergoing prophylaxis following GYN surgery."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"Even though a large PE could cause sudden death, I elected to score as a 2 given that is uncommon."}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"The only effectiveness metric listed is a decrease in VTE events with LMWH, which is modest. Could be persuaded to go 2 here. I gave the evidence as a B as it is from a guideline, but could to D or E since the guideline authors noted problems with the quality of the studies."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Score based on Perioperative VTE."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"0B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"bieseckerl","properties":{"First Name":{"value":"Les"},"Last Name":{"value":"Biesecker"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"I am scoring this primarily on PE, considering this \"possible death'"}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"I generally think that keeping a close eye out for something is low risk. The assumption being that if a need  for some other intervention I am not rating the risk of that other intervention."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"I generally think that keeping a close eye out for something is low risk. The assumption being that if a need  for some other intervention I am not rating the risk of that other intervention."}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Why don't we get to rate avoidance of contraceptives?"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Venous thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0C","properties":{"Notes":{"value":"Positive fhx includes other risk factors"}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"High risk obstetric care for pregnant women (includes pharmacological prophylaxis)","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"decreased evide level based on notes"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacological prophylaxis in high-risk situations for men and non-pregnant women","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.1","properties":{"Notes":{"value":"First stable release.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36161},"ReasonCode":{"value":"Q0","properties":{"Reason":{"value":"Initial Release"}}},"Date":{"value":"2017-10-06"},"ReleasedBy":{"value":"ronakypatel","properties":{"First Name":{"value":"Ronak"},"Last Name":{"value":"Patel"}}}}}}}},
{"ActionabilityDocID":{"value":"AC138","properties":{"Status":{"value":"Released"},"Genes":{"value":3,"items":[{"Gene":{"value":"DMD","properties":{"GeneFunction":{"value":"dystrophin"},"HGNCId":{"value":"HGNC:2928"},"GeneOMIM":{"value":"300377"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"302045"}}]}}}},{"Gene":{"value":"LMNA","properties":{"GeneFunction":{"value":"lamin A/C"},"HGNCId":{"value":"HGNC:6636"},"GeneOMIM":{"value":"150330"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"115200"}}]}}}},{"Gene":{"value":"TNNT2","properties":{"GeneFunction":{"value":"troponin T type 2 (cardiac)"},"HGNCId":{"value":"HGNC:11949"},"GeneOMIM":{"value":"191045"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"601494"}}]}}}}]},"Syndrome":{"value":"Dilated cardiomyopathy","properties":{"OmimIDs":{"value":3,"items":[{"OmimID":{"value":"115200"}},{"OmimID":{"value":"601494"}},{"OmimID":{"value":"302045"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"154"}}]},"Overview":{"value":""},"Acronyms":{"value":0,"items":[]}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":2,"items":[{"Scorer Stage1":{"value":"hunterj","properties":{"First Name":{"value":"Jessica"},"Last Name":{"value":"Hunter"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}},{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)"}},{"Intervention":{"value":"Surveillance and pharmacotherapy"}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors"}}]}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Little data is available for the prevalence of idiopathic dilated cardiomyopathy (DCM). Only one formal prevalence study has been conducted, which took place in Minnesota in the 1980s. The prevalence of DCM was estimated as 1/2500 to 1/2700. This estimate was twice the prevalence of hypertrophic cardiomyopathy (HCM), estimated in the same study as ~1/5000. Given more recent epidemiologic studies have shown an HCM prevalence of approximately 1:500 and experts estimate that DCM is at least as common as HCM. The prevalence of DCM has likely been underestimated due to the fact that individuals may remain asymptomatic until marked ventricular dysfunction has occurred. However, further studies have not been published. It is not clear how many DCM cases are due to genetic pathogenic variants in LMNA, TNNT2, and DMD."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000631"}},{"Reference":{"value":"/coll/reference_model/doc/RF000251"}},{"Reference":{"value":"/coll/reference_model/doc/RF000632"}},{"Reference":{"value":"/coll/reference_model/doc/RF000633"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"DCM is a heart muscle disease characterized by left ventricular dilation and systolic dysfunction. DCM typically presents with heart failure [with symptoms of congestion (edema, orthopnea, paroxysmal nocturnal dyspnea) and/or reduced cardiac output (fatigue, dyspnea on exertion)], arrhythmias and/or conduction system disease, and thromboembolic disease including stroke. Patients with DCM are at risk of premature death."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000631"}},{"Reference":{"value":"/coll/reference_model/doc/RF000632"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"DCM may be asymptomatic with only mild ventricular dilation and dysfunction for years. Presentation of clinical symptoms usually occurs late in the disease course.  Usually, by the time of the diagnosis individuals have severe impairment of the left ventricular ejection function (LVEF) and are in New York Heart Association (NYHA) functional class III-IV. Patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection fraction have a low survival rate and may require heart transplant. DCM has a highly variable age of onset, from infancy to late adulthood with 10% of cases diagnosed prior to age 20 and 60% diagnosed by age 40.\\n\\nDCM due to pathogenic variants in LMNA presents with mild dilation and severe dysfunction of the left ventricle, conduction defects, supraventricular arrhythmias, variable skeletal muscle involvement and variable serum creatine kinase (CK) levels. The prognosis for many of these patients is not favorable. DCM due to pathogenic variants in DMD has a less severe prognosis and presents with increased CK, muscular abnormalities, and the typical signs of dystrophinopathy at the skeletal muscle biopsy. A meta-analysis of DCM cases, estimated that patients with LMNA pathogenic variants had a mean age of onset of 40 years (95% CI: 35-45), while patients with TNNT2 pathogenic variants had an earlier mean age of onset at 35 years (95% CI: 23-47). Among patients included in the meta-analysis, the rate of heart transplantation was 27% for LMNA and 17% for TNNT2."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000631"}},{"Reference":{"value":"/coll/reference_model/doc/RF000251"}},{"Reference":{"value":"/coll/reference_model/doc/RF000632"}},{"Reference":{"value":"/coll/reference_model/doc/RF000661"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1130","properties":{"Key Text":{"value":"ACE inhibitors and beta-blockers"},"Tier":{"value":"2"},"Recommendation Text":{"value":"ACE inhibitors and beta-blockers are recommended in patients with a reduced ejection fraction to prevent heart failure."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000634"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC264","properties":{"Recommendation":{"value":"There was no evidence specifically for pharmacotherapy and sudden cardiac death. However, there was evidence for pharmacotherapy and all-cause mortality. One follow-up study among 6797 patients with reduced left ventricular ejection fraction (LVEF) indicated that enalapril (ACE inhibitor) was associated with a significantly increased life expectancy (HR=0.90, 95% CI=0.84-0.95, p=0.0003). In addition, a meta-analysis of randomized clinical trials indicated a reduction mortality in patients with reduced LVEF associated with beta-blockers (RR in men=0.66, 95% CI=0.59-0.75; RR in women=0.63, 95% CI=0.44-0.91). However, the heart failure mortality benefit of ACE inhibitors was detected in men (RR=0.82, 95% CI=0.74-0.90) but not women (RR=0.92, 95% CI=0.81-1.04)."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000635"}},{"Reference":{"value":"/coll/reference_model/doc/RF000636"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1129","properties":{"Key Text":{"value":"Implantable cardiac device (ICD)"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Implantable cardiac device (ICD) therapy should be considered in patients with a familial cardiomyopathy associated with sudden cardiac death (SCD). Other indicators for ICD implantation include a left ventricular ejection fraction (LVEF) ≤35%, LVEF >35% and a family history of SCD, or LMNA mutations. Multiple randomized trials now supplement observational studies that have reported the role of ICD in primary prevention of SCD in patients with nonischemic DCM. Specifically for patients with LMNA mutations, one prospective cohort study of 19 patients with an LMNA mutation and an ICD showed that 42% (N=8) received appropriate ICD therapy in response to ventricular tachycardia (N=2) and ventricular fibrillation (N=6) across a 34 month period. While not specific to DCM, a meta-analysis of randomized control trials of patients with nonischemic cardiomyopathy reported an overall reduction in mortality with ICD therapy (RR=0.69, 95% CI=0.56-0.86; p=0.002). Two randomized controlled trials assessed mortality in patients with DCM with and without an ICD, but were discontinued due to lack of statistical power associated with low rates of all-cause mortaility in both groups."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000005"}},{"Reference":{"value":"/coll/reference_model/doc/RF000218"}}]}}}},{"Patient Management":{"value":"ACPM1131","properties":{"Key Text":{"value":"Abortion management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Pregnant women with DCM seeking a first trimester induced abortion should be referred to a hospital-based provider (with patient permission)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000217"}}]}}}},{"Patient Management":{"value":"ACPM1132","properties":{"Key Text":{"value":"General management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Management of FDC can include general measures (salt and fluid restriction, treatment of hypertension, limitation of alcohol intake, control of body weight, moderate exercise)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000631"}},{"Reference":{"value":"/coll/reference_model/doc/RF000632"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU603","properties":{"Key Text":{"value":"Screening for cardiomyopathy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Clinical screening for DCM is recommended in asymptomatic individuals known to carry a disease-causing mutation. This screening should occur at any time that signs or symptoms appear or every 1 to 3 years. Screening should include: family history (with special attention to heart failure symptoms, arrhythmias, presyncope, and syncope), physical exam (with special attention to the cardiac and skeletal muscle systems), electrocardiogram (ECG), echocardiogram, and CK-MM (initial evaluation only). The basis of these extensive clinical screening recommendations is that cardiomyopathy can be treated in almost all cases, improving survival and/or quality of life. Echocardiograms and ECGs are important for risk assessment as patients with FDC often do not manifest symptoms of heart failure or arrhythmias until late in the disease process, usually with moderate or severe LVEF and systolic dysfunction."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000218"}}]}}}},{"Surveillance":{"value":"ACSU604","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Pregnancy is contraindicated in DCM, and is associated with a risk of peripartum cardiomyopathy and pregnancy-associated cardiomyopathy. Thus pregnant women with FDC should be followed by a high risk obstetrician."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000632"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM409","properties":{"Key Text":{"value":"Clinical screening for cardiomyopathy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Clinical screening for DCM is recommended in asymptomatic first-degree relatives in individuals with DCM who have not had genetic testing or when a disease-causing mutation was not identified. This screening should occur at any time that signs or symptoms appear or every 3-5 years. Screening should include: family history (with special attention to heart failure symptoms, arrhythmias, presyncope, and syncope), physical exam (with special attention to the cardiac and skeletal muscle systems), electrocardiogram, echocardiogram, and creatinine kinase MM isoenzyme (initial evaluation only)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000218"}}]}}}},{"Family Management":{"value":"ACFM410","properties":{"Key Text":{"value":"Genetic counseling and testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Genetic and family counseling is recommended for families with a history of cardiomyopathy. Referral to centers expert in genetic evaluation and family-based management should be considered."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000218"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":"TNNT2- and LMNA- associated DCM is inherited in an autosomal dominant manner. DMD-associated DCM is inherited in an X-linked manner."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000632"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Tier":{"value":"1"},"Notes":{"value":"A meta-analysis reported that pathogenic variants in LMNA had a pooled frequency of 5% (95% CI: 3-7%) among familial and sporadic DCM cases, and TNNT2 had a pooled frequency of 2% (95% CI: 1-3%)."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000661"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC065","properties":{"Recommendation":{"value":"It is unknown how many cases of DCM are associated with DMD."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000632"}}]}}}},{"RecommendationID":{"value":"REC064","properties":{"Recommendation":{"value":"Information on the prevalence of pathogenic variants associated with DCM in the general population was not available."},"Tier":{"value":"Not provided"},"References":{"value":null,"items":[]}}}}]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE586","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"Overall, DCM has age-related penetrance: 10% by age <20 years, 34% by age 30, 60% by age 40, and 90% for more advanced ages (>40)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000251"}},{"Reference":{"value":"/coll/reference_model/doc/RF000632"}}]}}}},{"Penetrance":{"value":"ACPE587","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"1"},"Notes":{"value":"A meta-analysis reported rates of heart transplantation of 27% for LMNA and 17% for TNNT2. Additional penetrance estimates specific to LMNA-related DCM were also reported:\\n\\nDCM or left ventricle dysfunction = 45%\\nConduction system disorders (included sinus dysfunction, atrioventricular conduction blocks, bundle branch blocks, or hemiblocks) =52% (74% in those with DCM, 40% in those without DCM)\\nSupraventricular tachycardia (included atrial fibrillation, atrial flutter, or ectopy) = 43% (62% in those with DCM, 13% in those without DCM)\\nVentricular arrhythmia = 29% (50% in those with DCM, 5% in those without DCM)\\nSCD = 6% (19% in those with DCM, 3% in those without DCM) \\nSkeletal muscle affection: 26% (46% in those with DCM, 26% in those without DCM."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000661"}}]}}}},{"Penetrance":{"value":"ACPE588","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"Specific penetrance estimates of DCM were not available for TNNT2- or DMD- related DCM."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN267","properties":{"Key Text":{"value":"DCM has highly variable age of onset."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000632"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI272","properties":{"Key Text":{"value":"Identified interventions include non-invasive surveillance, pharmacotherapy, and possible ICD implantation, which could be associated with moderate risk."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC266","properties":{"Key Text":{"value":"DCM is typically an adult-onset disorder, with many asymptomatic years. DCM may be detected in an asymptomatic individual during a medical evaluation for another reason, but patients often present with heart failure."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000632"}}]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2B","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Overall Score":{"value":"9BB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Overall Score":{"value":"10BN"},"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3B","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Overall Score":{"value":"10BN"},"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":7,"items":[{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2B"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2B"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2B"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2B"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"1N"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"1"}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2B"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"1B"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":7,"items":[{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"It's not clear whether the pharmacologic interventions were specific to DCM, or reduced LVEF, all cause. This requires some extrapolation of the evidence and specific for sudden cardiac death, which is a tier 5 study so I chose E."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3A","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":"I'm a little confused about why we're scoring these separate. Certainly the dysrhythmias associated with DCM mean that occasionally someone will \"present\" with sudden death as the first manifestation of disease. But it's far more common to present with heart failure. But if we're considering sudden death as the outcome in this instance then it pretty much has to get a \"3\"."}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":"We really don't have data specific to this outcome. Dysrhythmia does not equal sudden death and most people with DCM die due to their CHF. So I give it a zero since we don't really know what the penetrance is for this very specific outcome. Why are we splitting this up?"}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Having an ICD is not completely trivial due to false positive activiation"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Having an ICD is not completely trivial due to false positive activiation"}}}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"1N","properties":{"Notes":{"value":"We don't know much about the efficacy of pharmacotherapy and SCD but certainly in the setting of documented dysrhthtmia there are recommended Rxs."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3A","properties":{"Notes":{"value":"I'm confused about why the outcome is called \"delay hearth failure\"...what is the \"delay\" doing there? I'm assuming the outcome is heart failure..."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"I'm not sure why we're reinventing the wheel here. ACEI and BBs have long been the mainstay of heart failure Rx."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"These are generally well tolerated agents."}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"Could also go to a 3 score here."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Combination between a tier 5 and 2"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":"Went with the SCD rate for LMNA."}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"Wavered between 2C and 1B - we're going off of small trials or having to extrapolate from non-DCM context."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"Would be helpful to hear more about burden of side effects."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"Would be helpful to hear more about burden of side effects."}}}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":"Hard to know which of the LMNA associated outcomes should be considered heart failure. Went with heart transplantation, though this is probably an underestimate."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"1N","properties":{"Notes":{"value":"Docked the effectiveness because there was no heart rate mortality benefit for women."}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":"Would be helpful to hear more about burden of side effects."}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"1N","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3B","properties":{"Notes":{"value":"should this just say heart failure?"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3A","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Surveillance and implantable cardiac device (ICD)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Surveillance and pharmacotherapy","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Earlier heart failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance and ACE inhibitors","properties":{"Effectiveness":{"value":"1N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"2.0.2","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36163},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-01-09"},"ReleasedBy":{"value":"hunterj","properties":{"First Name":{"value":"Jessica"},"Last Name":{"value":"Hunter"}}}}}}}},
{"ActionabilityDocID":{"value":"AC139","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"BAP1","properties":{"HGNCId":{"value":"HGNC:950"},"GeneOMIM":{"value":"603089"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"614327"}}]}}}}]},"Syndrome":{"value":"Tumor Predisposition Syndrome","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"614327"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"289539"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"BAP1","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-07-06"},"Notes":{"value":""},"Label":{"value":"BAP1"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}},"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Malignant Mesothelioma","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Imaging","properties":{"FullName":{"value":"Imaging"}}}}]},"FullName":{"value":"Malignant Mesothelioma"}}}},{"Outcome":{"value":"Melanoma","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual full-body dermatology exam","properties":{"FullName":{"value":"Annual full-body dermatology exam"}}}}]},"FullName":{"value":"Melanoma"}}}},{"Outcome":{"value":"Uveal Melanoma","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual eye exam, including dilated eye exam, by ocular oncologist","properties":{"FullName":{"value":"Annual eye exam, including dilated eye exam, by ocular oncologist"}}}}]},"FullName":{"value":"Uveal Melanoma"}}}},{"Outcome":{"value":"Clear Cell Renal Cell Carcinoma","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Abdominal Ultrasound","properties":{"FullName":{"value":"Abdominal Ultrasound"}}}}]},"FullName":{"value":"Clear Cell Renal Cell Carcinoma"}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"The population prevalence of BAP1 tumor predisposition syndrome (BAP1-TPDS) is unknown, though estimated to be rare. A 2015 review identified 57 published families with 174 individuals with BAP-TPDS. The prevalence of germline mutations in individuals with BAP1 associated cancers include: uveal melanoma (1-3%), malignant mesothelioma (6%), and cutaneous melanoma (0.6%). The prevalence of BAP1-TPDS in persons with other cancers is unknown."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000638"}},{"Reference":{"value":"/coll/reference_model/doc/RF000639"}},{"Reference":{"value":"/coll/reference_model/doc/RF000640"}},{"Reference":{"value":"/coll/reference_model/doc/RF000641"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"BAP1-TPDS is characterized by heterozygous pathogenic variants in the BAP1 gene, resulting in haploinsufficiency of the putative tumor suppressor protein BAP1. Tumors develop from cell types in which loss of heterozygosity occurs. Atypical Spitz tumors (ASTs), a specific type of skin lesion, may be the most common manifestation of BAP1-TPDS. These lesions are skin-colored to reddish brown, average 5 mm in diameter, and are histologically between those of a Spitz nevus and melanoma. In addition to ASTs, patients are at increased risk for certain malignancies. Individuals with pathogenic BAP1 mutations are prone to develop uveal melanoma, malignant mesothelioma, cutaneous melanoma, clear cell renal cell carcinoma (ccRCC), and basal cell carcinoma. Affected individuals can have more than one type of primary cancer. Other cancers with some, but inconsistent, evidence for their inclusion in the spectrum of BAP1-TPDS malignancies are breast cancer, cholangiocarcinoma, meningioma, neuroendocrine tumors, non-small cell lung adenocarcinoma, and thyroid cancer."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000638"}},{"Reference":{"value":"/coll/reference_model/doc/RF000639"}},{"Reference":{"value":"/coll/reference_model/doc/RF000642"}},{"Reference":{"value":"/coll/reference_model/doc/RF000643"}},{"Reference":{"value":"/coll/reference_model/doc/RF000644"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Patients are reported to develop ASTs as early as the second decade of life, and for some patients these may be the first presenting symptom. However, patients have been found to have a low number of melanomas compared to the number of atypical Spitz tumors, suggesting the risk of malignant progression in individual tumors is low. Almost all malignancies associated with BAP1-TPDS have an earlier onset than in the general population and a worse prognosis. Uveal melanoma in BAP1-TPDS has an earlier age of onset compared with the general population (51 years vs 62 years) and are typically more aggressive with a poorer prognosis (average survival of 4.74 years versus 9.97 years for persons with tumors expressing BAP1). Malignant mesothelioma occurs significantly earlier than that of sporadic malignant mesothelioma (55-58 years vs 68-72 years), with higher rates of peritoneal involvement and the majority of peritoneal cases occurring in women. In contrast to other BAP1-TPDS cancers, survival in persons with BAP1-related malignant mesothelioma may be longer than in sporadic cases, although data are not consistent. Growing evidence suggests that asbestos exposure increases the risk for mesothelioma in patients with pathogenic variants in BAP1. Cutaneous melanoma often occurs with multiple primary melanomas and has an earlier onset (46 years vs 58 years). The data regarding aggressiveness of BAP1-associated cutaneous melanoma relative to sporadic instances is inconsistent. Median age of ccRCC diagnosis is earlier than that of sporadic ccRCC (47 vs 64 years), and length of survival is also decreased with individuals generally having a higher grade of cancer at diagnosis. Based on limited data basal cell carcinoma appears to have a median age of onset at 50 years."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000638"}},{"Reference":{"value":"/coll/reference_model/doc/RF000639"}},{"Reference":{"value":"/coll/reference_model/doc/RF000641"}},{"Reference":{"value":"/coll/reference_model/doc/RF000642"}},{"Reference":{"value":"/coll/reference_model/doc/RF000644"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1133","properties":{"Key Text":{"value":"Evaluation following diagnosis"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Following diagnosis, the patient should be thoroughly evaluated for ASTs, cutaneous melanoma, and/or basal cell carcinoma, uveal melanoma, malignant mesothelioma, and clear cell renal cell carcinoma. Initial workup for cutaneous disease should include full body skin examination by a dermatologist with excision of any lesions suggestive of an AST. Initial examination for uveal melanoma should include a dilated eye examination and imaging by an ocular oncologist. For ccRCC, an abdominal ultrasound exam, urinalysis, and abdominal MRI are recommended. It is recommended that MRI evaluation of the peritoneum and pleura be considered to evaluate for malignant mesothelioma.  The use of spiral chest CT is controversial due to the risk of cancer from radiation exposure."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Malignant Mesothelioma"}},{"Outcome":{"value":"Melanoma"}},{"Outcome":{"value":"Uveal Melanoma"}},{"Outcome":{"value":"Clear Cell Renal Cell Carcinoma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000638"}},{"Reference":{"value":"/coll/reference_model/doc/RF000639"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU610","properties":{"Key Text":{"value":"Yearly eye exam"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Yearly dilated eye examinations and imaging by an ocular oncologist are recommended for the detection of uveal melanoma.  In the case of a uveal melanoma diagnosis, consider high-risk patient monitoring protocol for systemic metastatic surveillance (e.g., liver-directed imaging every 3-6 months, pulmonary imaging every 6-12 months)"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Uveal Melanoma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000638"}},{"Reference":{"value":"/coll/reference_model/doc/RF000639"}}]}}}},{"Surveillance":{"value":"ACSU609","properties":{"Key Text":{"value":"Uveal melanoma effectiveness"},"Tier":{"value":"4"},"Recommendation Text":{"value":"No data exist regarding the effectiveness of uveal melanoma surveillance or treatment in this population. Surveillance for uveal melanoma may allow detection at an earlier stage. Uveal melanomas in BAP1-TPDS are aggressive and should be managed according to standard practice for more aggressive tumors, even when detected at an earlier stage."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Uveal Melanoma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000638"}},{"Reference":{"value":"/coll/reference_model/doc/RF000639"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC045","properties":{"Recommendation":{"value":"Because tumor size and stage are correlated with prognosis and risk of metastasis in average-risk populations, it is suggestive that early diagnosis and treatment may improve outcomes."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000645"}},{"Reference":{"value":"/coll/reference_model/doc/RF000646"}},{"Reference":{"value":"/coll/reference_model/doc/RF000647"}}]}}}}]}}}},{"Surveillance":{"value":"ACSU608","properties":{"Key Text":{"value":"Annual dermatology exam"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals should undergo an annual full-body dermatology exam beginning around age 20 years. In addition, patients should perform skin self-exam following the characteristics of melanoma."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Melanoma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000638"}},{"Reference":{"value":"/coll/reference_model/doc/RF000639"}}]}}}},{"Surveillance":{"value":"ACSU607","properties":{"Key Text":{"value":"Effectiveness of melanoma surveillance"},"Tier":{"value":"5"},"Recommendation Text":{"value":"No data exist regarding the effectiveness of melanoma surveillance in this population.  A systematic review addressing visual screening for skin cancer identified no trials addressing the effectiveness of skin cancer screening on morbidity and mortality in average-risk individuals. One ecological study found that after the implementation of a population based skin cancer screening program the population age- and sex-adjusted melanoma mortality decreased by 48% with an absolute mortality difference of 0.8 melanoma deaths per 100,000 persons. Eight observational studies examined the association between lesion thickness or stage at diagnosis and mortality. All studies demonstrated a consistent linear increase in the risk of melanoma mortality with increasing tumor thickness. Tumor thickness >4.0mm was associated with a hazard ratio of 3.1-32.6 in multivariate models, indicating increased risk of melanoma mortality compared with thinner lesions."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Melanoma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000383"}}]}}}},{"Surveillance":{"value":"ACSU606","properties":{"Key Text":{"value":"Malignant mesothelioma surveillance and effectiveness"},"Tier":{"value":"4"},"Recommendation Text":{"value":"No reliable early disease symptoms or screening modalities for malignant mesothelioma exist. However, annual evaluation is recommended for the detection of late manifestations of mesothelioma (e.g., chest pain, cough, shortness of breath), signs of pleurisy (pleural inflammation), peritonitis, ascites, and/or pleural effusion.  If abdominal MRI is being performed to evaluate for ccRCC, evaluation of peritoneum and pleura can be considered. Recommendation for spiral chest CT is controversial due to the risk of cancer from radiation exposure. In general, malignant mesothelioma is highly refractory to conventional therapies including surgical intervention and multimodal strategies; thus a cure is unlikely."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Malignant Mesothelioma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000638"}},{"Reference":{"value":"/coll/reference_model/doc/RF000639"}}]}}}},{"Surveillance":{"value":"ACSU605","properties":{"Key Text":{"value":"Clear Cell Renal Cell Carcinoma Surveillance"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Annual abdominal ultrasound examination is recommended along with consideration of annual urinalysis and abdominal MRI every two years for the detection of ccRCC.  ccRCC in BAP1-TPDS should be managed according to standard practice."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clear Cell Renal Cell Carcinoma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000638"}},{"Reference":{"value":"/coll/reference_model/doc/RF000639"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM411","properties":{"Key Text":{"value":"Genetic testing of asymptomatic relatives"},"Tier":{"value":"4"},"Recommendation Text":{"value":"It is appropriate to clarify the genetic status of asymptomatic older and younger (including pre-adolescents) at-risk relatives of a known affected individual by molecular genetic testing for the BAP1 pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of screening and preventive measures."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Malignant Mesothelioma"}},{"Outcome":{"value":"Melanoma"}},{"Outcome":{"value":"Uveal Melanoma"}},{"Outcome":{"value":"Clear Cell Renal Cell Carcinoma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000638"}},{"Reference":{"value":"/coll/reference_model/doc/RF000639"}},{"Reference":{"value":"/coll/reference_model/doc/RF000644"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA505","properties":{"Key Text":{"value":"Arc welding"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Arc welding has been associated with risk of uveal melanoma and should be avoided if possible."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Uveal Melanoma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000639"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA504","properties":{"Key Text":{"value":"Smoking and asbestos exposure"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Because of the increased risk for malignant mesothelioma, individuals should avoid smoking and asbestos exposure."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Malignant Mesothelioma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000639"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA503","properties":{"Key Text":{"value":"Prolonged sun exposure"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals should avoid unnecessary and prolonged sun exposure and utilize sun protection (sunscreen and protective clothing) due to an increased risk of melanoma and basal cell carcinoma. The use of sunglasses with high UVA and UVB protection may help reduce the risk of cancer on the eye lids, but data regarding the benefits of sunglasses for uveal melanoma are lacking."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Melanoma"}},{"Outcome":{"value":"Uveal Melanoma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000638"}},{"Reference":{"value":"/coll/reference_model/doc/RF000639"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"No data were found on the population prevalence of pathogenic germline mutations in BAP1."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE589","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"A review of family reports from the literature found that overall 148 of 174 individuals (85%) with BAP1-TPDS had a malignant manifestation \n     - Uveal melanoma: 54/174 (31%)\n     - Malignant mesothelioma: 39/174 (22%) \n     - Cutaneous melanoma: 23/174 (13%)\n     - Renal cell carcinoma: 18/174 (10%)\n     - Cutaneous melanocytic lesions (ASTs): 31/43 (72%)\n\nPotentially associated cancers:\n     - Breast cancer: 9/95 (9.5%)\n     - Basal cell carcinoma: 11/174 (6.3%)\n\nIt is likely, however, that these penetrance data are inflated by test bias since the patients and family members who get tested are generally those affected by cancer. Of the 57 reported families, only the affected proband was tested in 30, and only 17 families had more than 3 individuals tested. Thus, the true penetrance for BAP1 mutations may well be lower than currently estimated."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Malignant Mesothelioma"}},{"Outcome":{"value":"Melanoma"}},{"Outcome":{"value":"Uveal Melanoma"}},{"Outcome":{"value":"Clear Cell Renal Cell Carcinoma"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000638"}},{"Reference":{"value":"/coll/reference_model/doc/RF000639"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR244","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No data were found regarding the relative risk of manifestations of BAP1-TPDS."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN268","properties":{"Key Text":{"value":"The type of BAP1-related tumors can vary among different members of the same family."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000639"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI273","properties":{"Key Text":{"value":"Most recommended interventions are non-invasive surveillance and thorough initial work-up and have little associated risks. If a spiral chest CT is performed to examine the patient for mesothelioma, the test carries some risk of cancer development from the radiation exposure itself."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000639"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC267","properties":{"Key Text":{"value":"Cancers associated with this condition are earlier onset and typically more aggressive than those in the general population. Because there are no standard recommendations for screenings related to these types of cancer, there is a high chance for them to escape clinical detection in the setting of recommended care. Both cutaneous melanomas and uveal melanomas can be cured when found at an early stage but are fatal upon metastasis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000639"}},{"Reference":{"value":"/coll/reference_model/doc/RF000644"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2017-10-30"},"Scorers Present":{"value":6,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"weaverm"}},{"Scorer":{"value":"odanielj"}}]},"Notes":{"value":""}}},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Malignant Mesothelioma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Imaging","properties":{"Overall Score":{"value":"6CC"},"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual full-body dermatology exam","properties":{"Overall Score":{"value":"9CN"},"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Uveal Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual eye exam, including dilated eye exam, by ocular oncologist","properties":{"Overall Score":{"value":"7CC"},"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clear Cell Renal Cell Carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Abdominal Ultrasound","properties":{"Overall Score":{"value":"10CD"},"Effectiveness":{"value":"3D","properties":{"Notes":{"value":""}}},"Nature Of 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benefit."}}}}}}]}}}},{"Outcome":{"value":"Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual full-body dermatology exam","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"I'm between a 1 and 2 on this."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Uveal Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual eye exam, including dilated eye exam, by ocular oncologist","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":"Between a 1 and 2 here. Given the information, I think a D level of evidence is most appropriate. Interested for the discussion on this."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clear Cell Renal Cell Carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Abdominal Ultrasound","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Extrapolated from other syndromes with risk for renal cell carcinoma"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Malignant Mesothelioma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Imaging","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"\"annual evaluation is recommended for the detection of late manifestations\". Not exactly a ringing endorsement."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual full-body dermatology exam","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"I could be bumped up to a 3 since the survival in melanoma is so closely linked to the local stage of disease."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Uveal Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual eye exam, including dilated eye exam, by ocular 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Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual eye exam, including dilated eye exam, by ocular oncologist","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clear Cell Renal Cell Carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Abdominal Ultrasound","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":"Effectiveness is not mentioned"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last 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Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual eye exam, including dilated eye exam, by ocular oncologist","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"tho not in our summary, 5 yr survival rate 80% when confined to eye and 15% when spreads beyond eye.  per american cancer society. not BAP specific"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clear Cell Renal Cell Carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Abdominal Ultrasound","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"I think what we needed all along is a way to say that the effectiveness score is based on studies of the disease but no necessarily specific for this gene.  We do it all the time but have not recorded that, yes?"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Malignant Mesothelioma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Imaging","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"IN might be reasonable"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"could be convinced to go with 1 to account for ascertainment bias"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual full-body dermatology exam","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"can we extrapolate from CDKN2A?"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Uveal Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual eye exam, including dilated eye exam, by ocular oncologist","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clear Cell Renal Cell Carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"1C","properties":{"Notes":{"value":"dropped to 1 due to ascertainment bias"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Abdominal Ultrasound","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"no data on effectiveness here, though perhaps could extrapolate from other genes associated with renal cancer risk"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Malignant Mesothelioma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Imaging","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual full-body dermatology exam","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"Torn b/w a 3D and 2E"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Uveal Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual eye exam, including dilated eye exam, by ocular oncologist","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clear Cell Renal Cell Carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Abdominal Ultrasound","properties":{"Effectiveness":{"value":"3D","properties":{"Notes":{"value":"Extrapolated from VHL and downgraded evidence level"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Malignant Mesothelioma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Imaging","properties":{"Effectiveness":{"value":"0N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Melanoma","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual full-body dermatology exam","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Uveal Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual eye exam, including dilated eye exam, by ocular oncologist","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clear Cell Renal Cell Carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Abdominal Ultrasound","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Incomplete"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Malignant Mesothelioma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Imaging","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual full-body dermatology exam","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Uveal Melanoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Annual eye exam, including dilated eye exam, by ocular oncologist","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clear Cell Renal Cell Carcinoma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Abdominal Ultrasound","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.2","properties":{"Notes":{"value":"updated gene-disease pairs\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36165},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2017-11-20"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC142","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"GCDH","properties":{"HGNCId":{"value":"HGNC:4189"},"GeneOMIM":{"value":"608801"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"231670"}}]}}}}]},"Syndrome":{"value":"Glutaric Acidemia I","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"231670"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"25"}}]},"Overview":{"value":""},"Acronyms":{"value":0,"items":[]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-09-19"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}},"Scorers Stage1":{"value":2,"items":[{"Scorer Stage1":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}},{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neurologic crises and functional decline","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Low protein/lysine diet","properties":{"FullName":{"value":"Low protein/lysine diet"}}}},{"Intervention":{"value":"Management by metabolic clinic","properties":{"FullName":{"value":"Management by metabolic clinic"}}}}]},"FullName":{"value":"Neurologic crises and functional decline"}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Notes":{"value":"The prevalence of glutaric acidemia I (GA-I) based on newborn screening with tandem mass spectrometry is estimated to be 1.06 per 100,000 births (95% CI: 0.90 to 1.24 per 100,000) in Western populations and 1.40 per 100,000 births worldwide (95% CI: 1.07 to 1.84 per 100,000 births). However, this may be an underestimate as screening may not be able to identify those patients classified as low excretors, as they tend to have normal concentrations of glutarylcarnitines."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000440"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"GA-I is a metabolic disorder of lysine metabolism characterized by the accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA), glutaconic acid, and glutarylcaranitine. Diagnosis of GA-I is confirmed by significantly reduced enzyme activity and/or detection of disease-causing mutations in both GCDH alleles. Two arbitrarily defined biochemical subgroups have been described based on urinary metabolite excretion of GA: low excretors (with up to 30% residual enzyme activity) and high excretors. Both subtypes appear to show a similar clinical course and a high risk of developing striatal injury if untreated. \n\nIn neonates and infants, unspecific neurologic symptoms such as muscular hypotonia and delayed motor development occur in about half of all individuals with GA-I, the remaining individuals are asymptomatic. Macrocephaly occurs in approximately 75% of individuals.  Untreated, 80-90% of infants will develop neurologic disease during brain development (mainly between 3 and 36 months) following an acute encephalopathic crisis precipitated by illness, vaccination, or surgical intervention. These crises characteristically result in the gradual development of complex movement disorders in the following months and years. Dystonia at rest with action-induced exacerbation, which profoundly interferes with any voluntary movement, is often incapacitating. Dysarthria and dysphagia are also common. Cognitive function in generally considered to be preserved; however comprehensive studies on cognitive functions in GA-I have not been reported. Given the characteristic cerebral abnormalities frequently observed in GA-I and the impact of similar white matter changes observed in other neurologic diseases, individuals with GA-I might be at risk for cognitive dysfunction. In approximately 10-20% of individuals with “insidious onset” type, neurologic disease and striatal injury occur in the absence of encephalopathic crises.\n\nIndividuals with the late-onset form of GA-I can present with nonspecific neurologic symptoms such as headaches, vertigo, transient ataxic gait, reduced fine motor skills, or fainting after exercise often presenting in adolescence or adulthood.  These individuals do not generally develop striatal injury. Single cases of neoplastic brain lesions have been reported; however, it remains unclear whether these findings are coincidental or whether adults with GA-I have an increased risk of brain neoplasms. A few case reports of previously healthy adolescences and adults developing neurologic signs have been published. \n\nFrequency of epilepsy is increased in patients with GA-I, and seizures may be the initial clinical presentation.  GA-I is primarily a neurological disorder; however, recent publications have demonstrated that the peripheral nervous system and kidney disease might also be involved in the long-term disease course."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000655"}},{"Reference":{"value":"/coll/reference_model/doc/RF000656"}},{"Reference":{"value":"/coll/reference_model/doc/RF000559"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"The morbidity and mortality is high for untreated infants and neonates. In contrast, long-term prognosis for individuals diagnosed early appears promising, although mortality rates following the introduction of newborn screening are not yet available. During the last three decades, following the introduction, establishment, and optimization of therapeutic goals for individuals identified through newborn screening, there has been a considerable reduction in the frequency of acute encephalopathic crises and subsequent movement disorders (now 10-20% from 80-90%), and subsequently reduced morbidity and mortality in individuals who are diagnosed early."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000655"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1139","properties":{"Key Text":{"value":"Diagnostic workup"},"Tier":{"value":"1"},"Recommendation Text":{"value":"When GA-I is suspected, diagnostic workup, development of treatment plans, and appropriate information and training of affected individuals and their families should be provided in a specialized metabolic center. For 52 patients identified by newborn screening outcomes were best for those who were cared for under the supervision of a metabolic center were more likely to have care adherent to practice guidelines (35/45) compared to patients not treated through a metabolic center (2/7). In children not followed by a specialized metabolic center movement disorders and encephalopathic crises were more frequent (OR: 10.5 (95% CI: 1.57-70.25)), and morbidity score was higher than in children followed by metabolic centers (p=0.002)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic crises and functional decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000655"}}]}}}},{"Patient Management":{"value":"ACPM1137","properties":{"Key Text":{"value":"Dietary management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"There is evidence for a correlation of the genotype with biochemical parameters and residual enzyme activity but not with clinical phenotype. Therefore, all diagnosed individuals should receive the same form of maintenance treatment.\n• Protein-controlled diet and dietary advice: The effectiveness of dietary treatment after 6 years of age has not been systematically studied. However, as the clinical course is unknown, controlled protein intake using natural protein with a low lysine content and avoiding lysine-rich food is advisable. \n• L-carnitine supplementation: Although no randomized controlled studies demonstrate a specific positive effect of L-carnitine on clinical outcomes, L-carnitine supplementation is considered to contribute to reduced risk for striatal injury in individuals diagnosed early and reduced mortality rates in symptomatic individuals with GA-I. \n• Adequate supplies of specialized dietetic products and medication required for maintenance and emergency treatment should always be maintained at home."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic crises and functional decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000655"}}]}}}},{"Patient Management":{"value":"ACPM1134","properties":{"Key Text":{"value":"Emergency treatment"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Emergency treatment should be considered during severe illness or perioperative management. After age 6 years, the risk for developing an acute crisis is considerably reduced and encephalopathic crises have not been reported; however, the possibility of subclinical cerebral injury cannot be excluded, and the threshold to start emergency treatment should be low in this age group. If alarming symptoms such as recurrent vomiting, recurrent diarrhea, reduced nutrient intake, spiking temperature, or suspicious neurologic signs evolve, individuals should immediately be transferred to the closest hospital or metabolic center to start emergency treatment. Inadequate or delayed start of emergency treatment results in a high risk of striatal injury and dystonia. Written protocols for maintenance and emergency treatment should be regularly updated and provided to all persons involved. An emergency card should be provided summarizing key information and principles of emergency treatment and containing contact information of the treating metabolic center."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic crises and functional decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000655"}}]}}}},{"Patient Management":{"value":"ACPM1135","properties":{"Key Text":{"value":"Surgical management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"If an elective or emergency surgical intervention is planned, the responsible metabolic center should be informed in advance to discuss perioperative management with surgeons and anesthesiologists.  Particular perioperative and intraoperative steps should be taken in individuals with GA-I including: \n• Extubation at the end of surgical procedure after the patient is awake and when protective reflexes become present\n• Doubling of carnitine dosage \n• Limiting of fasting\n• Antiemetic prophylaxis\n• Monitoring of neuromuscular blockade if neuromuscular blocking agents are used\n• Monitoring body temperature \n• Consideration of serial intraoperative arterial blood gas analysis for monitoring of pH status, electrolytes, lactate, and glucose levels."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic crises and functional decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000658"}}]}}}},{"Patient Management":{"value":"ACPM1136","properties":{"Key Text":{"value":"Monitoring after head trauma"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals with GA-I should be admitted to a hospital and closely monitored after head trauma. Even under recommended treatment and without macrocephaly, subdermal hematoma may occur after minor head trauma. A case report of one child found a subdermal hematoma following minor head trauma in the absence of enlargement of subdural spaces, and therefore subdural hematoma should be considered in any unwell patient after minor accidental head injury."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000655"}}]}}}},{"Patient Management":{"value":"ACPM1138","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Management of pregnancy should be supervised by the responsible interdisciplinary team. Evidence and/or sufficient clinical experience regarding efficacy or necessity of emergency treatment during the peripartum period is not available. However, for surgical procedures (e.g., C-section), recommendations for perioperative management should be regarded as valid.  Uneventful clinical course for mother and child has been reported for women receiving emergency treatment during the peripartum period as well as women who did not receive any specific treatment. \n• In the case of a 23-year-old woman with a history of GA-I diagnosed in infancy, management during pregnancy included continued protein restriction, echocardiogram, biochemical monitoring, and increased carnitine supplementation. A successful C-section was performed with reduced perioperative fasting and perioperative infusion of L-carnitine. The woman remained asymptomatic and was discharged home on the third postoperative day. \n• One woman with a two uneventful pregnancies and deliveries had been followed from 15 months to 10 years for learning disabilities; however, she had graduated from school with special teaching support. She was identified as having GA-I following newborn screening in her second child. The physical examination of the mother was unremarkable except for a moderate mental deficit. Elevated GA and 3-OHGA were identified in urine and gene testing showed two heterozygous mutations in the GCDH gene.  \n• One woman presented at age 8 with macrocephaly, mild developmental delay, and epilepsy. At age 20 she had an uneventful pregnancy and delivery. Antiepileptic medications were modified, however she received no carnitine supplementation."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic crises and functional decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000655"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU612","properties":{"Key Text":{"value":"Clinical monitoring"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Therapeutic effectiveness should be monitored by regular follow-up and intensified at any age if symptoms progress, new symptoms manifest (disease- or therapy-related), or nonadherence to treatment recommendations is suspected. Yearly clinical monitoring should include clinical history, anthropometrics, clinical examination, neurologic assessment, specific psychological tests, dietary assessment, biochemistry (i.e., plasma amino acids, carnitine, and kidney function), quality of life, and psychological counseling (on request). Because urinary concentrations of GA and 3-OH-GA do not correlate with clinical parameters, analysis of urinary concentrations of GA and 3-OH-GA should not be used for treatment monitoring."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic crises and functional decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000655"}}]}}}},{"Surveillance":{"value":"ACSU611","properties":{"Key Text":{"value":"Neuroradiologic investigation"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Neuroradiologic investigation should be performed if signs or neurologic deterioration occur. Neurologic (i.e., epilepsy, movement disorder) or neurosurgical complications should be managed by a neurologist and/or neurosurgeon in close cooperation with a metabolic specialist. While diagnosis made after manifestation of neurologic disease is associated with a limited therapeutic impact, some affected individuals may benefit by prevention of progressive neurologic deterioration. In general, treatment of movement disorder associated with GA-I is challenging, with little evidence regarding the effectiveness of specific drugs. Potential treatments include: baclofen, benzodiazepines, anticholinergics, and botulinum toxin. No study has analyzed the effectiveness of antiepileptic agents in GA-I; however, valproate and vigabatrin should be avoided."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic crises and functional decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000655"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM412","properties":{"Key Text":{"value":"Genetic counseling"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Genetic counseling is recommended and should be offered to affected families together with genetic testing, as inheritance is autosomal recessive."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000656"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA509","properties":{"Key Text":{"value":"Lysine"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Avoiding lysine-rich food is advisable."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic crises and functional decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000655"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA508","properties":{"Key Text":{"value":"Valporate/vigabatrin"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Valproate and vigabatrin should be avoided; vigabatrin may induce peripheral visual field defects as a putative side effect and valproate may negatively affect acetyl-CoA/CoA ratio."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic crises and functional decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000655"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA507","properties":{"Key Text":{"value":"Propofol"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Reports that propofol can cause lipid overload and inhibit oxidative phosphorylation, carnitine palmitoyltransferase transport of long-chain fatty acids, and β-oxidation of fatty acids in mitochondria raise concerns about the possibility of occurrence of propofol infusion syndrome and severe metabolic acidosis. Long procedures with total intravenous anesthesia with propofol are probably not advisable. There are reports of use of thiopentone for induction without complications."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic crises and functional decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000658"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA506","properties":{"Key Text":{"value":"Ringers lactate"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Intraoperatively Ringer’s lactate should be avoided since it contains lactic acid."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Neurologic crises and functional decline"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000658"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"No information the prevalence of genetic mutations was identified."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE590","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"An international registry included 150 individuals with GA-I diagnosed via onset of symptoms, newborn screening, or metabolic cascade testing in high-risk families. Median age at diagnosis was 270 days; however, some outlier patients were diagnosed as adults. Of these 150, 3 individuals were classified as having early onset disease (having a neonatal crisis at ≤28 days), 48 individuals as having late onset disease (crisis after 28 days), 26 individuals with late onset disease without an acute crisis, and 73 of 150 patients were classified as asymptomatic.  Of the symptomatic individuals the median age at onset of symptoms was 300 days (IQR: 145-428) with 51 individuals presented with an encephalopathic crisis as the initial clinical manifestation. Of the 74 late-onset patients, 12 showed epilepsy as the initial clinical presentation and 29 presented with dystonic movement disorders without preceding encephalopathic crisis. \n\nOverall, neurologic manifestations of GA-I (including those with crisis during the newborn period) included: decreased muscle strength (28%), muscular hypotonia (25%), muscular hypertonia (17%), abnormal gross motor development (40%), abnormal fine motor development (46%), disturbed balance (39%), movement disorder (46%), seizures (7%), and EEG abnormalities (34%). Arterial hypertension was observed in 3 of patients."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000659"}},{"Reference":{"value":"/coll/reference_model/doc/RF000660"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR245","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN269","properties":{"Key Text":{"value":"No information on expressivity was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI274","properties":{"Key Text":{"value":"Interventions for GA-I may include: limiting dietary protein, supplementation with L-carnitine, management during pregnancy and emergency setting, avoidance of medications, avoidance of fasting, and biochemical and neurologic monitoring. Use of oral L-carnitine may be associated with diarrhea and a fishy odor."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000655"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC268","properties":{"Key Text":{"value":"The screen-detected prevalence is much higher than the prevalence based on clinical detection in Western countries (1.06 versus 0.28 per 100,000) and worldwide (1.40 versus 0.35 per 100,000). Under-ascertainment by clinical diagnosis is likely, due to the heterogeneous clinical presentation of GA-I."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000440"}}]},"Tier":{"value":"1"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Incomplete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2017-11-20"},"Scorers Present":{"value":8,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"srego"}}]},"Notes":{"value":""}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neurologic crises and functional decline","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2D","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Low protein/lysine diet","properties":{"Overall Score":{"value":"6DD"},"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Management by metabolic clinic","properties":{"Overall Score":{"value":"10DD"},"Effectiveness":{"value":"3D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":9,"items":[{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neurologic crises and functional decline","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Low protein/lysine diet","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Management by metabolic clinic","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neurologic crises and functional decline","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2D"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Low protein/lysine diet","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Management by metabolic clinic","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neurologic crises and functional decline","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Low protein/lysine diet","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Management by metabolic clinic","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neurologic crises and functional 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Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neurologic crises and functional decline","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2D"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Low protein/lysine diet","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Management by metabolic clinic","properties":{"Effectiveness":{"value":"3D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neurologic crises and functional decline","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"0D"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Low 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2."}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Low protein/lysine diet","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"Probably meets the threshold for modestly burdensome diet"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Probably meets the threshold for modestly burdensome diet"}}}}}},{"Intervention":{"value":"Management by metabolic clinic","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":"Small numbers, but it's been studied."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neurologic crises and functional 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This seems quite impressive and is likely due to more than just dietary interventions."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neurologic crises and functional decline","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"Could go to a 3 here"}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Low protein/lysine diet","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"0 or 1"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Management by metabolic clinic","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neurologic crises and functional decline","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"we are scoring just for previously undiagnosed adults"}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Low protein/lysine diet","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Management by metabolic clinic","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Neurologic crises and functional decline","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Low protein/lysine diet","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Management by metabolic clinic","properties":{"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First 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penetrance in terms of adults only"}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Low protein/lysine diet","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Management by metabolic clinic","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.1","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36167},"ReasonCode":{"value":"Q0","properties":{"Reason":{"value":"Initial Release"}}},"Date":{"value":"2017-11-20"},"ReleasedBy":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last 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{"ActionabilityDocID":{"value":"AC143","properties":{"Status":{"value":"Released"},"Genes":{"value":3,"items":[{"Gene":{"value":"LMNA","properties":{"HGNCId":{"value":"HGNC:6636"},"GeneOMIM":{"value":"150330"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"181350"}}]}}}},{"Gene":{"value":"EMD","properties":{"HGNCId":{"value":"HGNC:3331"},"GeneOMIM":{"value":"300384"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"310300"}}]}}}},{"Gene":{"value":"FHL1","properties":{"HGNCId":{"value":"HGNC:3702"},"GeneOMIM":{"value":"300163"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"300696"}}]}}}}]},"Syndrome":{"value":"Emery-Dreifuss Muscular Dystrophy (AD, XL)","properties":{"OmimIDs":{"value":3,"items":[{"OmimID":{"value":"181350"}},{"OmimID":{"value":"300696"}},{"OmimID":{"value":"310300"}}]},"OrphanetIDs":{"value":2,"items":[{"OrphanetID":{"value":"261"}},{"OrphanetID":{"value":"98853"}}]},"Overview":{"value":""},"Acronyms":{"value":0,"items":[]}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":2,"items":[{"Scorer Stage1":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"},"Notes":{"value":"penetrance was marked unknown"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}},{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":7,"items":[{"Outcome":{"value":"Complications from pregnancy","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pregnancy 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failure","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy/cardiac surveillance","properties":{"FullName":{"value":"Pharmacotherapy/cardiac surveillance"}}}}]},"FullName":{"value":"Congestive heart failure"}}}},{"Outcome":{"value":"Complications from anesthesia/surgery","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Anesthesia management","properties":{"FullName":{"value":"Anesthesia management"}}}}]},"FullName":{"value":"Complications from anesthesia/surgery"}}}},{"Outcome":{"value":"Morbidity due to disorders of glucose and lipid metabolism associated with partial lipodystrophy","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Metabolic evaluation","properties":{"FullName":{"value":"Metabolic evaluation"}}}}]},"FullName":{"value":"Morbidity due to disorders of glucose and lipid metabolism associated with partial lipodystropy"}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"Sources differ regarding the prevalence of Emery-Dreifuss muscular dystrophy (EDMD). The overall prevalence has been cited at 0.13-0.3 per 100,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}},{"Reference":{"value":"/coll/reference_model/doc/RF000663"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"EDMD is clinically characterized by the presence of the clinical triad of joint contractures, slowly progressive muscle weakness and wasting, and cardiac involvement. Autosomal dominant EDMD (AD-EDMD) and X-linked EDMD (XL-EDMD) have similar, but not identical, neuromuscular and cardiac involvement. Joint contractures predominate in the elbows, ankles, and post-cervical muscles. Contractures in the post-cervical muscles are responsible for limitation of neck flexion followed by limitation in movement of the entire spine. Slowly progressive muscle weakness and wasting is initially in humero-peroneal distribution but can later extend to the scapular and pelvic girdle muscles. Cardiac involvement may include palpitations, presyncope and syncope, poor exercise tolerance, congestive heart failure, and a variable combination of supraventricular arrhythmias, disorders of atrioventricular conduction, ventricular arrhythmias, dilated cardiomyopathy, and sudden death despite pacemaker implantation.  Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, Wenckebach phenomenon, third-degree atrioventricular block, and bundle-branch block. Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent.  A generalized dilated or hypertrophic cardiomyopathy often occurs. In AD-EDMD, the risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilation and dysfunction is higher than in XL-EDMD. Individuals are at risk for cerebral emboli and sudden death. Respiratory function may also be impaired. In a woman with EDMD, pregnancy complications may include the development of cardiomyopathy or progression of preexisting cardiomyopathy, preterm delivery, respiratory involvement, cephalopelvic disproportion, and delivery of a low birth-weight infant.  Heterozygous females with XL-EDMD are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype.  AD-EDMD is caused by mutations in LMNA while XL-EDMD is caused by mutation of EDMD or FHL1. Even in the same family, mutations in LMNA (OMIM: 150330) are also responsible for other phenotypic presentations, such as dilated cardiomyopathy 1A and limb-girdle muscular dystrophy 1B. Dilated cardiomyopathy 1A is addressed in a separate report."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}},{"Reference":{"value":"/coll/reference_model/doc/RF000663"}},{"Reference":{"value":"/coll/reference_model/doc/RF000664"}},{"Reference":{"value":"/coll/reference_model/doc/RF000665"}},{"Reference":{"value":"/coll/reference_model/doc/RF000666"}},{"Reference":{"value":"/coll/reference_model/doc/RF000667"}},{"Reference":{"value":"/coll/reference_model/doc/RF000668"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. The degree and progression of contractures are variable and not always age related. In XL-EDMD, joint contractures are typically the first sign, but in AD-EDMD, muscle weakness may onset prior to joint contractures. Severe contractures may lead to loss of ambulation by limitation of movement of the spine and lower limbs. Progression of muscle wasting is usually slow in the first three decades of life, after which it becomes more rapid. Loss of ambulation can occur in AD-EDMD but is rare in XL-EDMD. Cardiac involvement usually occurs after the second decade. On occasion, sudden cardiac death is the first manifestation of the disorder."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}},{"Reference":{"value":"/coll/reference_model/doc/RF000663"}},{"Reference":{"value":"/coll/reference_model/doc/RF000665"}},{"Reference":{"value":"/coll/reference_model/doc/RF000666"}},{"Reference":{"value":"/coll/reference_model/doc/RF000667"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1147","properties":{"Key Text":{"value":"Management in specialized clinic"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Clinicians should refer patients to a clinic that has access to multiple specialties designed specifically to care for patients with muscular dystrophy and other neuromuscular disorders to provide efficient and effective long-term care. Evidence from studies in other neuromuscular diseases, such as amyotrophic lateral sclerosis, indicates that a multidisciplinary approach is the most effective way to deliver care and is associated with improved survival, higher quality of life, increased use of treatments and interventions, and increased use of adaptive equipment."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Scoliosis"}},{"Outcome":{"value":"Complications from pregnancy"}},{"Outcome":{"value":"Cerebral thromboembolism"}},{"Outcome":{"value":"Arrhythmias"}},{"Outcome":{"value":"Congestive heart failure"}},{"Outcome":{"value":"Complications from anesthesia/surgery"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}},{"Patient Management":{"value":"ACPM1145","properties":{"Key Text":{"value":"Cardiology Evaluation"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Patients newly diagnosed should be referred for cardiology evaluation, including electrocardiogram (ECG) and structural evaluation (echocardiography or cardiac MRI), even if they are asymptomatic, to guide appropriate management. Patients with cardiac involvement often do not have symptoms that precede cardiac morbidity or sudden cardiac death and serious cardiac manifestations are often identified only with cardiology testing. Thus the detection and appropriate management of cardiac dysfunction are important to reduce morbidity and mortality. Patients with muscular dystrophy often have improved quality of life following appropriate pharmacologic treatment, device placement, or surgical intervention for their cardiac involvement."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Arrhythmias"}},{"Outcome":{"value":"Congestive heart failure"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}},{"Patient Management":{"value":"ACPM1141","properties":{"Key Text":{"value":"Pulmonary function testing and respiratory exam"},"Tier":{"value":"1"},"Recommendation Text":{"value":"At the time of diagnosis, patients should be referred for pulmonary function testing (spirometry and maximal inspiratory/expiratory force in the upright and, if normal, supine positions) or pulmonary evaluation (to identify and treat respiratory insufficiency). Patients with respiratory failure from neuromuscular-related weakness often do not have symptoms that precede the onset of respiratory failure. Impending respiratory failure is often identified only with pulmonary function tests. Patients with respiratory failure secondary to muscle weakness often have improved quality of life with noninvasive pulmonary ventilation due to improvement in energy, vitality, shortness of breath, daytime somnolence, depression, concentration problems, sleep quality, and physical fatigue."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}},{"Patient Management":{"value":"ACPM1142","properties":{"Key Text":{"value":"Metabolic evaluation"},"Tier":{"value":"3"},"Recommendation Text":{"value":"At the time of diagnosis, individuals with LMNA-linked EDMD should undergo evaluation of metabolic functions (glycemia, insulinemia, triglyceridemia), as rarely this phenotype can overlap with features of partial lipodystrophy."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Morbidity due to disorders of glucose and lipid metabolism associated with partial lipodystrophy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}}]}}}},{"Patient Management":{"value":"ACPM1143","properties":{"Key Text":{"value":"Low impact exercise"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Clinicians may advise patients that gentle, low impact aerobic exercise improves cardiovascular performance, increases muscle efficiency, and lessens fatigue. In a study of 27 patients with undescribed slowly progressive neuromuscular disease, moderate resistance exercise resulted in significantly improved strength equal to that of healthy control subjects. Another study of 8 subjects with progressive neuromuscular disease diagnoses that did not include EDMD demonstrated increased aerobic capacity and power output after a 12-week moderate intensity aerobic walking program."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Congestive heart failure"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}},{"Patient Management":{"value":"ACPM1146","properties":{"Key Text":{"value":"ICD implantation and antithromboembolic drugs"},"Tier":{"value":"3"},"Recommendation Text":{"value":"The following are recommended to prevent primary manifestations and secondary complications:\\n- Implantation of cardiac defibrillators to reduce the risk of sudden death. In a prospective study of 19 patients with LMNA mutations, including 9 patients with EDMD, who received ICD implantation, 8 patients received appropriate ICD shocks which may have prevented sudden death due to lethal tachyarrhythmias. Six patients received ICD shocks for ventricular fibrillation, 2 received shocks for ventricular tachycardia, and one received antitachycardia pacing for ventricular tachycardia. It is unclear how many patients with EDMD received a shock. \\n- Anithromboembolic drugs to prevent cerebral thromboembolism of cardiac origin in individuals with decreased left ventricular function or atrial arrhythmias. In a case series of patients with EDMD, 4 of 11 patients with atrial arrhythmia incurred thromboembolic events, indicating a high risk for thromboembolic events in this subset of patients. None were on anticoagulant prophylaxis."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Arrhythmias"}},{"Outcome":{"value":"Cerebral thromboembolism"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}}]}}}},{"Patient Management":{"value":"ACPM1144","properties":{"Key Text":{"value":"Preoperative cardiac evaluation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Preoperatively, the following additional diagnostic procedures are recommended:\\n- ECG\\n- Echocardiography and 24 hour ambulatory ECG telemetry\\n- Cardiac electrophysiological testing should be considered for patients with conduction defects"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Complications from anesthesia/surgery"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000670"}}]}}}},{"Patient Management":{"value":"ACPM1140","properties":{"Key Text":{"value":"Surgical and anesthesia management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Surgical and anesthesia recommendations to prevent potential complications include:\\n- An airway management plan to address aspiration risk and restricted neck movement\\n- Consideration of anti-fibrinolytics and early treatment of acquired coagulopathy\\n- An opioid-sparing technique and careful titrations of muscle relaxants \\n- Judicious use of fluids and a means of external pacing should it be necessary\\n- Electrolyte monitoring and DC cardioversion should be available\\n- Invasive arterial pressure monitoring and central venous pressure monitoring\\n- Neuromuscular blockade should be monitored routinely\\n- Potentiation of neuromuscular blockade by hypothermia should be avoided\\n- High dependency care should be considered particularly following intra-abdominal or thoracic surgery"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Complications from anesthesia/surgery"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000670"}}]}}}},{"Patient Management":{"value":"ACPM1148","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"In a woman with EDMD, pregnancy complications may include the development of cardiomyopathy or progression of preexisting cardiomyopathy, preterm delivery, respiratory involvement, cephalopelvic disproportion, and delivery of a low birth-weight infant. Pregnancy management is challenging, with very limited literature addressing the issue. Caesarean section delivery may be required. Referral of an affected pregnant woman to a specialized obstetric unit in close collaboration with a cardiologist is recommended for optimal pregnancy outcome."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Complications from pregnancy"}}]},"References":{"value":null,"items":[]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU617","properties":{"Key Text":{"value":"Annual cardiac assessment"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Annual cardiac assessment consisting of ECG, Holter monitoring, and echocardiography is appropriate in order to detect asymptomatic cardiac disease. More advanced and invasive cardiac assessment may be required."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Arrhythmias"}},{"Outcome":{"value":"Congestive heart failure"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}}]}}}},{"Surveillance":{"value":"ACSU616","properties":{"Key Text":{"value":"Respiratory function monitoring"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Monitoring of respiratory function should be performed."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}}]}}}},{"Surveillance":{"value":"ACSU615","properties":{"Key Text":{"value":"Body weight monitoring"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Body weight should be monitored, as affected individuals may be predisposed to obesity."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}}]}}}},{"Surveillance":{"value":"ACSU614","properties":{"Key Text":{"value":"Glucocorticoids and surveillance for scoliosis"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Clinicians should monitor patients for the development of spinal deformities to prevent complications and preserve function. Management is important to reduce discomfort, maintain normal posture, assist mobility, maintain cardiopulmonary function, and optimize quality of life. Management may include daily glucocorticoid treatment, which has been shown to reduce the risk of scoliosis, with patients not treated with glucocorticoids having a 90% chance of developing significant, progressive scoliosis. Management may also include surgery such as spinal fusion to straighten the spine, which prevents worsening of deformity, eliminates pain due to vertebral fracture with osteoporosis, and slows the rate of respiratory decline."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Scoliosis"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}},{"Surveillance":{"value":"ACSU613","properties":{"Key Text":{"value":"Physical and occupational assessment"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should have periodic assessments by physical and occupational therapist for symptomatic and preventive screening. Currently available data are not adequate to assess the effect of any rehabilitation modality (endurance and strength training, bracing, assistive devices, new computer-based technology). However, the principles of long-term management emphasize maintaining mobility and functional independence for as long as possible, with a focus on maximizing quality of life."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM413","properties":{"Key Text":{"value":"Genetic testing of family members"},"Tier":{"value":"3"},"Recommendation Text":{"value":"It is appropriate to evaluate apparently asymptomatic at-risk siblings, parents, and relatives of individuals with EDMD because of the high risk for cardiac complications including sudden death. Evaluation may allow early identification of family members who would benefit from initiation of treatment and preventive measures. Evaluations can include molecular genetic testing if the pathogenic variant in the family is known or cardiac evaluation if the pathogenic variant is not known."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Complications from pregnancy"}},{"Outcome":{"value":"Scoliosis"}},{"Outcome":{"value":"Cerebral thromboembolism"}},{"Outcome":{"value":"Arrhythmias"}},{"Outcome":{"value":"Congestive heart failure"}},{"Outcome":{"value":"Complications from anesthesia/surgery"}},{"Outcome":{"value":"Morbidity due to disorders of glucose and lipid metabolism associated with partial lipodystrophy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA512","properties":{"Key Text":{"value":"Avoid dehydration and intense exercise"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Avoid dehydration, exercising to exhaustion, and supramaximal high-intensity exercise due to the risk of exercise-induced muscle damage, myoglobinuria, and subsequent overwork weakness"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA511","properties":{"Key Text":{"value":"Avoid depolarizing muscle relaxants and volatile anesthetics"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Although malignant hyperthermia susceptibility has not been described in EDMD, it is appropriate to anticipate a possible malignant hyperthermia reaction and to avoid triggering agents such as depolarizing muscle relaxants (succinylcholine) and volatile anesthetic drugs (halothane, isoflurane)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Complications from anesthesia/surgery"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA510","properties":{"Key Text":{"value":"Avoid suxamethonium and inhalation anesthetics during first decade"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Although evidence is lacking it may be prudent to avoid suxamethonium and inhalational anesthetics during the first decade of life to avoid anesthesia-induced rhabdomyolysis."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Complications from anesthesia/surgery"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000670"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":"Autosomal Dominant (LMNA) or X-linked recessive (EMD; FHL1)"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}},{"Reference":{"value":"/coll/reference_model/doc/RF000665"}},{"Reference":{"value":"/coll/reference_model/doc/RF000666"}},{"Reference":{"value":"/coll/reference_model/doc/RF000667"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Information regarding prevalence of pathogenic variants associated with EDMD in the general population was not identified. However, roughly 45% of AD-EMDM is attributed to pathogenic variants in LMNA, roughly 61% of XL-EMDM is attributed to EMD, and roughly 10% of XL-EMDM is attributed to FHL1."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}}]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE591","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Five LMNA pathogenic variants were reported with reduced penetrance in families with AD-EDMD or other LMNA-related disorders. One study summarized clinical outcomes 4 families that harbored 4 unique missense pathogenic variants, where 2 in 2 (100%), 2 in 3 (67%), 1 in 3 (33%), and 0 in 4 (0%) individuals who harbored the familial variant in each family, respectively, were affected, indicating that variants could range from silent to fully penetrant. A second study focused on the R644C variant of LMNA reported penetrance rates across 5 families with more than one individual harboring the variant: 1 in 4 (25%), 1 in 2 (50%), 1 in 2 (50%), 2 in 5 (60%), and 2 in 3 (67%)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}}]}}}},{"Penetrance":{"value":"ACPE592","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"Additional information on penetrance was not identified."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR246","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information regarding relative risk was not identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN270","properties":{"Key Text":{"value":"LMNA variants do not show a clear genotype/phenotype correlation, with marked intra- and interfamilial variability observed.  Note that pathogenic variants in LMNA can result in variable phenotypes with different clinical designations. The same pathogenic variant may lead to different diagnostic phenotypes (AD-EDMD, LGMD1B, or isolated DCM-CD) in the same family."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}}]},"Tier":{"value":"3"}}}},{"Expressivity Note":{"value":"EN271","properties":{"Key Text":{"value":"Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI275","properties":{"Key Text":{"value":"The nature of intervention includes surgeries to treat manifestation, ICD implantation to prevent sudden cardiac death, extensive cardiac workup and monitoring, and anesthetic precautions."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}},{"Reference":{"value":"/coll/reference_model/doc/RF000664"}},{"Reference":{"value":"/coll/reference_model/doc/RF000670"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC269","properties":{"Key Text":{"value":"Because sudden cardiac death can be the first and single clinical manifestation of the disease, there is a chance to escape clinical detection prior to death due to disease."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000662"}}]},"Tier":{"value":"3"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2017-12-04"},"Scorers Present":{"value":9,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"srego"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"weaverm"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"lindorl"}}]},"Notes":{"value":""}}},"Outcomes":{"value":7,"items":[{"Outcome":{"value":"Complications from pregnancy","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pregnancy management","properties":{"Overall Score":{"value":"7DC"},"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Scoliosis","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoids","properties":{"Overall Score":{"value":"5DA"},"Effectiveness":{"value":"2A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Cerebral thromboembolism","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Antithrombotic medications","properties":{"Overall Score":{"value":"6DC"},"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Arrhythmias","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Defibrillator/cardiac surveillance","properties":{"Overall Score":{"value":"7DC"},"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Congestive heart failure","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy/cardiac surveillance","properties":{"Overall Score":{"value":"7DC"},"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Complications from anesthesia/surgery","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Anesthesia management","properties":{"Overall Score":{"value":"7DC"},"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Morbidity due to disorders of glucose and lipid metabolism associated with partial lipodystrophy","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Metabolic evaluation","properties":{"Overall Score":{"value":"7DC"},"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":10,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":7,"items":[{"Outcome":{"value":"Complications from pregnancy","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pregnancy management","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Scoliosis","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoids","properties":{"Effectiveness":{"value":"2A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Cerebral thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Antithrombotic medications","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Arrhythmias","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Defibrillator/cardiac surveillance","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Congestive heart failure","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy/cardiac surveillance","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Complications from anesthesia/surgery","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Anesthesia management","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Morbidity due to disorders of glucose and lipid metabolism associated with partial lipodystrophy","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Metabolic evaluation","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":7,"items":[{"Outcome":{"value":"Complications from pregnancy","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pregnancy management","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Scoliosis","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoids","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Cerebral thromboembolism","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Antithrombotic medications","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Arrhythmias","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Defibrillator/cardiac surveillance","properties":{"Effectiveness":{"value":"3C"},"Nature Of 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{"ActionabilityDocID":{"value":"AC144","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"VWF","properties":{"HGNCId":{"value":"HGNC:12726"},"GeneOMIM":{"value":"613160"},"SyndromeOMIMs":{"value":3,"items":[{"OMIM":{"value":"193400"}},{"OMIM":{"value":"613554"}},{"OMIM":{"value":"277480"}}]}}}}]},"Syndrome":{"value":"von Willebrand Disease","properties":{"OmimIDs":{"value":3,"items":[{"OmimID":{"value":"193400"}},{"OmimID":{"value":"613554"}},{"OmimID":{"value":"277480"}}]},"OrphanetIDs":{"value":4,"items":[{"OrphanetID":{"value":"903"}},{"OrphanetID":{"value":"166078"}},{"OrphanetID":{"value":"166081"}},{"OrphanetID":{"value":"166096"}}]}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)"}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)"}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)"}}]},"FullName":{"value":"Enter value here..."}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)"}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)"}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)"}}]}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Notes":{"value":"Von Willebrand disease (VWD) is the most common inherited bleeding disorder with prevalence estimates from <0.1% to 2% in the general population, with variation in estimates likely based on diagnostic criteria. Clinically relevant cases may have a 10-fold lower prevalence, estimated between 1/50,000 to 1/8,500. The prevalence of VWD type 3 has been estimated as 0.5 to 6 per million, increasing with the rate of consanguinity."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000671"}},{"Reference":{"value":"/coll/reference_model/doc/RF000672"}},{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000674"}},{"Reference":{"value":"/coll/reference_model/doc/RF000675"}},{"Reference":{"value":"/coll/reference_model/doc/RF000676"}},{"Reference":{"value":"/coll/reference_model/doc/RF000677"}},{"Reference":{"value":"/coll/reference_model/doc/RF000678"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000680"}},{"Reference":{"value":"/coll/reference_model/doc/RF000681"}},{"Reference":{"value":"/coll/reference_model/doc/RF000682"}},{"Reference":{"value":"/coll/reference_model/doc/RF000683"}},{"Reference":{"value":"/coll/reference_model/doc/RF000684"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"VWD is a bleeding disorder due to deficient or defective plasma von Willebrand factor (VWF), a large, multimeric protein that mediates platelet adhesion and stabilizes coagulation factor VIII (FVIII). Individuals primarily manifest mucocutaneous bleeding such as bruising, gingival bleeding, epistaxis, and menorrhagia. Bleeding after dental extraction, minor wounds, and surgical procedures are common. Spontaneous bleeding (joint and gastrointestinal bleeding) is not common except in more severe cases. Diagnosis is based on bleeding symptoms and confirmed VWF impairment. There are 3 types of VWD and each may be categorized into mild, moderate, and severe based on severity of VWF impairment.\\n\\nType 1 (50-75% VWD) is a partial deficiency of functionally normal VWF. It typically manifests as mild to moderate bleeding, but may be more severe with low VWF levels. Type 2 (~20-45% VWD) has normal or modestly decreased VWF levels but VWF function is abnormal. It typically manifests as mild to moderate bleeding, but may be more severe. Type 2 is divided into 4 subtypes depending on the VWF dysfunction. Type 2A has reduced VWF binding to platelets due to a deficiency of VWF multimers. Type 2B has increased VWF binding to platelets, leading to depletion of VWF multimers. Manifestations may include thrombocytopenia that worsens in stressful situations, such as infection, surgery, pregnancy, or treatment with desmopressin. Type 2M has reduced VWF binding to platelets with normal levels of VWF multimers. Type 2N has impaired binding to FVIII which lowers FVIII levels and mimics mild hemophilia A. Type 3 (<5% of VWD) is a complete deficiency of VWF with very low levels of FVIII and manifests with severe mucocutaneous and musculoskeletal bleeding."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}},{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000674"}},{"Reference":{"value":"/coll/reference_model/doc/RF000675"}},{"Reference":{"value":"/coll/reference_model/doc/RF000676"}},{"Reference":{"value":"/coll/reference_model/doc/RF000677"}},{"Reference":{"value":"/coll/reference_model/doc/RF000678"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000680"}},{"Reference":{"value":"/coll/reference_model/doc/RF000681"}},{"Reference":{"value":"/coll/reference_model/doc/RF000682"}},{"Reference":{"value":"/coll/reference_model/doc/RF000683"}},{"Reference":{"value":"/coll/reference_model/doc/RF000684"}},{"Reference":{"value":"/coll/reference_model/doc/RF000276"}},{"Reference":{"value":"/coll/reference_model/doc/RF000685"}},{"Reference":{"value":"/coll/reference_model/doc/RF000686"}},{"Reference":{"value":"/coll/reference_model/doc/RF000687"}},{"Reference":{"value":"/coll/reference_model/doc/RF000688"}},{"Reference":{"value":"/coll/reference_model/doc/RF000689"}},{"Reference":{"value":"/coll/reference_model/doc/RF000690"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"The severity of bleeding symptoms varies and depends on the primary deficiency of VWF and secondary deficiency of FVIII. ABO blood group appears to be an important contributor to penetrance and reduced VWF level in type 1 VWD Individuals; non-O blood groups have higher VWF levels than those with O blood group. VWD may only become apparent on hemostatic challenge. Bleeding history may become more apparent with increasing age. Type 3 is often apparent early in life, though cases have been diagnosed in adulthood. Mild type 1 may not be diagnosed until midlife, despite a history of bleeding episodes. Joint bleeds, or hemarthrosis, is not a common symptom but can lead to arthropathy and joint damage. Life-threatening bleeding that involves the brain or gastrointestinal tract can occur in individuals with type 3, in some individuals with type 2, and, rarely, in individuals with type 1. VWD affects males and females with equal frequency, though it may be disproportionately symptomatic in women of child-bearing age due to the increased risk of menorrhagia, hemorrhagic ovarian cysts, and post-partum hemorrhage. For patients managed within specialized centers, prognosis is favorable even for the most severe forms."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}},{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000674"}},{"Reference":{"value":"/coll/reference_model/doc/RF000677"}},{"Reference":{"value":"/coll/reference_model/doc/RF000680"}},{"Reference":{"value":"/coll/reference_model/doc/RF000681"}},{"Reference":{"value":"/coll/reference_model/doc/RF000682"}},{"Reference":{"value":"/coll/reference_model/doc/RF000684"}},{"Reference":{"value":"/coll/reference_model/doc/RF000686"}},{"Reference":{"value":"/coll/reference_model/doc/RF000688"}},{"Reference":{"value":"/coll/reference_model/doc/RF000689"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1156","properties":{"Key Text":{"value":"VWD treatment options"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"Note on VWD treatment options:  There are three common treatment options that may be used alone or at the same time. The most common and preferred treatment is desmopressin, which increases the plasma concentration of VWF by releasing endogenous stores. However, not all patients respond to desmopressin and it may be contraindicated in type 2B and type 3. A second option is replacement therapy with factor concentrates (VWF or combined VWF/FVIII). A third option is agents that promote hemostasis and wound healing, but do not alter VWF levels, such as oral contraceptives, topical agents (bovine thrombin and fibrin sealant), and antifibrinolytics (tranexamic acid and aminoproic acid). Treatment depends on VWD type and severity, bleeding history, treatment response, age, comorbidities, and the nature or potential bleeding."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}},{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000675"}},{"Reference":{"value":"/coll/reference_model/doc/RF000677"}},{"Reference":{"value":"/coll/reference_model/doc/RF000678"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000680"}},{"Reference":{"value":"/coll/reference_model/doc/RF000684"}},{"Reference":{"value":"/coll/reference_model/doc/RF000276"}},{"Reference":{"value":"/coll/reference_model/doc/RF000685"}},{"Reference":{"value":"/coll/reference_model/doc/RF000687"}},{"Reference":{"value":"/coll/reference_model/doc/RF000691"}}]}}}},{"Patient Management":{"value":"ACPM1149","properties":{"Key Text":{"value":"Evaluations after diagnosis"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual with VWD, the following evaluations are recommended at diagnosis:\\n• A personal and family history of bleeding to help predict severity and tailor treatment\\n• A joint and muscle evaluation for those with type 3 VWD\\n• Screening for hepatitis B and C and HIV if the diagnosis is type 3 VWD or if the individual received blood products or plasma-derived clotting factor concentrates before 1985\\n• Baseline serum iron and ferritin to assess iron stores, as many individuals with VWD (particularly women with menorrhagia) are iron deficient."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}}]}}}},{"Patient Management":{"value":"ACPM1161","properties":{"Key Text":{"value":"Comprehensive care"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Affected individuals benefit from care in a comprehensive bleeding disorders program for education, treatment, and genetic counseling."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}}]}}}},{"Patient Management":{"value":"ACPM1155","properties":{"Key Text":{"value":"Prophylactic therapy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"As most cases of VWD are relatively mild and patients do not suffer from serious spontaneous bleeding, prophylaxis is rarely indicated. Exceptions include patients with more severe VWD. Evidence for prophylactic treatment with factor concentrates is insufficient and limited to observational and retrospective studies. However, clinical experience with prophylaxis indicates reduced bleeding frequency, joint disease, and improved quality of life. Thus some believe that prophylactic treatment of VWD is justified, particularly for type 3. Three studies of mostly patients with type 3 have reported that prophylaxis is effective in abolishing bleeding, with a reduction in mucosal bleeding of 50-60% reported in one study."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000678"}},{"Reference":{"value":"/coll/reference_model/doc/RF000687"}},{"Reference":{"value":"/coll/reference_model/doc/RF000690"}},{"Reference":{"value":"/coll/reference_model/doc/RF000692"}}]}}}},{"Patient Management":{"value":"ACPM1150","properties":{"Key Text":{"value":"Desmopressin test"},"Tier":{"value":"1"},"Recommendation Text":{"value":"To determine clinical response to desmopressin, a test infusion during a non-bleeding state should be performed at diagnosis. The majority of patients with type 1 respond adequately. In a prospective study of 77 patients with type 1, 83% had complete and 13% had partial responses. However, desmopressin response is reduced in other VWD types. Only 13% of type 2 patients were responsive in a prospective study. Desmopressin may be useful and efficacious in type 2A only when FVIII levels need to be raised. Its use in type 2B is controversial due to thrombocytopenia and lack of evidence on effectiveness, but a test of response is acceptable. There is limited experience with type 2M. Type 2N typically responds to desmopressin, but the altered VWF has a reduced half-life. Type 3 is typically unresponsive. Some guidelines limit this testing recommendation to only those with type 1 and selected patients with type 2."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000675"}},{"Reference":{"value":"/coll/reference_model/doc/RF000684"}}]}}}},{"Patient Management":{"value":"ACPM1152","properties":{"Key Text":{"value":"Bleeding prevention for major surgery"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Before major surgery, a dosing study of factor concentrates should be considered, particularly in patients with type 3."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000684"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC266","properties":{"Recommendation":{"value":"Patients should also be monitored for factor activity during surgery. Whenever possible, major surgical procedures should be performed in hospitals with around-the-clock laboratory capability and with clinical monitoring by a team that includes a hematologist and a surgeon skilled in the management of bleeding disorders."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000676"}}]}}}},{"RecommendationID":{"value":"REC265","properties":{"Recommendation":{"value":"In a prospective study, VWF/FVIII concentrate was administered for 71 surgical or invasive diagnostic procedures in 39 patients with a good clinical response observed in 71% of procedures. Additional studies have reported even higher efficacy in surgical events (excellent or good results in 100%). In a prospective study of VWF concentrate, 50 patients with clinically severe VWD (5 with type 1, 27 with type 2 and 18 with type 3) were treated for 108 surgical or invasive procedures, with an excellent or good outcome in 100% of cases."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000684"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1154","properties":{"Key Text":{"value":"Surgical management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"General anesthesia is preferred, and regional anesthesia must be performed with caution, particularly when spinal and epi-medullar anesthetic procedures are planned. In that case, no formal recommendations exist and contraindications are relative. Special attention should be paid to patients with increased risk of difficult intubation. In case of difficult intubation, the use of a fiberscope or videolaryngoscope may reduce the risk of bleeding and mucosal lesions. Avoiding any trauma during positioning, transport, and mobilization is the rule."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000680"}}]}}}},{"Patient Management":{"value":"ACPM1151","properties":{"Key Text":{"value":"Bleeding prevention for minor surgery"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Prophylaxis before minor surgery is recommended. A systematic review of 8 studies assessed minor surgeries covered with desmopressin (total of 609 patients of whom 225 underwent 232 procedures; most patients had type 1). Results indicated consistent prevention of bleeding control associated with surgery, with bleeding only observed in 1.8%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000675"}},{"Reference":{"value":"/coll/reference_model/doc/RF000684"}}]}}}},{"Patient Management":{"value":"ACPM1159","properties":{"Key Text":{"value":"Bleeding prevention for dental procedures"},"Tier":{"value":"2"},"Recommendation Text":{"value":"During dental procedures where a deep cleaning is needed or heavy plaque and/or calculus accumulation may induce bleeding with scaling, adequate coverage should be given prior to and possibly after the procedure. The procedure may also be carried out in several visits to prevent excessive bleeding."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000276"}},{"Reference":{"value":"/coll/reference_model/doc/RF000685"}}]}}}},{"Patient Management":{"value":"ACPM1163","properties":{"Key Text":{"value":"Bleeding prevention for oral surgery"},"Tier":{"value":"1"},"Recommendation Text":{"value":"Prophylaxis for oral surgery is recommended in persons with mild to moderate VWD. Effectiveness data for antifibrinolytics in oral surgery for patients with VWD was not available. However, two randomized, controlled trials of people with hemophilia undergoing dental extraction (total of 58 individuals) indicated beneficial effects in reducing the number of bleedings, the amount of blood loss, and the need for therapeutic clotting factor concentrates. For postoperative bleeding, the combined risk difference of both trials was -0.57 (95% CI: -0.76 to -0.37), with the quality of the evidence for this outcome is rated as moderate."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000675"}},{"Reference":{"value":"/coll/reference_model/doc/RF000684"}},{"Reference":{"value":"/coll/reference_model/doc/RF000693"}}]}}}},{"Patient Management":{"value":"ACPM1158","properties":{"Key Text":{"value":"Bleeding prevention for oral surgery"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Topical agents, such as fibrin sealant or bovine thrombin, have been used with good results as adjuncts for oral surgery in persons with VWD. Careful attention to hemostasis of an extraction socket and suturing of sockets is also important in oral surgery."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000673"}}]}}}},{"Patient Management":{"value":"ACPM1164","properties":{"Key Text":{"value":"Hepatitis A and B vaccines"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals with VWD should be vaccinated against hepatitis A and B, particularly those who may receive replacement therapy."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000677"}},{"Reference":{"value":"/coll/reference_model/doc/RF000691"}}]}}}},{"Patient Management":{"value":"ACPM1162","properties":{"Key Text":{"value":"Carry medical alert information"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should wear or carry medical alert information (e.g., bracelet or card) and have an emergency treatment letter available."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000678"}},{"Reference":{"value":"/coll/reference_model/doc/RF000685"}}]}}}},{"Patient Management":{"value":"ACPM1157","properties":{"Key Text":{"value":"Oral contraceptives"},"Tier":{"value":"2"},"Recommendation Text":{"value":"To prevent hemorrhagic ovarian cysts, combined oral contraceptives may be used."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000676"}}]}}}},{"Patient Management":{"value":"ACPM1160","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Women planning for pregnancy should have, before conception, an evaluation with a hematologist and high-risk obstetrician skilled in management of VWD. Bleeding phenotype should be assessed, historical diagnosis reviewed, and response to treatment established. Pregnant women should be referred to a center or team with high-risk obstetrics capabilities and expertise in hemostasis for prenatal care, delivery, termination of pregnancy, miscarriage management, and factor monitoring. Women with type 1 generally do not require prophylaxis for delivery. In type 2, treatment is required for operative delivery or if there is perineal trauma. Women with type 3 require treatment for all types of delivery. Bleeding after delivery is not common in type 1, whereas type 2A, 2B, and 3 women usually need replacement therapy post-partum to prevent immediate or delayed bleeding. Healthcare providers should inform women of the risk of delayed bleeding, encourage them to report any excessive bleeding, and continue to monitor factor levels during the post-partum period."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000676"}},{"Reference":{"value":"/coll/reference_model/doc/RF000677"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000684"}},{"Reference":{"value":"/coll/reference_model/doc/RF000686"}},{"Reference":{"value":"/coll/reference_model/doc/RF000687"}}]}}}},{"Patient Management":{"value":"ACPM1153","properties":{"Key Text":{"value":"Pregnancy management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"In one study of women with VWD, 30% had bleeding following miscarriage and 10% of spontaneous or elective abortions were complicated by excessive bleeding requiring transfusion. Factor levels should be checked in women presenting with spontaneous miscarriages and in those opting for termination of pregnancy. Women with moderate or severe VWD are best served with abortion care at a center with an obstetrician, hematologist, and anesthesiologist experience in managing coagulation disorders."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000676"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000217"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU618","properties":{"Key Text":{"value":"Treatment centers"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals with milder forms of VWD can benefit from being followed by treatment centers with experience in the management of bleeding disorders."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}}]}}}},{"Surveillance":{"value":"ACSU619","properties":{"Key Text":{"value":"Physiotherapist"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals with type 3 should be followed in experienced centers and should have periodic evaluations by a physiotherapist to monitor joint mobility."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM414","properties":{"Key Text":{"value":"Genetic testing and counseling"},"Tier":{"value":"2"},"Recommendation Text":{"value":"When a diagnosis of VWD is made, it is appropriate to test first degree relatives with or without a positive bleeding history. In this circumstance, a presumptive diagnosis of VWD may be made on the basis of laboratory findings alone."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000687"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA514","properties":{"Key Text":{"value":"NSAIDs"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Persons with VWD should be counseled to avoid aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), and other platelet-inhibiting drugs."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000676"}},{"Reference":{"value":"/coll/reference_model/doc/RF000276"}},{"Reference":{"value":"/coll/reference_model/doc/RF000217"}},{"Reference":{"value":"/coll/reference_model/doc/RF000694"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA513","properties":{"Key Text":{"value":"VTE prophylaxis"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with untreated VDW should not be offered prophylaxis (mechanical or pharmaceutical) for venous thrombotic embolism (VTE), unless the risk of VTE outweighs the risk of bleeding."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000678"}},{"Reference":{"value":"/coll/reference_model/doc/RF000695"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA516","properties":{"Key Text":{"value":"Traumatic oro-tracheal intubation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"During preparation for airway management during surgery, traumatic oro-tracheal intubation should be avoided."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000680"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA517","properties":{"Key Text":{"value":"Central neuraxial anesthesia"},"Tier":{"value":"2"},"Recommendation Text":{"value":"For patients with type 2, central neuraxial anesthesia should be avoided unless VWF activity is more than 0.5 iu/ml and the hemostatic defect has been corrected. This may be difficult to achieve in type 2 and neuroaxial anesthesia should not be given in cases of type 3."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000679"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA515","properties":{"Key Text":{"value":"Activities with high trauma risk"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals should avoid activities involving a high trauma risk, particularly head injury."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":"Most VWD type 1 and most type 2A, type 2B, and type 2M are inherited in an autosomal dominant (AD) manner. VWD type 2N (more commonly identified in a compound heterozygous state rather than classical homozygous form), type 3 and rarely some types of 2A are inherited in an autosomal recessive (AR) manner."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}},{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000678"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000681"}},{"Reference":{"value":"/coll/reference_model/doc/RF000682"}},{"Reference":{"value":"/coll/reference_model/doc/RF000683"}},{"Reference":{"value":"/coll/reference_model/doc/RF000684"}},{"Reference":{"value":"/coll/reference_model/doc/RF000687"}},{"Reference":{"value":"/coll/reference_model/doc/RF000689"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"The prevalence of VWF pathogenic variants in the general population is unknown. VWF is the only gene in which pathogenic variants are known to cause VWD. However, not all individuals with VWD have a pathogenic variant in VWF. Pathogenic variants have been identified in 50-65% of individuals with type 1, ~90% with type 2, and ~90% with type 3."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}},{"Reference":{"value":"/coll/reference_model/doc/RF000681"}}]}}},"Penetrances":{"value":4,"items":[{"Penetrance":{"value":"ACPE596","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Type 1 is marked by incomplete penetrance. Pathogenic variants for type 1 resulting in plasma VWF levels lower than 25 IU/dL are mostly fully penetrant. Those resulting in higher VWF levels are often incompletely penetrant. Pathogenic variants causal for AD types other than type 1 (types 2A, 2B, and 2M) are often fully penetrant."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}},{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000681"}},{"Reference":{"value":"/coll/reference_model/doc/RF000684"}},{"Reference":{"value":"/coll/reference_model/doc/RF000688"}}]}}}},{"Penetrance":{"value":"ACPE594","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"The prevalence of self-reported bleeding symptoms in patients with VWD registered at hemophilia treatment centers are:\nEpistaxis: Type 1=53-61%, Type 2=63%, Type 3=66-77%\nMenorrhagia: Type 1=32%, Type 2=32%, Type 3=56-69%\nBleeding after dental extraction: Type 1=17-31%, Type 2=39%, Type 3=53-70%\nEcchymoses: Type 1=50%, Type 2=not reported, Type 3=not reported\nBleeding from minor cuts or abrasions: Type 1=36%, Type 2=40% Type 3=50%\nGingival bleeding: Type 1=29–31%, Type 2=35%, Type 3=56%\nPostoperative bleeding: Type 1=20–47%, Type 2=23%, Type 3=41%\nHemarthrosis: Type 1=2–3%, Type 2=4%, Type 3=37–45%\nGastrointestinal bleeding: Type 1=5%, Type 2=8%, Type 3=20%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000673"}}]}}}},{"Penetrance":{"value":"ACPE595","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"The prevalence of ovarian cysts in women with VWD has been estimated as 6.6%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000294"}}]}}}},{"Penetrance":{"value":"ACPE593","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Women are at an increased risk of bleeding complications during pregnancy compared to controls, with a 10-fold antepartum hemorrhage risk. Risk of post-partum hemorrhage is also higher, 15-30% in the first 24 hours and 22-29% after 24 hours compared with <1-5% in the general population."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000684"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR247","properties":{"Key Text":{"value":">3"},"Notes":{"value":"The frequency of symptoms in 222 patients with VWD (43% with mild VWD) compared to 341 healthy controls are: \\n     Profuse bleeding from small wounds: OR=30.0 (95% CI: 8.1–111.1)\\n     Profuse bleeding at site of tonsillectomy/adenoidectomy: OR=11.5 (95% CI: 1.2–111.9)\\n     Easy bruising: OR=9.9 (95% CI: 3.0–32.3)\\n     Profuse bleeding after surgery: OR=5.8 (95% CI: 1.3–26.4)\\n     Muscle bleeding (ever): OR=4.8 (95% CI: 0.7–31.4)\\n     Frequent nosebleeds: OR=3.8 (95% CI: 0.9–15.7)\\n     Profuse bleeding at site of dental extraction: OR=3.2 (95% CI: 0.9–11.3)\\n     Blood in stool (ever): OR=2.8 (95% CI: 0.7–11.7)\\n     Joint bleeding (ever): OR=2.5 (95% CI: 0.6–10.2)\\n     Menorrhagia: OR=2.5 (95% CI: 0.6–9.9)\\n     Hemorrhage at time of delivery: OR=2.1 (95% CI: 0.3–13.5)\\n     Frequent gingival bleeding: OR=0.7 (95% CI: 0.3–2.0)\\n     Hematuria (ever): OR= 0.5 (95% CI: 0.1–2.3)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000673"}}]},"Tier":{"value":"3"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN272","properties":{"Key Text":{"value":"Type 1 is marked by variable expressivity, while there is largely consistent expressivity of specific VWF mutations causing Type 2."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000681"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC027","properties":{"Recommendation":{"value":"The relationship between VWF level and VWD phenotype is only partially explained by specific VWF variants as there are multifactorial genetic and environmental influences on VWF levels."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000679"}}]}}}},{"RecommendationID":{"value":"REC028","properties":{"Recommendation":{"value":"Blood group contributes approximately 25% of the variance in plasma VWF level given ABO glycosylation of VWF influences its rate of clearance."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}}]}}}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI276","properties":{"Key Text":{"value":"Desmopressin is administered subcutaneously, intravenously, or intranasally. It is safe in pregnancy and at delivery. The main limitation of desmopressin is the progressive reduction of responsiveness after repeated treatments. Its strong antidiuretic effects are also a concern. Minor adverse effects of desmopressin are common but these effects rarely limit clinical use. Cases of stroke and seizure have rarely been reported.\\n\\nFactor concentrates are administered intravenously. Adverse reactions are rare. Severe reaction may reveal the development of antibodies against the administered factor. There is a risk of deep vein thrombosis with sustained levels of FVIII, making close monitoring necessary. A meta-analysis of thrombotic events reported 7 events among 361 patients with VWD (<2%). A separate meta-analysis of non-thrombotic, non-inhibitor adverse events in 374 patients with VDW, reported 39 adverse events (10%), though none were severe. \\n\\nAntifibrinolytic drugs can be administered orally or intravenously. Adverse effects include nausea, vomiting, diarrhea, and abdominal pain. Tranexamic acid is not contraindicated during pregnancy or puerperium."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}},{"Reference":{"value":"/coll/reference_model/doc/RF000673"}},{"Reference":{"value":"/coll/reference_model/doc/RF000678"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000680"}},{"Reference":{"value":"/coll/reference_model/doc/RF000684"}},{"Reference":{"value":"/coll/reference_model/doc/RF000276"}},{"Reference":{"value":"/coll/reference_model/doc/RF000687"}},{"Reference":{"value":"/coll/reference_model/doc/RF000691"}},{"Reference":{"value":"/coll/reference_model/doc/RF000696"}},{"Reference":{"value":"/coll/reference_model/doc/RF000697"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC270","properties":{"Key Text":{"value":"Mild type 1 may not be diagnosed until midlife, despite a history of bleeding episodes, indicating a delay in diagnosis despite clinical symptoms."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000672"}}]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2017-11-20"},"Scorers Present":{"value":8,"items":[{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"srego"}}]},"Notes":{"value":""}}},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Overall Score":{"value":"10CA"},"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Overall Score":{"value":"10CA"},"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Overall Score":{"value":"6CB"},"Effectiveness":{"value":"0B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Overall Score":{"value":"10CA"},"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Overall Score":{"value":"10CA"},"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Overall Score":{"value":"9CB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":10,"items":[{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"0B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"0B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"0B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"0B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"0B"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 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3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"3A"},"Nature Of Intervention":{"value":"2"}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}}]}}},"Scorers":{"value":10,"items":[{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"did not see discussion of trauma management but I scored for surgery and prevention anyhow"}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":"still confused"}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2B","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3B","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"does this include factor concentrate infusions?"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"does this include factor concentrate infusions?"}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"are we topical hemostasis agents? factor concentrates?"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3B","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"INC","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"Most VWF is pretty innocuous so I went with a 1. This is, I believe, \"minimal\" for most people. However, sometimes Type 2 can be pretty bad so I could be talked into a 2. The problem with scoring a 2 here is that it leaves nowhere to reflect the clearly worse manifestations in Type 3. So I'm going with a 1 here and a 2 for Type 2."}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"I'm sure all of these figures are inflated since ascertainment via bleeding/hemophilia centers would inevitably select for the most severe cases. There are probably many out there with VWF who never come to attention (especially men). But I'll go with the data we have. As we start to ascertain these folks through sequencing in unselected ways I can't imagine we won't see the penetrance drop significantly. This is a major limitation of our ability to score this and should be noted."}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":"I'm going with the discussion of \"Bleeding prevention for minor surgery\", in which there seems to be good evidence of benefit."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"\"Adverse reactions are rare\" for desmopressin."}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"I don't see a discussion of interventions in the setting of trauma, per se. Thus, I'm extrapolating from the context of major surgery and thus reducing my evidence score a notch."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"These would likely be platelets, FFP, etc. but are still very well tolerated."}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"INB","properties":{"Notes":{"value":"It's pretty clearly not recommended and is not indicated. Thus I think this should get an IN. This highlights a deficiency in our scoring in that we don't really have a category for \"not indicated\", which would be better in this context than \"ineffective\""}}},"Nature Of Intervention":{"value":"0","properties":{"Notes":{"value":"Clearly it's not a problematic Rx, but if we deem it \"ineffective\" given that it's not typically recommended, we usually don't score the \"burden\" of something that isn't recommended, right?"}}}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"See my note above"}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":"I was informed by the discussion of \"minor surgery\" which seems most akin to \"scheduled procedures\""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"Again, I see no specific discussion of trauma but am taking my cues from the major surgery section and reducing evidence level for extrapolation."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"It's clearly a bit controversial given the wording of the discussion on prophylaxis. Given the statement that \" Thus some believe that prophylactic treatment of VWD is justified, particularly for type 3. Three studies of mostly patients with type 3 have reported that prophylaxis is effective in abolishing bleeding, with a reduction in mucosal bleeding of 50-60% reported in one study.\" I'm going with a 2E"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"williamsm","properties":{"First Name":{"value":"Marc"},"Last Name":{"value":"Williams"},"Status":{"value":"Complete"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"I was between 1 and 2. I ultimately chose 2 to reflect the full spectrum of bleeding that can be seen. I would be comfortable going to a 1 if one makes the assumption that the more severe forms are likely to be diagnosed clinically rather than by genomic analysis."}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":"The score of 3 is based on desmopressin. VWF infusion is more likely a 2, so I could support a score of 2, since this would be needed for most Type 2."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"The score of 3 is based on desmopressin. VWF infusion is more likely a 2, so I could support a score of 2, since this would be needed for most Type 2."}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"Not Scored","properties":{"Notes":{"value":"I didn't score this as I didn't see literature summary that specifically addressed it."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"Same"}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":"For this we probably should have split out type 1 and type 2. Type 1 has an excellent response to desmopressin, but type 2 is much less. Prophylaxis with factor therapy is based on anecdotal data. My score reflects type 1."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"Same"}}}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":"3 is based on intracranial hemorrhage. I could go to a 2 here."}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":"Small numbers but a good response."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Scoring 2 here based on VWF infusion, since desmopressin is ineffective"}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"Not Scored","properties":{"Notes":{"value":"Same issue as above--no specific discussion of the literature here"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Same"}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Score is based on the 3 case series. I chose moderate based on the 50-60% reduction. Evidence level C based on 3 case series, although E could also be appropriate"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Same"}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"Extrapolating from planned procedures"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"0B","properties":{"Notes":{"value":"It's essentially not necessary/recommended, so not sure which number to use here. Maybe this intervention shouldn't be scored?"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"Extrapolating from planned procedures"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 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2)","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"Might have missed relevant evidence"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 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There is the Nichols/Mannucci studies that suggest this could be a 3A, though"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"Not 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2)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2B","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":4,"items":[{"Outcome":{"value":"Bleeding complications (Types 1 and 2)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":"Could be A or B"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Types 1 and 2)","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Types 1 and 2)","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Types 1 and 2)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Bleeding complications (Type 3)","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Pharmacological intervention for scheduled procedures (Type 3)","properties":{"Effectiveness":{"value":"3A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Anti-hemorrhagic interventions in trauma settings (Type 3)","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant bleeding (Type 3)","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacological prophylaxis (Type 3)","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.3","properties":{"Notes":{"value":"Added some text edits from Kristy Lee that I missed during 1.0.1\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36171},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffacted"}}},"Date":{"value":"2018-07-24"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC145","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"TTR","properties":{"HGNCId":{"value":"HGNC:12405"},"GeneOMIM":{"value":"176300"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"105210"}}]}}}}]},"Syndrome":{"value":"Hereditary transthyretin-related amyloidosis","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"105210"}}]},"OrphanetIDs":{"value":2,"items":[{"OrphanetID":{"value":"85447"}},{"OrphanetID":{"value":"85451"}}]}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Severe visceral, neurological, or cardiac involvement","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplant"}}]}}}},{"Outcome":{"value":"Sudden cardiac death","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Implantable cardiac device"}}]}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"The frequency of familial transthyretin (TTR) amyloidosis caused by the Val30Met variant, the most widely studied variant, is estimated as 1 in 538 in northern Portugal, the largest cluster worldwide. In individuals of northern European origin in the US, the frequency of Val30Met-related familial TTR amyloidosis is estimated as 1 in 100,000. In Europe, the prevalence is estimated as less than 1 in 100,000 individuals. In some areas of Japan, the prevalence is approximately 1 in 1,000,000. The worldwide prevalence of cardiac TTR amyloidosis is unknown, but it is almost certainly underdiagnosed, particularly in the African American population."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000706"}},{"Reference":{"value":"/coll/reference_model/doc/RF000707"}},{"Reference":{"value":"/coll/reference_model/doc/RF000708"}},{"Reference":{"value":"/coll/reference_model/doc/RF000709"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"TTR amyloidosis is characterized by extracellular deposition of amyloid fibrils composed of TTR that accumulate in various organs and tissues. Presence of a disease-causing variant is not considered diagnostic due to variable penetrance. Clinical observation and tissue biopsy are required for diagnosis. Clinical features include peripheral sensorimotor and autonomic neuropathies and non-neuropathic cardiomyopathy, nephropathy, vitreous opacities, and central nervous system (CNS) amyloidosis. The spectrum of cardiovascular involvement is wide, ranging from asymptomatic atrioventricular and bundle branch block to severe, rapidly progressive heart failure due to restrictive pathophysiology. The majority of TTR cases are neuropathic, but there are several manifestations:\n- TTR amyloid neuropathy (familial amyloid polyneuropathy type I; Portuguese-Swedish-Japanese type) is mostly due to the Val30Met variant. This phenotype includes slowly progressive sensory neuropathy begins in the lower extremities, followed by motor neuropathy within a few years.  Sensory neuropathy progresses to sensory loss, muscle atrophy, and weakness of the extremities. Autonomic neuropathy may occur as the first symptom of the disease and may produce the most significant morbidity. It includes orthostatic hypotension, disturbances of gastrointestinal motility, sexual impotence, anhidrosis, and urinary retention or incontinence. Cardiac disease occurs in approximately 50% of individuals, most commonly amyloid cardiomyopathy. Individuals may also have ocular and renal involvement. Cachexia is a common feature at the late stage of the disease.\n- TTR amyloid neuropathy (familial amyloid polyneuropathy type II; Indiana/Swiss or Maryland/ German type) is associated with the Ile84Ser variant and starts in the upper extremities as carpal tunnel syndrome. Sensorimotor neuropathy and autonomic neuropathy are accompanied by visceral involvement. Cardiomyopathy and/or nephropathy are frequent in advanced disease.\n- TTR cardiac amyloidosis is characterized by progressive cardiomyopathy without peripheral neuropathy and is associated with the Val122Il3 variant. It generally presents with restrictive cardiomyopathy with varying degrees of chronic heart failure and possible brady/ tachyarrhythmias.\n- Leptomeningeal amyloidosis is associated with the Asp18Gly variant and is a relatively rare subtype associated with CNS findings: dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage. Polyneuropathy is absent or, if present, less evident. When associated with vitreous amyloid deposits, leptomeningeal amyloidosis is known as familial oculoleptomeningeal amyloidosis (FOLMA)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000706"}},{"Reference":{"value":"/coll/reference_model/doc/RF000707"}},{"Reference":{"value":"/coll/reference_model/doc/RF000708"}},{"Reference":{"value":"/coll/reference_model/doc/RF000709"}},{"Reference":{"value":"/coll/reference_model/doc/RF000711"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"TTR amyloidosis is clinically heterogeneous, with the presentation depending on genotype and geographic origin. The age at onset varies between the second and ninth decades of life, with great variations across different populations. TTR amyloid neuropathy usually begins in the third to fifth decade (mean age of 33 years) in persons from endemic foci in Portugal and Japan. Onset is later in persons from other areas (e.g., 56 years in Sweden). Even in foci generally considered early-onset, some subgroups of patients experience a later onset. Sensorimotor neuropathy and autonomic neuropathy progress over ten to 20 years, with a mean period of 10 years from onset to death. Cardiac amyloidosis is usually late onset; most individuals develop cardiac symptoms after age 30 years. Cardiac amyloidosis is four times more common among blacks than whites. Homozygotes present with a slightly more severe clinical course (higher incidence rate and earlier onset) than heterozygotes within the same family. In patients with cardiac-related symptoms, 5-year survival is less than 50%. Affected individuals usually die of cardiac failure, renal failure, or infection."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000706"}},{"Reference":{"value":"/coll/reference_model/doc/RF000707"}},{"Reference":{"value":"/coll/reference_model/doc/RF000708"}},{"Reference":{"value":"/coll/reference_model/doc/RF000709"}},{"Reference":{"value":"/coll/reference_model/doc/RF000711"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1167","properties":{"Key Text":{"value":"Evaluations at diagnosis"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"To establish the extent of disease in an individual diagnosed with familial transthyretin (TTR) amyloidosis, the following evaluations are recommended:\n- Gadolinium-enhanced MRI of the brain and spinal cord to evaluate CNS amyloidosis (Tier 3)\n- Ophthalmologic evaluation (Tier 4)\n- Evaluation of renal function (Tier 4)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000706"}}]}}}},{"Patient Management":{"value":"ACPM1169","properties":{"Key Text":{"value":"Tissue biopsy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"To confirm amyloidosis, demonstration of amyloid deposits via tissue biopsy is essential."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]}}}},{"Patient Management":{"value":"ACPM1166","properties":{"Key Text":{"value":"Neurologic assessment"},"Tier":{"value":"2"},"Recommendation Text":{"value":"At diagnosis, individuals should undergo a complete neurologic assessment which may include electromyographic testing with sympathetic skin response (SSR), quantitative sensory testing, heart rate deep breathing, and other autonomic tests, determined by presenting physical signs. Symptoms and stage of disease progression can be identified by neurologic scales/tests and the modified body mass index (mBMI; BMI multiplied by serum albumin level [g/L] to compensate for edema formation), a measure of nutritional status and wasting."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]}}}},{"Patient Management":{"value":"ACPM1171","properties":{"Key Text":{"value":"Cardiac assessment"},"Tier":{"value":"2"},"Recommendation Text":{"value":"A cardiologist should look for signs of cardiac amyloid involvement. Electrocardiography (ECG), echocardiography, scintigraphy with bone tracers, biomarkers (brain natriuretic peptide [BNP] and troponin I or T) and cardiac magnetic resonance imaging usually provide all the necessary information to diagnose infiltrative cardiomyopathy. Holter monitoring may also be recommended."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]}}}},{"Patient Management":{"value":"ACPM1170","properties":{"Key Text":{"value":"Implantable cardiac device"},"Tier":{"value":"2"},"Recommendation Text":{"value":"An implantable cardiac device (ICD) should be considered in patients with hereditary TTR-associated cardiac amyloidosis with ventricular arrhythmia (VA) causing hemodynamic instability who are expected to survive 1 year with good functional status. There is currently insufficient data to provide recommendations on primary prophylaxis. Case reports describe successful termination of sustained VA with ICDs. A study of 19 patients with histologically proven cardiac amyloidosis and a history of syncope (n=4), ventricular extra beats (n=10), or both (n=5) received an ICD. During a mean follow-up of 811 +/- 151 days, 2 patients with sustained VAs were successfully treated. Two patients underwent heart transplantation, and 7 died due to electromechanical dissociation (n=6) or glioblastoma (n=1). Nonsurvivors more often showed progression of left ventricular wall thickness, higher levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), low-voltage pattern on echocardiogram, and ventricular extra beats more often than in survivors, indicating ICD is not appropriate for all patients."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000710"}}]}}}},{"Patient Management":{"value":"ACPM1165","properties":{"Key Text":{"value":"Pharmacotherapy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Pharmacotherapy with TTR stabilizing agents can be prescribed at an early stage (stage 0 or I) of disease in anticipation of liver transplantation or potentially delaying the need for liver transplant. However, there is limited data to support the efficacy and safety of treatment given these agents are still in clinical trials."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]}}}},{"Patient Management":{"value":"ACPM1168","properties":{"Key Text":{"value":"Liver transplant"},"Tier":{"value":"2"},"Recommendation Text":{"value":"For individuals with mild (stage I, symptomatic but ambulatory) or moderate disease (stage II, ambulatory with assistance) and a confirmed diagnosis by biopsy, liver transplant is the current standard of care. Since variant TTR is produced largely in the liver, liver transplant should almost completely eliminate production of the variant protein (removes roughly 95%) and halt disease progression outside the brain and eyes.  Nerve function rarely improves after successful liver transplantation; however, a lessening of autonomic disturbances may occur. Liver transplant does not effectively prevent cardiomyopathy in most cases and is not recommended for patients with late-stage TTR amyloidosis or leptomeningeal-type amyloidosis. Moreover, cardiac disease may progress even after successful liver transplant, especially in patients with variants other than Val30Met. Organ impairment that occurred before the transplant does not usually reverse.  However, long-term observations show clear regression of amyloid deposits and an overall patient survival rate at 5 years of >77% with variant-specific utility survival: 10-year survival rate of 74% for Val30Met versus 44% for non-Val30Met patients. Some patients continue to have disease progression after transplant."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU620","properties":{"Key Text":{"value":"Monitor disease progression"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals should undergo the following assessments every 6 months to monitor disease progression:\n- Neurologic assessment and nerve conduction and sensory assessments\n- Autonomic function should be assessed by heart rate deep breathing measures\n- Echocardiography\n- Holter monitoring\n- Ophthalmologic testing\n- mBMI\n- Electrophysiologic evaluation\n- Cardiac and renal laboratory measures (plasma brain natriuretic peptide (BNP), NT-proNBP, serum troponin, creatinine clearance, albuminuria)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM415","properties":{"Key Text":{"value":"Genetic counseling and testing"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Genetic testing should be performed on relatives of patients when they are capable of comprehending the medical, social, and psychological ramifications of a positive result. Relatives should be strongly encouraged to undergo genetic testing and, if positive, tissue biopsies. However, for some individuals, including those with a family history of late-onset disease, early genetic testing may produce severe anxiety to which the physician needs to be sensitive. In all cases, genetic counseling and, if necessary, psychological support should be offered to affected family members."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA518","properties":{"Key Text":{"value":"Local heating appliances"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals should not use local heating appliances, such as hot-water bottles, which can cause low-temperature burn injury in those with decreased temperature and pain perception."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000706"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Tier":{"value":"3"},"Notes":{"value":"Val30Met is the most prevalent TTR variant in the world, focused in Portugal, Sweden, Japan, Brazil, and Majorca. It is believed to have arisen independently in Portugal and Sweden. In endemic areas of northern Sweden, the frequency of Val30Met is 4%. The frequency of heterozygotes is 1.5% in the northern part of Sweden."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000706"}},{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC067","properties":{"Recommendation":{"value":"Families with variants other than Val30Met have also been identified worldwide."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000706"}},{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]}}}},{"RecommendationID":{"value":"REC068","properties":{"Recommendation":{"value":"The cardiomyopathy-related Leu111Met and Val122Ile variants are found primarily in Danish and African American populations, respectively."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]}}}},{"RecommendationID":{"value":"REC066","properties":{"Recommendation":{"value":"The frequency of Val122Ile in the African American population is 3.0-3.9%. More than 5% of the population in some areas of West Africa is heterozygous for this variant. In the US, the frequency of Val122Ile in the white and Hispanic populations is 0.44% and 0.0%, respectively."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000706"}},{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]}}}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE597","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Penetrance for familial TTR amyloidosis is not 100%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000706"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC074","properties":{"Recommendation":{"value":"Within a global longitudinal study on the natural history of TTR amyloidosis, 611 of 885 individuals with a TTR pathogenic variant (Val30Met, Val122Ile, Leu111Met, or Glu89Gln) were symptomatic and had received a clinical diagnosis of TTR amyloidosis. Among symptomatic patients, 86.1% reported signs/symptoms of sensory neuropathy, 42.1% had signs/symptoms of cardiac disease. Gastrointestinal manifestations and autonomic neuropathy were recorded in 65.5% and 50.1%, respectively."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000712"}}]}}}},{"RecommendationID":{"value":"REC075","properties":{"Recommendation":{"value":"Penetrance may vary by variant, geographic region, or ethnic group. It is generally accepted that penetrance is much higher in individuals in endemic foci than outside. In Portugal, cumulative risk of disease in individuals with the Val30Met variant is estimated at 80% by age 50 and 91% by age 70 years, whereas the risk in French heterozygotes is 14% by age 50 and 50% by age 70 years. In Sweden, the penetrance is much lower: 1.7% by age 30, 5% by age 40, 11% by age 50, 22% by age 60, 36% by age 70, 52% by age 80, and 69% by age 90, respectively."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000706"}},{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]}}}}]}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN273","properties":{"Key Text":{"value":"Phenotypes are not always uniform, and the same point mutation may have varied phenotypes even within the same family."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI277","properties":{"Key Text":{"value":"Management includes regular invasive and non-invasive surveillance. Recommendations also include potential pharmacotherapy (with associated side effects), liver transplant, and ICD implantation. Preliminary evidence of pharmacotherapies in clinical trials indicate that these agents are well-tolerated. Many patients are able to live relatively normal lives after liver transplant. However, in addition to the risks of liver transplant surgery, patients also need to remain on immunosuppressants for the rest of their lives. Cardiac risks and complications constitute major adverse events in patients undergoing orthotopic liver transplant for TTR-FAP. Cardiovascular complications account for about 39% of deaths following liver transplant, almost half of which occur within the first 3 months. Implantation of an ICD in 19 patients was complicated by a lead revision because of low sensing (n=1) or frequent discharges due to atrial fibrillation with high ventricular rate response (n=2) over a median of 536 days. None of the patients died of perioperative complications. No other relevant technical complications or device failures occurred during follow-up."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000707"}},{"Reference":{"value":"/coll/reference_model/doc/RF000710"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC271","properties":{"Key Text":{"value":"Given its phenotypic unpredictability and variability, TTR amyloidosis can be difficult to recognize and manage. Misdiagnosis is common, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000707"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2017-12-04"},"Scorers Present":{"value":9,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"srego"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"weaverm"}},{"Scorer":{"value":"lindorl"}}]},"Notes":{"value":"The AWG had originally had a third scoring pair (Outcome: Need for earlier liver transplant or liver transplant, Intervention: pharmacotherapy to delay or alleviated the need for a liver transplant). However, when we were going through the scores there was a lot of confusion about the working of the outcome. Given there was little evidence on the effectiveness of the pharmacotherapy, the AWG decided not to score this pair after all and it was deleted. JEH, 12.07.2017"}}},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Severe visceral, neurological, or cardiac involvement","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplant","properties":{"Overall Score":{"value":"7NB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"0","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Implantable cardiac device","properties":{"Overall Score":{"value":"6DB"},"Effectiveness":{"value":"1B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":10,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Severe visceral, neurological, or cardiac involvement","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplant","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"0"}}}}]}}}},{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Implantable cardiac device","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Severe visceral, neurological, or cardiac involvement","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplant","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"0"}}}}]}}}},{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Implantable cardiac device","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Severe visceral, neurological, or cardiac 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But most people present with a variety of other morbidities so I went with how the majority manifest."}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":"I didn't want to consider only the Portugal cohort so went with the general study, hence my Tier 5 score."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver transplant","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Since some progress and 77% leaves a lot to be desired, I scored it as a 2..."}}},"Nature Of Intervention":{"value":"1","properties":{"Notes":{"value":"This is a very morbid procedure."}}}}}}]}}}},{"Outcome":{"value":"Liver transplant or earlier liver transplant due to disease progression","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy with transthyretin stabilizing agents","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"\"can be prescribed at an early stage\" is hardly a ringing endorsement....Hence my low score."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Sudden cardiac death","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":"By definition!"}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":"I'm essentially guessing here. I don't really think we have enough data as provided to score this."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Implantable cardiac device","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"7/19 died of EMD so it was hard for me to give it a 3, even though an ICD isn't really intended to or able to treat EMD"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":3,"items":[{"Outcome":{"value":"Severe visceral, neurological, or cardiac involvement","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Liver 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Tier 2 evidence based on 19 patients is still minimal to me."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.1","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36173},"ReasonCode":{"value":"Q0","properties":{"Reason":{"value":"Initial Release"}}},"Date":{"value":"2017-12-08"},"ReleasedBy":{"value":"hunterj","properties":{"First Name":{"value":"Jessica"},"Last Name":{"value":"Hunter"}}}}}}}},
{"ActionabilityDocID":{"value":"AC146","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"BMPR2","properties":{"HGNCId":{"value":"HGNC:1078"},"GeneOMIM":{"value":"600799"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"178600"}}]}}}}]},"Syndrome":{"value":"Primary pulmonary hypertension 1","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"178600"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"275777"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-09-11"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":2,"items":[{"Scorer Stage1":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}},{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"FullName":{"value":"Annual echocardiogram and clinical assessment to guide care and initiation of pharmacotherapy"}}}},{"Intervention":{"value":"Pharmacotherapy"}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"FullName":{"value":"Avoidance of exacerbation exposures such as estrogen compounds, appetite-suppressant medications, and hypoxia that accompanies high altitude"}}}}]},"FullName":{"value":"Enter value here..."}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Estimates of the prevalence of pulmonary arterial hypertension (PAH) range from 15 to 60 cases per million adult population. Estimate of PAH incidence range from 2.4 to 10 cases per million adult population per year. These statistics include individuals with idiopathic, heritable, and drug induced PAH. PAH is inherited in less than 10% of cases. Pathogenic variants in BMPR2 are the most common genetic cause of familial PAH."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000713"}},{"Reference":{"value":"/coll/reference_model/doc/RF000714"}},{"Reference":{"value":"/coll/reference_model/doc/RF000715"}},{"Reference":{"value":"/coll/reference_model/doc/RF000716"}},{"Reference":{"value":"/coll/reference_model/doc/RF000717"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"PAH, a subset of pulmonary hypertension (PH), is characterized by widespread obstruction and obliteration of the smallest pulmonary arteries leading to the resistance to blood flow through the lungs. As a result, the right ventricle attempts to compensate by generating higher pressure to maintain pulmonary blood flow, which eventually progresses to heart failure and premature death.  Right heart catheterization with a mean pulmonary artery pressure of 25mm Hg or more with a pulmonary artery wedge pressure of 15mm Hg or less is needed to confirm the diagnosis of PAH. \n\nThe symptoms of PH are non-specific and mainly related to progressive right ventricular dysfunction. Initial symptoms are typically induced by exertion and may include: shortness of breath, fatigue, weakness, angina, and syncope. Less commonly patients may also describe dry cough and exercise-induced nausea and vomiting. Symptoms at rest occur only in advanced cases. Individuals with PAH are classified into four functional categories by the World Health Organization (WHO FC): class I: no limitation of physical activity, class II: slight limitation of physical activity, class III: marked limitation of physical activity, class IV: inability to care out physical activity without symptoms."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000713"}},{"Reference":{"value":"/coll/reference_model/doc/RF000714"}},{"Reference":{"value":"/coll/reference_model/doc/RF000715"}},{"Reference":{"value":"/coll/reference_model/doc/RF000716"}},{"Reference":{"value":"/coll/reference_model/doc/RF000718"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"All ages are affected, but the mean age at diagnosis of PAH has been reported as ranging from 36 to 65 years. Because the symptoms of PAH are nonspecific and develop slowly diagnosis is often delayed for months or even years.  It is currently not possible to predict those who will ultimately develop PAH, although women are at increased risk compared to men. Females are twice as likely to be affected as males; however, survival is worse in males than females. Studies suggest that the female predisposition to PAH may be directly related to the effects of the metabolites of estrogen. Before the availability of disease-specific therapy in the mid-1980’s, the median life expectancy at the time of diagnosis was 2.8 years. Current therapy improves clinical function, but has a modest effect on survival.\n\nPAH associated with a pathogenic variant in BMPR2 occurs at an earlier age and is associated with more severe and rapidly progressive disease.  Data from an individual patient meta-analysis (N=1,550 patients with PAH; 29% with an identified BMPR2 pathogenic variant) found that at diagnosis, individuals with a BMPR2 pathogenic variant were younger (mean age 35.4 years vs. 42 years; p<0.0001) and had a higher mean pulmonary artery pressure and pulmonary vascular resistance, and a lower cardiac index. During a median of 5.4 years of follow up, individuals with a BMPR2 pathogenic variant were more likely to reach the composite outcome of death or lung transplantation (HR: 1.42 (95% CI: 1.15-1.75; p=0.0011) with similar results among men and women."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000713"}},{"Reference":{"value":"/coll/reference_model/doc/RF000714"}},{"Reference":{"value":"/coll/reference_model/doc/RF000715"}},{"Reference":{"value":"/coll/reference_model/doc/RF000716"}},{"Reference":{"value":"/coll/reference_model/doc/RF000717"}},{"Reference":{"value":"/coll/reference_model/doc/RF000718"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1172","properties":{"Key Text":{"value":"Management of medical conditions"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals at risk for PAH should undergo aggressive treatment for any existing conditions that contribute to the development or worsening of PH (e.g., sleep apnea and systemic hypertension)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000718"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU623","properties":{"Key Text":{"value":"Monitoring for development of PAH"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Even in the absence of symptoms, individuals known to be at risk for the development of PAH based on the presence of a known pathogenic variant in BMPR2 should undergo monitoring for the development of PAH. The appropriate interval and type of screening has not been established. Recommendations for screening vary from annual echocardiography to ongoing clinical monitoring for the development of symptoms that would signal disease progression and warrant initiation of pharmacotherapy. There is an ongoing longitudinal study that should clarify issues such as optimal screening strategies and predictors of progression to PAH in asymptomatic BMPR2 carriers (NCT01600898)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000715"}},{"Reference":{"value":"/coll/reference_model/doc/RF000717"}},{"Reference":{"value":"/coll/reference_model/doc/RF000718"}}]}}}},{"Surveillance":{"value":"ACSU622","properties":{"Key Text":{"value":"Pharmacotherapy"},"Tier":{"value":"3"},"Recommendation Text":{"value":"No approved therapy for PAH has been shown to prevent progression of the underlying pulmonary vascular disease. PAH remains an incurable disease; currently, with clinicians attempt to manage it with pharmacotherapy. The prognosis of PAH is significantly worse in patients with advanced disease, PAH therapies delay clinical worsening and data are accumulating suggesting that early treatment improves long-term outcome."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000715"}},{"Reference":{"value":"/coll/reference_model/doc/RF000718"}}]}}}},{"Surveillance":{"value":"ACSU621","properties":{"Key Text":{"value":"Pharmacotherapy"},"Tier":{"value":"1"},"Recommendation Text":{"value":"A systematic review of 37 studies involving 4,192 patients that assess the effectiveness of drug treatment for adults with diagnosed PAH found inconclusive evidence regarding mortality reduction. The reviewers note that few deaths were observed in these studies due to their limited duration, leading to wide confidence intervals and lack of statistical power to detect a difference in mortality; however, a consistent direction of effect and demonstrated improvements in other outcomes, including functional and hemodynamic measures, support that a mortality reduction might exist. Increases in 6-minute walk distance (6MWD) ranging from 27.9 meters (95% CI, 10.3 to 45.4) to 39.9 meters (CI, 21.4 to 58.4) were observed in trials of all drug classes when compared with placebo or standard therapy. The reported minimal clinically meaningful difference in 6MWD is 33 meters for individuals with PAH."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000716"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM416","properties":{"Key Text":{"value":"Family management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"First-degree relatives at risk for PAH should undergo genetic counseling and genotyping as well as screening as outlined above."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000715"}},{"Reference":{"value":"/coll/reference_model/doc/RF000717"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA522","properties":{"Key Text":{"value":"Avoidance of appetite-suppressant medications"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Individuals who are at risk for PAH should avoid appetite-suppressant medications as these have been associated with an increased risk of PH."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000713"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA521","properties":{"Key Text":{"value":"Avoidance of vasoconstriction"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Cocaine, amphetamines, and related compounds causing vasoconstriction, have been anecdotally associated with PH."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000713"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA520","properties":{"Key Text":{"value":"avoidance of estrogen containing medications"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Other medications that have anecdotal suggestion of increased risk of PH, including estrogen compounds used as oral contraceptives or hormone replacement therapy. Anecdotal reports associating pregnancy with onset of PH raise some concern about the risks involved with pregnancy; however, there is no published consensus regarding the best approach to birth control in women with PAH. Because avoidance of exogenous systemic estrogen is desirable, many experts prefer intrauterine devices (IUDs)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000713"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA519","properties":{"Key Text":{"value":"Avoidance of hypoxia"},"Tier":{"value":"4"},"Recommendation Text":{"value":"The hypoxia that accompanies high altitude is associated with pulmonary vasoconstriction and PH in susceptible individuals."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000713"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Heterozygous BMPR2 pathogenic variants account for approximately 75% of familial PAH and up to 40% of apparently sporadic cases.  Hereditary transmission has been reported in approximately 6 to 10% of patients with PAH. Pathogenic variants in BMPR2 have been identified in 50-90% of these individuals."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000714"}},{"Reference":{"value":"/coll/reference_model/doc/RF000715"}},{"Reference":{"value":"/coll/reference_model/doc/RF000717"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC069","properties":{"Recommendation":{"value":"To date, more than 200 families with heritable PAH are known in the US, including 120 families in whom the specific BMPR2 pathogenic variant is known."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000713"}}]}}}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE598","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"BMPR2 pathogenic variants have a penetrance of 20-30%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000713"}},{"Reference":{"value":"/coll/reference_model/doc/RF000714"}},{"Reference":{"value":"/coll/reference_model/doc/RF000715"}},{"Reference":{"value":"/coll/reference_model/doc/RF000717"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC076","properties":{"Recommendation":{"value":"The lifetime risk of PAH for males with a BMPR2 pathogenic variant is 14%, for females the risk is 42%."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000713"}}]}}}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR248","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information related to relative risk was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN274","properties":{"Key Text":{"value":"For those patients who develop PAH the variability in survival across patients is broad, ranging from sudden death to decades (rare)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000713"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC029","properties":{"Recommendation":{"value":"The phenotype is not expressed in all generations, but when expressed, occurs at an earlier age and is associated with more severe and rapidly progressive disease."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000717"}}]}}}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI278","properties":{"Key Text":{"value":"The initial screening for PAH may include cardiac imaging including echocardiography. Other universal management may include the avoidance of factors that may increase the likelihood of PAH. For those with signs of PH, right heart catheterization is used for diagnosis. For the minority of patients diagnosed with PAH, treatment can be varied and may eventually progress to supportive care, symptomatic treatment, disease-specific agents, and potentially lung transplantation."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000713"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC272","properties":{"Key Text":{"value":"Because the symptoms of heritable PAH are nonspecific and develop slowly, affected individuals often mistakenly attribute their initial symptoms to aging, poor physical conditioning, or being overweight. Some patients report no symptoms, and diagnosis is suspected on an incidental basis because of cardiac findings such as murmur, then supported by echocardiogram. Diagnosis is often delayed for months or even years, in part because heritable PAH is uncommon and thus rarely considered. The time to diagnosis from onset of symptoms may be shorter in familial PAH, perhaps because of heightened familial awareness."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000713"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2018-01-29"},"Scorers Present":{"value":8,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"srego"}},{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"odanielj"}}]},"Notes":{"value":""}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Overall Score":{"value":"8CB"},"Effectiveness":{"value":"1B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Overall Score":{"value":"8CA"},"Effectiveness":{"value":"1A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Overall Score":{"value":"7CC"},"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":8,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"1A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"0B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"1A"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"1A"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"IN"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"0N"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"0N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"1A"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"1A"},"Nature Of Intervention":{"value":"2"}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"1A"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"0"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"0A"},"Nature Of Intervention":{"value":"3"}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":8,"items":[{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"I'm going with minimally effective since there isn't even agreement on what type of surveillance (e.g. for symptoms or by echo) is warranted. Not to mention that it's mainly used to think about initiating pharmacotherapy, which itself has only modest evidence to suggest efficacy. This is one we'll want to revisit when the pending large study is published."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":"No good evidence of mortality reduction but some evidence of a small, clinically meaningful improvement in 6MWD leads me to a \"1\"."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"All the evidence seems pretty weak with regard to avoidance."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"Kind of depends on how much you like your cocaine and amphetamines..."}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"Extrapolated from Marfan"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"Used the newer references"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":"These were hard to score together. Everyone should probably avoid cocaine. Some seem like no brainers to avoid and some have no evidence."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"0B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":"1 or 2"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"Depends on medication"}}}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Considered going with a 1, since data are limited."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"Though could go with 2 due to burden of avoiding estrogen."}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"IN","properties":{"Notes":{"value":"its a diagnostic, not a therapy"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"0N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"0N","properties":{"Notes":{"value":"did not see studies addressing efficacy"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"When penetrance differs between genders or other subcategorizations, how have you scored penetrance in the past? I could see an argument for a 3 because for women penetrance is 42%, but went with a 2 because the overall penetrance is 20-30%."}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":"Do we know anything about the side effects of pharmacotherapy for PAH?"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Would defer to someone who knows more about the side effects of pharmacotherapy for PAH."}}}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Deterioration of pulmonary and cardiac function","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":3,"items":[{"Intervention":{"value":"Annual echocardiogram","properties":{"Effectiveness":{"value":"0","properties":{"Notes":{"value":"currently being studied"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Pharmacotherapy","properties":{"Effectiveness":{"value":"0A","properties":{"Notes":{"value":"Trend toward efficacy but evidence was inconclusive"}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":"agents and risks not described"}}}}}},{"Intervention":{"value":"Avoidance of exacerbating exposures","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"the reduced risk / efficacy is not given"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.1","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36175},"ReasonCode":{"value":"Q0","properties":{"Reason":{"value":"Initial Release"}}},"Date":{"value":"2018-01-29"},"ReleasedBy":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"}}}}}}}},
{"ActionabilityDocID":{"value":"AC147","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"SLC2A10","properties":{"HGNCId":{"value":"HGNC:13444"},"GeneOMIM":{"value":"606145"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"208050"}}]}}}}]},"Syndrome":{"value":"Arterial tortuosity syndrome","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"208050"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"3342"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Arterial Tortuosity Syndrome","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-10-18"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Unknown"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":2,"items":[{"Scorer Stage1":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Unknown"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}},{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Unknown"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"FullName":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers"}}}}]},"FullName":{"value":"Aortic Dilation Progression"}}}},{"Outcome":{"value":"Clinically significant aortic aneurysms","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"FullName":{"value":"Surveillance"}}}}]},"FullName":{"value":"Clinically significant aortic aneurysms"}}}},{"Outcome":{"value":"Visual deterioration","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic follow-up in ophthalmology clinic","properties":{"FullName":{"value":"Periodic follow-up in ophthalmology clinic"}}}}]},"FullName":{"value":"Visual deterioration"}}}},{"Outcome":{"value":"Pregnancy-associated complications","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"FullName":{"value":"High risk pregnancy management"}}}}]},"FullName":{"value":"Pregnancy-associated complications"}}}},{"Outcome":{"value":"Adverse effects of sports and other risky physical activities","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoid contact sports and other risky physical activities","properties":{"FullName":{"value":"Avoid contact sports and other risky physical activities"}}}}]},"FullName":{"value":"Adverse effects of sports and other risky physical activities"}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"The prevalence of arterial tortuosity syndrome (ATS) is unknown but the disorder is exceedingly rare, with approximately 100 cases described in literature. Incidence estimates vary between <1/1,000,000 to 1/100,000 live births."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000719"}},{"Reference":{"value":"/coll/reference_model/doc/RF000720"}},{"Reference":{"value":"/coll/reference_model/doc/RF000721"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"ATS is a connective tissue disorder characterized by tortuosity (twisting) and elongation of the aorta and large- and medium-sized arteries. Clinical manifestations are variable, depending on the arteries affected.  Cardiovascular manifestations are the major source of morbidity and mortality, with an increased risk at any age for aneurysm formation and dissection both at the aortic root and throughout the arterial tree and increased risk at any age for ischemic events.  Cardiovascular anomalies may lead to right ventricular hypertension, acute respiratory symptoms, ventricular hypertrophy, pulmonary hypertension, and cardiac failure. In addition, large veins may be dilated and valvular regurgitation and mitral valve prolapse can occur. Other manifestations include dysmorphic features (e.g., an elongated face, high palate, dental crowding, and beaked nose) usually becoming more prominent in older children and adults, soft and hyperextensible skin, loose skin folds, hernias, skeletal abnormalities (e.g., scoliosis), joint hypermobility, congenital contracture, ocular involvement (myopia, keratoconus), and generalized hypotonia.  Joint hypermobility leads to increased risk for sprains and dislocation, and adults are at increased risk for joint pain and fatigue.  Although the causal relation remains to be established, a higher rate of Raynaud phenomenon and orthostatic hypotension is reported."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000719"}},{"Reference":{"value":"/coll/reference_model/doc/RF000720"}},{"Reference":{"value":"/coll/reference_model/doc/RF000721"}},{"Reference":{"value":"/coll/reference_model/doc/RF000722"}},{"Reference":{"value":"/coll/reference_model/doc/RF000723"}},{"Reference":{"value":"/coll/reference_model/doc/RF000049"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"ATS is a highly variable disorder ranging from early mortality during infancy to limited manifestations in adulthood. Onset and identification usually occurs in infancy or early childhood, often because of a cardiac murmur or cyanosis; however, there are cases where ATS is revealed in late childhood or adulthood by cardiovascular complications or with joint aches and premature aging as the main presenting features. The prognosis can be severe, with a mortality rate of up to 12%, usually before the age of five years. The main causes of premature death are respiratory insufficiency, ventricular hypertrophy resulting in global heart failure, myocarditis, and ischemic events leading to organ infarction. Women are more prone to prolapse of the bladder, uterus, and rectum, especially following childbirth.\\n\\nThe frequency of ATS does not seem to vary between different ethnical backgrounds. Most reported cases are from Europe and the Middle East.  The male to female ratio is 1:1."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000719"}},{"Reference":{"value":"/coll/reference_model/doc/RF000720"}},{"Reference":{"value":"/coll/reference_model/doc/RF000721"}},{"Reference":{"value":"/coll/reference_model/doc/RF000722"}},{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1175","properties":{"Key Text":{"value":"Establish extent of disease"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish extent of disease and needs in an individual diagnosed with ATS, initial evaluation should include echocardiography; MRA or CT scan with 3D reconstruction from head to pelvis; lung function tests and imaging if emphysema is suspected; skeletal radiographs depending on clinical findings; consideration for bone densitometry based on patient history and risk factors; evaluation of the palate and orthodontia; and eye examination by an ophthalmologist with expertise in connective tissue disorders."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Aortic Dilation Progression"}},{"Outcome":{"value":"Clinically significant aortic aneurysms"}},{"Outcome":{"value":"Visual deterioration"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]}}}},{"Patient Management":{"value":"ACPM1176","properties":{"Key Text":{"value":"Multidisciplinary care"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Individuals with ATS benefit from a coordinated approach of multidisciplinary specialists in a medical center familiar with ATS or similar conditions."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Aortic Dilation Progression"}},{"Outcome":{"value":"Clinically significant aortic aneurysms"}},{"Outcome":{"value":"Visual deterioration"}},{"Outcome":{"value":"Pregnancy-associated complications"}},{"Outcome":{"value":"Adverse effects of sports and other risky physical activities"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]}}}},{"Patient Management":{"value":"ACPM1174","properties":{"Key Text":{"value":"Pharmacotherapy"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Although hemodynamic stress on arterial walls can be reduced with use of beta-adrenergic blockers or other medications including angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs) such as losartan, the efficacy of these treatments has not been established in ATS and caution is warranted when using blood pressure lowering medications in the presence of arterial stenosis (anatomic or functional due to severe tortuosity), especially renal artery stenosis,  as these medications may confer a risk for renal failure."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Aortic Dilation Progression"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC270","properties":{"Recommendation":{"value":"While data on the effectiveness of these drugs was not available for ATS, a systematic review of beta blockers, ACEIs, and ARBs in Marfan Syndrome (MFS) concluded that these medications slowed the progression of aortic dilation. Three of the included studies showed that the treatment group’s aortic dilation progressed by roughly 1mm/year less than the non-treatment group, though no information was provided on how this impacted clinical outcomes."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000486"}}]}}}},{"RecommendationID":{"value":"REC269","properties":{"Recommendation":{"value":"In addition, two randomized trials in patients with MFS reported reductions in aortic root dilation rate with ARB added to beta blockers at three-year follow-up, indicating that treatment with beta blockers and ARB may be more effective than beta blockers alone. In contrast, a double-blind randomized trial found no significant difference between ARB and placebo on aortic root dilation rate at median 3.5-year follow-up, with most patients in both treatment groups also on beta blockers (86%)."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000705"}},{"Reference":{"value":"/coll/reference_model/doc/RF000704"}},{"Reference":{"value":"/coll/reference_model/doc/RF000703"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1178","properties":{"Key Text":{"value":"Stitches in surgery"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Wound healing may be delayed following surgery; thus stitches should be placed without traction and remain in place approximately 10 days."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]}}}},{"Patient Management":{"value":"ACPM1177","properties":{"Key Text":{"value":"Surgical intervention for aneurysms and focal stenoses"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Aneurysms and focal stenoses are amenable to surgical intervention; however, no data are available on the aortic diameter at which intervention is appropriate. Thus, decision making should also include assessment of the family history or the affected individual’s personal assessment of risk versus benefit."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinically significant aortic aneurysms"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC267","properties":{"Recommendation":{"value":"However, timely repair of aortic aneurysms has been found to prolong survival to that approaching age-matched controls in patients with MFS."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000050"}}]}}}},{"RecommendationID":{"value":"REC268","properties":{"Recommendation":{"value":"Limited information is available on the effect of aortic repair on the outcomes of patients with ATS. A case report was identified of a pediatric patient with ATS who underwent successful surgical repair of an ascending aortic aneurysm via hemi-arch and ascending aortic replacement with tube graft. Related to surgical repair of stenosis, 7 patients with ATS (aged 7 months to 10 years) with severe bilateral pulmonary artery stenosis who underwent extensive reconstruction of the pulmonary arterial tree had significant improvement in right ventricular (RV) function prior to hospital discharge and no observed mortality. All patients were alive and asymptomatic with normal RV function after a mean follow-up of 17.6 +/- 9.1 months following surgical reconstruction."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000724"}},{"Reference":{"value":"/coll/reference_model/doc/RF000725"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1173","properties":{"Key Text":{"value":"Pregnancy Management"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Preconception counseling should include possible pregnancy-associated risks to the mother (mainly aortic root dilation and dissection) and recommendation to discontinue medications with possible teratogenic effects (e.g., ACEIs, angiotensin II receptor 1 antagonists [ATIIR1] such as losartan, and anticoagulant therapy) and to begin therapy with beta-blockers. As is common practice in management in MFS, elective aortic repair using a valve-sparing procedure (if possible) could be performed prior to conception when the aortic root diameter reaches 45 mm. Peripartum intensive monitoring is advised. Pregnancies should be followed by a high-risk obstetrician and a cardiologist familiar with this or related conditions. Increased surveillance of the aortic root and previously detected aneurysms during pregnancy and following delivery is recommended because of the increased risk for progressive dilation. Echocardiography is suggested every two to three months from conception until six months post-partum. Delivery should be planned in a center with experience with this or related conditions. It is currently unclear if vaginal delivery or caesarean section is preferable. No data are available on risk for pregnancy-associated uterine rupture (as is seen in Loeys-Dietz syndrome and Ehlers-Danlos syndrome, vascular type). Prenatal and postnatal physiotherapy can minimize risk for pelvic organ prolapse."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Pregnancy-associated complications"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC271","properties":{"Recommendation":{"value":"Overall, the obstetric aspects of ATS have not been elucidated. Of 5 cases reported, 4 had successful pregnancies with uncomplicated deliveries, suggesting that pregnancy can be safely handled with multidisciplinary management including close maternal and fetal surveillance."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000721"}}]}}}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU625","properties":{"Key Text":{"value":"Surveillance for aortic root dilation"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Annual echocardiogram is recommended if no aortic root dilation, and, in the presence of aortic root dilation, echocardiogram should be performed at least every 6 months."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinically significant aortic aneurysms"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000049"}}]}}}},{"Surveillance":{"value":"ACSU624","properties":{"Key Text":{"value":"Surveillance for aneurysm"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Annual magnetic resonance angiography of the head, neck, thorax, abdomen, and pelvis is recommended."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinically significant aortic aneurysms"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000049"}}]}}}},{"Surveillance":{"value":"ACSU627","properties":{"Key Text":{"value":"Echocardiographic surveillance"},"Tier":{"value":"4"},"Recommendation Text":{"value":"In the case of pulmonary hypertension secondary to pulmonary artery stenosis, regular echocardiographic follow-up should be initiated"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]}}}},{"Surveillance":{"value":"ACSU628","properties":{"Key Text":{"value":"Vigiliance for emphysema"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Increased vigilance for emphysema is appropriate"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]}}}},{"Surveillance":{"value":"ACSU626","properties":{"Key Text":{"value":"Ophthalmology follow-up"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Routine follow-up for refractive errors and keratoconus, when possible with an ophthalmologist with an expertise in connective tissue disorders, is recommended."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Visual deterioration"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM417","properties":{"Key Text":{"value":"Family testing"},"Tier":{"value":"4"},"Recommendation Text":{"value":"It is appropriate to evaluate the older and younger sibs of a proband with ATS to identify as early as possible those who would benefit from treatment and surveillance for complications."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA523","properties":{"Key Text":{"value":"Sports-related adverse effects"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Patients with ATS should avoid the following: contact sports, competitive sports, and isometric exercise; scuba diving; agents stimulating the cardiovascular system, including routine use of decongestants; tobacco; and sun tanning (which may lead to premature skin aging)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Adverse effects of sports and other risky physical activities"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"4"},"Notes":{"value":"No evidence regarding prevalence of pathogenic variants was identified. However, because nearly all cases of ATS are explained by a pathogenic variant in SLC2A10, the prevalence is likely approximate to that of the disorder itself, which is rare and estimated at <1/1,000,000 to 1/100,000 live births."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Aortic Dilation Progression"}},{"Outcome":{"value":"Clinically significant aortic aneurysms"}},{"Outcome":{"value":"Visual deterioration"}},{"Outcome":{"value":"Pregnancy-associated complications"}},{"Outcome":{"value":"Adverse effects of sports and other risky physical activities"}}]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000719"}},{"Reference":{"value":"/coll/reference_model/doc/RF000720"}},{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE599","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"5"},"Notes":{"value":"In a case series of 50 patients from 40 families combined with previous literature reports of 52 patients, for a total cohort of 102 patients (78 probands), the penetrance of various manifestations were reported as:\n\nOcular:\n-Keratoconus = 8/55 (15%)\n-Keratoglobus = 2/55 (4%)\n-Myopia = 23/53 (43%)\n\nSkeletal:\n-Scoliosis = 20/90 (22%)\n-Joint laxity = 72/95 (76%)\n-Joint pain = 10/69 (26%)\n\nCardiovascular:\n-Aortic tortuosity = 83/90 (92%)\n-Tortuosity of other arteries = 73/91 (80%)\n-Abnormal implantation of aortic branches = 11/88 (13%)\n-Aortic root aneurysm = 14/90 (16%)\n-Other arterial aneurysm = 11/87 (13%)\n-Arterial dissections = 0/87 (0%)\n-Stenosis of the pulmonary arteries = 52/91 (57%)\n-Aortic stenosis = 22/90 (24%)\n-Other stenosis = 12/81 (15%)\n\nOther manifestations:\n-Diaphragmatic hernia = 19/65 (29%)\n-Inguinal hernia = 35/92 (38%)\n-Respiratory symptoms = 10/67 (15%)\n-Urogenital abnormalities = 11/56 (20%)\n-Autonomic dysfunction = 10/57 (18%)"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Aortic Dilation Progression"}},{"Outcome":{"value":"Clinically significant aortic aneurysms"}},{"Outcome":{"value":"Visual deterioration"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000757"}}]}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN275","properties":{"Key Text":{"value":"ATS is a highly variable disorder ranging from early mortality during infancy to limited manifestations in adulthood."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000723"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI280","properties":{"Key Text":{"value":"The nature of intervention includes regular surveillance imaging, including imaging with radiation exposure. Treatment of manifestations include surgery and pharmacotherapy. Pharmacotherapy does pose a potential risk to fetal development, meaning alternative therapies would need to be considered during pregnancy."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000723"}},{"Reference":{"value":"/coll/reference_model/doc/RF000049"}}]}}}},{"Nature of Intervention":{"value":"NOI279","properties":{"Key Text":{"value":"A literature review of case studies suggests that complications have not been observed during cardiovascular surgery in ATS patients, and the risk of fatal events should be similar to the general population."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000721"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC273","properties":{"Key Text":{"value":"Because adults can present with cardiovascular complications and no previous sign of disease, there is a chance to escape clinical detection."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000720"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2018-01-22"},"Scorers Present":{"value":6,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"srego"}}]},"Notes":{"value":"For visual deterioration/ophthalmology exam, there was extensive discussion around this, and two experts were consulted. The first expert didn't add anything to discussion. The second expert stated, \"If someone were advised that there was a risk for keratoconus, then screening could be done, measuring corneal thickness and the topography of the cornea. Then certain risk factors could be avoided, such as contact lens wear and eye rubbing due to allergy.\" Jim chose to score it as \"ineffective\" while the others chose to give it a zero for effectiveness. Because Jim scored as IN, he didn't score NOI"}}},"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Overall Score":{"value":"10NB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Evidence level downgraded due to extrapolation from evidence in Marfan Syndrome."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant aortic aneurysms","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Overall Score":{"value":"10NB"},"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Visual deterioration","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic follow-up in ophthalmology clinic","properties":{"Overall Score":{"value":"6ND"},"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Pregnancy-associated complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Overall 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beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Clinically significant aortic aneurysms","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Visual deterioration","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic follow-up in ophthalmology clinic","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Pregnancy-associated complications","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy 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and other risky physical activities","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoid contact sports and other risky physical activities","properties":{"Effectiveness":{"value":"1D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Clinically significant aortic 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activities","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoid contact sports and other risky physical activities","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Clinically significant aortic aneurysms","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Visual deterioration","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic follow-up in ophthalmology clinic","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Pregnancy-associated complications","properties":{"Severity":{"value":"0"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Adverse effects of sports and other risky physical activities","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoid contact sports and other risky physical activities","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Clinically significant aortic aneurysms","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Visual deterioration","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic follow-up in ophthalmology clinic","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}},{"Outcome":{"value":"Pregnancy-associated complications","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Adverse effects of sports and other risky physical activities","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoid contact sports and other risky physical activities","properties":{"Effectiveness":{"value":"3D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Clinically significant aortic aneurysms","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Visual deterioration","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic follow-up in ophthalmology clinic","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Pregnancy-associated complications","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"0N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}},{"Outcome":{"value":"Adverse effects of sports and other risky physical activities","properties":{"Severity":{"value":"3"},"Likelihood":{"value":"0D"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoid contact sports and other risky physical activities","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}}]}}},"Scorers":{"value":7,"items":[{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"although theoretically I imagine these folks could present with sudden death due to aneurysmal rupture, it looks like this is rare."}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"I thought that the studies showing slowed progression by ~1mm/year were pretty impressive. I tended to disregard the negative RTC that showed no benefit because it seemed only to look at ARB and not beta blockers. Finally, I kicked the evidence level down a notch due to extrapolation from MFS."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"ARBs are extremely well tolerated and rarely have side effects (other than cough in some percentage). Beta blockers are typically also well tolerated in spite of popular lore to the contrary."}}}}}}]}}}},{"Outcome":{"value":"Clinically significant aortic aneurysms","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"This is kind of tough since we have so little data on exactly when to intervene surgically so it kind of undermines the utility of surveillance. But one couldn't not recommend surveillance. Also, it's all extrapolation from MFS hence my evidence level being lower."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Visual deterioration","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic follow-up in ophthalmology clinic","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"Not sure what the ophthalmologist would do in any kind of a specific intervention...refractive errors (and keratoconus) are symptomatic, almost by definition."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Pregnancy-associated complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"A paucity of evidence."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Adverse effects of sports and other risky physical activities","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoid contact sports and other risky physical activities","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Kind of guessed here. Certainly hard to give it a \"3\" since it's not going to typically impact the natural history. But it seems prudent. I could be talked into changing this score."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"It all depends on how much the patient likes scuba diving, I guess. I could be talked into a 3 on this one..."}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":"Did not extrapolate from other conditions b/c of concern over arterial stenosis"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant aortic 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Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":"2 or 3"}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"1A","properties":{"Notes":{"value":"1 or 2"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant aortic aneurysms","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":"2 or 3"}}},"Likelihood":{"value":"Not 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Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Adverse effects of sports and other risky physical activities","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"Does this apply to cardiac events or connective tissue related issues?"}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoid contact sports and other risky physical activities","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant aortic aneurysms","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Visual deterioration","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic follow-up in ophthalmology clinic","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Pregnancy-associated complications","properties":{"Severity":{"value":"Not Scored","properties":{"Notes":{"value":"no info"}}},"Likelihood":{"value":"0N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Adverse effects of sports and other risky physical activities","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":"laxity does not necessarly become morbidity unless there are dislocations so this is a bit of extrapolation"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoid contact sports and other risky physical activities","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant aortic aneurysms","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Visual deterioration","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic follow-up in ophthalmology clinic","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Pregnancy-associated complications","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"3N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Adverse effects of sports and other risky physical activities","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoid contact sports and other risky physical activities","properties":{"Effectiveness":{"value":"3N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Status":{"value":"Incomplete"},"Outcomes":{"value":5,"items":[{"Outcome":{"value":"Aortic Dilation Progression","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0N","properties":{"Notes":{"value":"The numbers here seem to small to be useful, so I went with 0Es across the board, but I\"m okay with scoring the likelihood of the outcome according to these numbers if thats what has been done with similar situations in the past, as long as we keep a low level of evidence."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Dropped evidence level because extrapolating from Marfan data"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant aortic aneurysms","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"I didn't see evidence for surveillance in of itself, but since surveillance guides imitation of pharmacotherapy and surgery I based my score on those interventions."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Visual deterioration","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Periodic follow-up in ophthalmology clinic","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Pregnancy-associated complications","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"High risk pregnancy management","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Adverse effects of sports and other risky physical activities","properties":{"Severity":{"value":"3","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Avoid contact sports and other risky physical activities","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.1.1","properties":{"Notes":{"value":"Released with updates to the penetrance information included. This penetrance information was used during scoring, and scores were reviewed.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36177},"ReasonCode":{"value":"Q2","properties":{"Reason":{"value":"Major content updates but <strong>scoring pairs unaffacted</strong>"}}},"Date":{"value":"2018-02-19"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC148","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"DNM2","properties":{"HGNCId":{"value":"HGNC:2974"},"GeneOMIM":{"value":"602378"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"606482"}}]}}}}]},"Syndrome":{"value":"DNM2-Related Intermediate Charcot-Marie-Tooth Neuropathy","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"606482"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"100044"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"DNM2","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2017-12-20"},"Notes":{"value":""},"Label":{"value":"DNM2"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":2,"items":[{"Scorer Stage1":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}},{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations"}},{"Intervention":{"value":"Avoidance of vincristine, paclitaxel, succinylcholine"}}]}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"Charcot-Marie-Tooth (CMT) hereditary neuropathy is the most common genetic cause of neuropathy. Estimates of the prevalence of CMT range from 9.7/100,000 in Serbia to 82.3/100,000 in Norway. DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB) is a rare cause of CMT. Up to 3.4% of CMT (in which CMT1A, 1B, and 1X have already been excluded) is caused by a DNM2 pathogenic variant."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}},{"Reference":{"value":"/coll/reference_model/doc/RF000727"}},{"Reference":{"value":"/coll/reference_model/doc/RF000728"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"CMT hereditary neuropathy refers to a group of disorders characterized by a chronic motor and sensory polyneuropathy resulting from involvement of peripheral nerves and affecting the motor system and/or the sensory system. DI-CMTB is considered a “dominant intermediate form” of CMT neuropathy given its autosomal dominant inheritance and “intermediate” findings between a demyelinating and axonal neuropathy using electrophysiologic criteria using nerve conduction velocities. DI-CMTB has a classic, mild to moderately severe Charcot-Marie-Tooth hereditary neuropathy phenotype that often includes pes cavus foot deformity (high instep), depressed tendon reflexes, distal muscle weakness and atrophy, and sensory loss. Some individuals require braces or other walking aids and 3% of individuals with DI-CMTB become wheelchair bound. Other findings include asymptomatic neutropenia and early-onset cataracts (often noted in childhood before age 15 years).\n\nIt is usually not possible to differentiate between DI-CMTB, other intermediate forms of CMT, and most CMT2 types based on clinical findings, unless cataract and/or neutropenia (occasional findings in DI-CMTB) are present."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}},{"Reference":{"value":"/coll/reference_model/doc/RF000727"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Individuals with CMT experience symmetric, slowly progressive distal motor neuropathy of the arms and legs usually beginning in the first to third decade. Age of onset varies greatly among affected individuals and ranges from age two to 50 years."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}},{"Reference":{"value":"/coll/reference_model/doc/RF000727"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1180","properties":{"Key Text":{"value":"Medical evaluation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with DI-CMTB, the following evaluations are recommended: neurological examination; electrophysiological studies to establish a baseline; complete blood count with absolute neutrophil count (to evaluate for neutropenia); ophthalmologic examination for cataract; and consultation with a medical geneticist and/or genetic counselor."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000727"}}]}}}},{"Patient Management":{"value":"ACPM1181","properties":{"Key Text":{"value":"Treatment"},"Tier":{"value":"4"},"Recommendation Text":{"value":"No treatment reverses or slows the natural progression of  DI-CMTB. Treatment of DI-CMTB is symptomatic and involves evaluation and management by a multidisciplinary team that includes neurologists, orthopedic surgeons, and physical and occupations therapists. Due to the great phenotypic variability, disease treatment should be tailored to the individual’s needs. These treatments may include: ankle/foot orthoses; orthopedic surgery; forearm crutches/canes/wheelchairs; treatment of musculoskeletal pain with acetaminophen or NSAIDS; and career and employment counseling."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000727"}}]}}}},{"Patient Management":{"value":"ACPM1179","properties":{"Key Text":{"value":"Physical therapy"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Physical therapies such as stretching and exercise are recommended to prevent secondary complications such as foot contractures, acquired deformities, difficulty walking, and, in severe cases, inability to ambulate."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000727"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC272","properties":{"Recommendation":{"value":"A systematic review of exercise interventions for individuals with CMT (not DI-CMTB specifically) identified 9 studies of 134 individuals with CMT (3 randomized trials, 5 quasi-experimental, 1 case report). This review found that although benefits appear to be gained from exercise in strength and function in some studies, most outcomes reported were not statistically significant. The authors concluded that the optimal exercise modality and intensity for people with CMT, the clinical relevance of the changes observed, and the safety of exercise in these patients is still unclear. A review of four RCTs (149 patients with neuromuscular disease) found no benefit of any intervention for increasing ankle range of motion."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000729"}},{"Reference":{"value":"/coll/reference_model/doc/RF000730"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1182","properties":{"Key Text":{"value":"Preoperative assessment"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Preoperative assessment for co-morbidities and autonomic denervation is recommended. During surgical positioning, transport and mobilization, cautious positioning and protection of pressure points is recommended to avoid nerve compression. Neuromuscular block monitoring during surgery is also recommended."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000735"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU629","properties":{"Key Text":{"value":"Assessment of neurologic status and functional decline"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Surveillance includes regular evaluation by a multidisciplinary team to determine neurologic status and function disability."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000727"}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM418","properties":{"Key Text":{"value":"Genetic counseling"},"Tier":{"value":"4"},"Recommendation Text":{"value":"It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of being affected."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000727"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA527","properties":{"Key Text":{"value":"Avoidance of vincristine and paclitaxel"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. Vincristine and paclitaxel (chemotherapeutic agents) pose a definite high risk and should be avoided by all patients with CMT, including those who are asymptomatic; other medications may pose moderate to significant risk."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000727"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA525","properties":{"Key Text":{"value":"Avoidance of succinylcholine"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Avoiding succinylcholine, a muscle relaxant used for anesthesia, is recommended."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000735"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA524","properties":{"Key Text":{"value":"Avoidance of medication"},"Tier":{"value":"5"},"Recommendation Text":{"value":"A review of case reports addressing CMT and toxic medication effects identified 22 reports (30 patients) addressing vincristine toxicity. 18 of 30 patients developed marked sensory symptoms or new onset weakness, with some developing dysarthria and dysphagia. Nearly all reports describe eventual improvement, but frequently not to baseline levels. These cases occurred in both adults (15) and children (15). Most individuals having a reaction were previously unsuspected or undiagnosed with CMT (26 of 30) and were only recognized following administration of vincristine; however, 10 cases, in retrospect, had overt clinical signs or a close relative with known CMT.  A review of the CMT North American Database (including 209 individuals) identified 19 medications associated with clinical worsening. The majority of cases reviewed did not have information on genotype of CMT subtype; however, of those cases with identified subtypes the vast majority were CMT1A."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000732"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA526","properties":{"Key Text":{"value":"Obesity"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Obesity should be avoided as it makes walking more difficult."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"Information on the prevalence of DNM2 pathogenic variants was not identified."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE600","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"34 individuals were examined among a cohort of 6 families with an identified DNM2 pathogenic variant. The mean age of onset was 16 years, ranging from 2 to 50 years. Of the 34 family members with an identified DNM2 pathogenic variant, 32 had signs of neuropathy. Among the two individuals reporting no symptoms of neuropathy (aged 18 and 23), one had hematological abnormalities and cataracts, the second was found to have some mild features of CMT upon examination. Two families had associated neutropenia, and 1 family developed early-onset cataracts."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000727"}},{"Reference":{"value":"/coll/reference_model/doc/RF000733"}},{"Reference":{"value":"/coll/reference_model/doc/RF000736"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR249","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN276","properties":{"Key Text":{"value":"Age of onset and symptoms can vary even within the same family."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000727"}},{"Reference":{"value":"/coll/reference_model/doc/RF000733"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI281","properties":{"Key Text":{"value":"Potential interventions include examinations (physical exam, electrophysiological, ophthalmologic, family history, genetics consultation), physical therapy/stretching, and avoidance of certain medications."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000589"}},{"Reference":{"value":"/coll/reference_model/doc/RF000727"}},{"Reference":{"value":"/coll/reference_model/doc/RF000729"}},{"Reference":{"value":"/coll/reference_model/doc/RF000730"}},{"Reference":{"value":"/coll/reference_model/doc/RF000735"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC274","properties":{"Key Text":{"value":"Evaluation may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000727"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2018-02-05"},"Scorers Present":{"value":6,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"weaverm"}},{"Scorer":{"value":"srego"}}]},"Notes":{"value":"Medical evaluation scored as ineffective because all treatment is symptomatic."}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Overall Score":{"value":"IN"},"Effectiveness":{"value":"IN","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"Not Scored","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"Avoidance of vincristine, paclitaxel, succinylcholine","properties":{"Overall Score":{"value":"9CC"},"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":8,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"INC"},"Nature Of Intervention":{"value":"Not Scored"}}}},{"Intervention":{"value":"Avoidance of vincristine, paclitaxel, succinylcholine","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Demyelinating peripheral neuropathy","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Regular medical evaluations","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of 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Release"}}},"Date":{"value":"2018-02-05"},"ReleasedBy":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"}}}}}}}},
{"ActionabilityDocID":{"value":"AC149","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"F5","properties":{"HGNCId":{"value":"HGNC:3542"},"GeneOMIM":{"value":"612309"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"227400"}}]}}}}]},"Syndrome":{"value":"F5: Factor V deficiency (AR)","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"227400"}}]},"OrphanetIDs":{"value":0,"items":[]}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"No"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":3,"items":[{"Scorer Stage1":{"value":"elizabeth.v.clarke@kpchr.org","properties":{"First Name":{"value":"Elizabeth"},"Last Name":{"value":"Clarke"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"No"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}},{"Scorer Stage1":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"No"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}},{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"No"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"FullName":{"value":"Development and implementation of comprehensive management plan based on activity levels"}}}}]},"FullName":{"value":"Severe or prolonged hemorrhage"}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Factor V (FV) deficiency is a rare inherited bleeding disorder with a prevalence estimate of severe deficiency (homozygous or compound heterozygous) of 1 in 1,000,000. Approximately 200 patients with FV deficiency have been described in the literature."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000743"}},{"Reference":{"value":"/coll/reference_model/doc/RF000744"}},{"Reference":{"value":"/coll/reference_model/doc/RF000745"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Congenital FV deficiency is caused by alterations in the F5 gene resulting in reduced production of plasma coagulation FV; activated FV serves as an essential protein in the coagulation pathway. Common clinical signs include epistaxis, bruising, mucosal bleeding, and soft tissue bleeding. Excessive and prolonged bleeding during or following surgery, delivery or trauma are frequent. Women often present with menorrhagia. Less common are symptoms of joint, muscle, genitourinary, gastrointestinal, and intracranial bleeding."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000743"}},{"Reference":{"value":"/coll/reference_model/doc/RF000744"}},{"Reference":{"value":"/coll/reference_model/doc/RF000746"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Congenital FV deficiency can manifest at any age, with the most severe forms manifesting in early life.  Prognosis is good with early diagnosis and treatment. There is limited correlation between FV activity and severity of bleeding. Patients who come to medical attention are typically symptomatic homozygotes or compound heterozygotes with FV activity levels less than 5%. No clear ethnic predisposition is apparent. Data from registries indicate patients are more likely to have skin and mucocutaneous bleeding rather than hemarthroses. Women are at risk of bleeding complications during menstruation and childbirth. Menorrhagia is the most common bleeding symptom in women and may be the first or only presenting symptom. Heterozygotes often have approximately half-normal levels of coagulation factors and are usually asymptomatic, though there may be an increase in bleeding symptoms in carriers."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000743"}},{"Reference":{"value":"/coll/reference_model/doc/RF000744"}},{"Reference":{"value":"/coll/reference_model/doc/RF000745"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1184","properties":{"Key Text":{"value":"General management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"In common with other heritable bleeding disorders, the treatment and prevention of bleeding in rare coagulation disorders requires general measures, such as selecting invasive procedures with minimum bleeding risk and ensuring adequate communication of treatment plans developed by hemophilia centers with appropriate expertise."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000743"}}]}}}},{"Patient Management":{"value":"ACPM1185","properties":{"Key Text":{"value":"Management of bleeding"},"Tier":{"value":"2"},"Recommendation Text":{"value":"There is currently no FV concentrate. For mild bleeding or minor surgery, consider tranexamic acid. For severe bleeding or major surgery, consider FV replacement with solvent detergent fresh frozen plasma (SD-FFP) and additional platelet transfusion. In an open label study of 41 treatment episodes in FV deficiency, SD-FFP increased FV activity and was effective for the treatment of spontaneous or traumatic bleeds and the prevention of surgical bleeds. Off-label recombinant factor VIIa (rFVIIa) was effective in cases with allergy to FFP or to avoid volume overload."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000743"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC275","properties":{"Recommendation":{"value":"Case reports were found for 3 pediatric cases of severe homozygous FV deficiency, totaling 13 surgeries in all that were successfully managed with prophylaxis (FFP, rFVIIa, tranexamic acid) and continued supplementation after surgery with FFP and platelets."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000747"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1183","properties":{"Key Text":{"value":"Dental management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Dental management in patients with inherited bleeding disorders should involve a liaison between a hemophilia center, hospital dentist, and general dental practice regarding the nature of the disorder, treatment plans, and risk of transfusion-transmitted infection.  Treatment planning for procedures is essential for a good outcome."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000276"}}]}}}},{"Patient Management":{"value":"ACPM1187","properties":{"Key Text":{"value":"Pregnancy Management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Pregnancy in women with inherited bleeding disorders may require a multidisciplinary approach. Women with severe bleeding disorders should deliver in a hospital or where there is access to consultants in obstetrics, anesthesiology, and hematology."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000748"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC274","properties":{"Recommendation":{"value":"FV deficiency is associated with post-partum hemorrhage (PPH). Cases have been described with patients with FV activity >0.1 IU/ml and severe bleeding; therefore, clinical history should be considered in addition to laboratory levels. Patients should be advised about the possibility of early and late PPH and instructed to report excessive postpartum bleeding immediately. In a case report of 3 pregnancies in 2 homozygous patients, prophylactic and continued treatment with FFP resulted in an uncomplicated Caesarean section in one patient. In the second patient, the condition was discovered due to excessive bleeding at delivery, successfully treated with whole blood and FFP postpartum. The authors also reviewed 18 successful pregnancies reported in the literature, 11 of which were accompanied by heavy bleeding requiring FFP or whole blood transfusion. The other 7 deliveries were uncomplicated due to successful prophylaxis."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000743"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000748"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1186","properties":{"Key Text":{"value":"Menorrhagia management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Treatment of menorrhagia in women with inherited bleeding disorders should be individualized and managed with a multidisciplinary approach including a hematologist and gynecologist. In a survey by the Centers for Disease Control and Prevention, 95% (71 of 75) of women receiving care in hemophilia treatment centers reported a strong positive opinion and satisfaction."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000743"}},{"Reference":{"value":"/coll/reference_model/doc/RF000748"}},{"Reference":{"value":"/coll/reference_model/doc/RF000749"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC273","properties":{"Recommendation":{"value":"A case report of 4 homozygote women treated with oral contraception reported decrease in menorrhagia without complications. One woman treated for twenty years showed progressive reduction of menstrual cycle, decreased transfusional needs, and a steady increase of hematocrit."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000750"}}]}}}}]}}}}]},"Family Managements":{"value":null,"items":[]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA530","properties":{"Key Text":{"value":"Avoid aspirin/NSAIDs"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Aspirin and other NSAIDs are contraindicated in patients with inherited bleeding disorders because they can increase bleeding risk and prolong bleeding times."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000276"}},{"Reference":{"value":"/coll/reference_model/doc/RF000748"}},{"Reference":{"value":"/coll/reference_model/doc/RF000749"}},{"Reference":{"value":"/coll/reference_model/doc/RF000751"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA529","properties":{"Key Text":{"value":"Avoid VTE prophylaxis unless VTE risk outweighs bleeding risk"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients with untreated inherited bleeding disorders should not be offered prophylaxis (mechanical or pharmaceutical) for venous thrombotic embolism (VTE), unless the risk of VTE outweighs the risk of bleeding."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000753"}},{"Reference":{"value":"/coll/reference_model/doc/RF000755"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA528","properties":{"Key Text":{"value":"Avoid tranexamic acid under certain circumstances"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Tranexamic acid is contraindicated for renal tract bleeding and in cases with high thrombotic risk."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000743"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"},"Notes":{"value":"So-called “severe” FV deficiency is inherited in an autosomal recessive (AR) manner. Compound heterozygous cases have been described, as well as some apparently heterozygous (AD) cases with “mild” FV deficiency and significant bleeding history."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000745"}},{"Reference":{"value":"/coll/reference_model/doc/RF000754"}},{"Reference":{"value":"/coll/reference_model/doc/RF000756"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE601","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"Not provided"},"Notes":{"value":"Three cohort studies of patients with FV deficiency have been reported from Iran, Korea, and Germany. The Iranian and Korean cohort were defined based on clinical Factor V levels, while the German cohort included genotype information."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage"}}]},"References":{"value":null,"items":[]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC077","properties":{"Recommendation":{"value":"In the Iranian cohort (n=35, plasma levels 0-10%), 57% of patients had epistaxis and oral mucosa bleeding, 50% of the women had menorrhagia, 43% had postprocedural or postpartum bleeding, 29% had muscle hematomas, and 26% had hemarthroses. Gastrointestinal, genitourinary, and CNS bleeding episodes were each present in 6% of the patients."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000745"}}]}}}},{"RecommendationID":{"value":"REC078","properties":{"Recommendation":{"value":"A North American cohort of 18 presumed homozygotes/compound heterozygotes (defined as FV<20%) with severe FV deficiency all had bleeding symptoms. Bleeding events were predominated by bleeding in skin and mucus membranes (44%), joints and muscles (23%), genitourinary (19%), and gastrointestinal tract (6%). Intracranial hemorrhage represented 8% of bleeding events. In the same North American cohort, 19 patients with a heterozygous FV deficiency (defined as FV≥20%) were also examined, and 50% were reported to be symptomatic with spontaneous bleeding events. Of those, bleeding events were predominated by skin and mucus membranes (62%), followed by musculoskeletal (19%) and genitourinary (19%)."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000745"}}]}}}},{"RecommendationID":{"value":"REC079","properties":{"Recommendation":{"value":"In the German cohort 9 patients with homozygous F5 pathogenic variants, 3 patients with compound heterozygous pathogenic variants and 1 patient with a pseudo-homozygous pathogenic variant in addition to Factor V Leiden were reported with bleeding phenotype data available. Of those patients who were homozygous or compound heterozygous (n = 12) for F5 pathogenic variants, 67% reported bleeding symptoms, with the remainder having no bleeding phenotype at the time of study. Bleeding symptoms included hematoma (50% of patients), bleedings following invasive procedures (42%), epistaxis (25%), menorrhagia (20% of females, although patient age was not reported), and severe bleedings (8%). The patient with a pseudo-homozygous genotype had no bleeding phenotype."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000756"}}]}}}},{"RecommendationID":{"value":"REC080","properties":{"Recommendation":{"value":"In the German cohort, 12 heterozygous patients were also reported with phenotype data available. Of these patients, 75% experienced at least one bleeding symptom, with 50% experiencing bleeding following invasive procedures, 25% experiencing hematoma, 17% experiencing epistaxis, 17% of females experiencing hypermenorrhea (although patient age was not reported), and 8% experiencing hematuria."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000756"}}]}}}}]}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN277","properties":{"Key Text":{"value":"Patients with identical pathogenic variants or activity levels, including related patients with identical genotypes and equally low (<1%) FV activities, can vary greatly in their bleeding symptoms."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000745"}}]},"Tier":{"value":"5"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI282","properties":{"Key Text":{"value":"The interventions included in this report include treatments with potential risk and side effects. FFP, platelets, and other blood products carry risk of infection transmission. FFP carries risk of volume overload.  Tranexamic acid carries risk of thrombosis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000743"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC275","properties":{"Key Text":{"value":"Congenital FV deficiency can manifest at any age, with intracranial hemorrhage possible as a first event, indicating a chance to escape clinical detection prior to diagnosis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000743"}},{"Reference":{"value":"/coll/reference_model/doc/RF000745"}}]},"Tier":{"value":"5"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2018-04-02"},"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"srego"}},{"Scorer":{"value":"sobreiran"}}]},"Notes":{"value":""}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Overall Score":{"value":"10NB"},"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":7,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"sobreiran","properties":{"First Name":{"value":"Nara Lygia"},"Last Name":{"value":"Sobreira"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":7,"items":[{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"This is a bit tricky since most people seem to be treated when they have symptoms. However, since anticipatory Rx is useful in surgery, dental work, etc., I felt this was the most relevant consideration in that it would be useful to know about a FV deficiency prior to such procedures."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"Given the risks of volume overload and infectious disease (I was around for the decimation of hemophila clinics b/o HIV contamination) I can't bring myself to score it a 3 and thus went with 2."}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"2 or 3; I chose moderate evidence but  could be persuaded to go lower."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"I gave a 2 for the risk of infection."}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3B","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"seems like we should be intervening based not just on activity levels but past experience in that patient."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"sobreiran","properties":{"First Name":{"value":"Nara Lygia"},"Last Name":{"value":"Sobreira"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Severe or prolonged hemorrhage","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.1","properties":{"Notes":{"value":"Version 1.0.0 released on 4/2/2018\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36181},"ReasonCode":{"value":"Q0","properties":{"Reason":{"value":"Initial Release"}}},"Date":{"value":"2018-04-02"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC150","properties":{"Status":{"value":"Released"},"Genes":{"value":7,"items":[{"Gene":{"value":"MAX","properties":{"GeneFunction":{"value":"MYC associated factor X"},"HGNCId":{"value":"HGNC:6913"},"GeneOMIM":{"value":"154950"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"171300"}}]}}}},{"Gene":{"value":"SDHA","properties":{"GeneFunction":{"value":"succinate dehydrogenase complex flavoprotein subunit A"},"HGNCId":{"value":"HGNC:10680"},"GeneOMIM":{"value":"600857"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"614165"}}]}}}},{"Gene":{"value":"SDHAF2","properties":{"GeneFunction":{"value":"succinate dehydrogenase complex assembly factor 2"},"HGNCId":{"value":"HGNC:26034"},"GeneOMIM":{"value":"613019"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"601650"}}]}}}},{"Gene":{"value":"SDHB","properties":{"GeneFunction":{"value":"succinate dehydrogenase complex iron sulfur subunit B"},"HGNCId":{"value":"HGNC:10681"},"GeneOMIM":{"value":"185470"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"115310"}}]}}}},{"Gene":{"value":"SDHC","properties":{"GeneFunction":{"value":"succinate dehydrogenase complex subunit C"},"HGNCId":{"value":"HGNC:10682"},"GeneOMIM":{"value":"602413"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"605373"}}]}}}},{"Gene":{"value":"SDHD","properties":{"GeneFunction":{"value":"succinate dehydrogenase complex subunit D"},"HGNCId":{"value":"HGNC:10683"},"GeneOMIM":{"value":"602690"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"168000"}}]}}}},{"Gene":{"value":"TMEM127","properties":{"GeneFunction":{"value":"transmembrane protein 127"},"HGNCId":{"value":"HGNC:26038"},"GeneOMIM":{"value":"613403"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"171300"}}]}}}}]},"Syndrome":{"value":"Paragangliomas 1, 2, 3, 4, 5; Pheochromocytoma","properties":{"OmimIDs":{"value":6,"items":[{"OmimID":{"value":"168000"}},{"OmimID":{"value":"601650"}},{"OmimID":{"value":"605373"}},{"OmimID":{"value":"115310"}},{"OmimID":{"value":"614165"}},{"OmimID":{"value":"171300"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"29072"}}]}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":2,"items":[{"Scorer Stage1":{"value":"hunterj","properties":{"First Name":{"value":"Jessica"},"Last Name":{"value":"Hunter"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}},{"Scorer Stage1":{"value":"acscorer","properties":{"First Name":{"value":"Actionability"},"Last Name":{"value":"Consensus Scorer"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance"}}]}}}}]},"Status":{"value":"Incomplete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome represents 30% of all PGL/PCC. The prevalence is approximately 1:500,000 for PCC and 1:1,000,000 for PGL."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000338"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Hereditary PGL/PCC syndromes are characterized by PGLs that arise from neuroendocrine tissue (paraganglia) distributed from the skull base to the pelvic floor and PCCs, PGLs that are confined to the adrenal medulla. PGLs in the skull base and neck (e.g., carotid body, vagal, and jugulotympanic) are associated with the parasympathetic nervous system and do not secrete catecholamines. PGLs in the thorax, abdomen, and pelvis are typically associated with the sympathetic nervous system and may hypersecrete catecholamines. Gastrointestinal stromal tumors (GISTs) may also occur in individuals with a pathogenic variant in SDHD, SDHA, SDHC, or SDHB. Renal clear cell carcinoma (RCC) and papillary thyroid carcinoma have been reported with pathogenic variants in SDHB and SBHD. Symptoms of PGL/PCC result from mass effects (e.g., hearing loss, tinnitus, cough, hoarseness, or difficulty swallowing for head and neck tumors) or catecholamine hypersecretion from sympathetic PGLs and PCCs (e.g., elevations in blood pressure and pulse, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for malignant transformation is greater for extra-adrenal sympathetic PGLs than for PCCs or skull base and neck PGLs."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000338"}},{"Reference":{"value":"/coll/reference_model/doc/RF000337"}},{"Reference":{"value":"/coll/reference_model/doc/RF000170"}},{"Reference":{"value":"/coll/reference_model/doc/RF000763"}},{"Reference":{"value":"/coll/reference_model/doc/RF000171"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Compared to individuals with sporadic tumors, individuals with SDHD, SDHAF2, SDHC, and SDHB pathogenic variants tend to present at younger ages, are more likely to have multifocal, bilateral, and recurrent disease, and have multiple synchronous neoplasms. SDHD is associated with parasympathetic skull base and neck PGLs, with ~50% presenting as multiple tumors and a <5% malignancy risk. SDHAF2 is associated with PGLs of the skull base and neck, with ~90% presenting as multiple tumors and a low malignancy risk. SDHA is associated with PGLs generally presenting as single tumors with a low malignancy risk. SDHC is associated with parasympathetic skull base and neck paragangliomas, with ~20% presenting as multiple tumors and a low malignancy risk. SDHB is associated with extra-adrenal sympathetic PGLs, with ~20% presenting as multiple tumors and a 34-97% malignancy risk, and, less frequently, benign or malignant PCCs and parasympathetic PGLs. SDHB is associated with higher morbidity and mortality compared to other genes, may develop malignant disease at any paraganglion site, and may predict a shorter survival for malignant PCCs and PGLs. MAX is associated with PCCs, with ~60% presenting as bilateral tumors and a 25% malignancy risk. A subset of individuals with MAX pathogenic variants may also go on to develop PGLs, but typically present with PCC initially. TMEM127 is associated with PCCs, with ~40% presenting as bilateral tumors and a <5% malignancy risk.\n\nAge of onset of has been reported as 14-47 years for SDHD, 29-47 years for SDHB, 28-35 for MAX, and 34-72 for TMEM127. Age at onset for SDHA, SDHAF2, and SDHC is unclear. PGL/PCCs may be fatal, but with targeted treatment based on tumor stage, some affected individuals have lived for 20 years or more. For PGL/PCCs that have not metastasized, operative treatment can be curative. However, once metastases have occurred, the disease is uniformly fatal, with only 50% of affected individuals surviving beyond 5 years. No reliable pathology studies are available to distinguish a primary benign from a primary malignant PGL/PCC."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000338"}},{"Reference":{"value":"/coll/reference_model/doc/RF000337"}},{"Reference":{"value":"/coll/reference_model/doc/RF000170"}},{"Reference":{"value":"/coll/reference_model/doc/RF000763"}},{"Reference":{"value":"/coll/reference_model/doc/RF000171"}},{"Reference":{"value":"/coll/reference_model/doc/RF000760"}},{"Reference":{"value":"/coll/reference_model/doc/RF000762"}},{"Reference":{"value":"/coll/reference_model/doc/RF000764"}},{"Reference":{"value":"/coll/reference_model/doc/RF000765"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1188","properties":{"Key Text":{"value":"Assessments at diagnosis"},"Tier":{"value":"4"},"Recommendation Text":{"value":"At diagnosis, the following are recommended to establish the extent of disease:\n• Imaging studies using MRI/CT, 123-1-MIBG, and possibly PET to identify tumors\n• Consider evaluation for GISTs in young adults who have unexplained gastrointestinal symptoms (e.g., abdominal pain, upper gastrointestinal bleeding, nausea, vomiting, difficulty swallowing) or who experience unexplained intestinal obstruction or anemia\n• Consider screening for RCC in individuals with SDHB pathogenic variants\n• Medical genetics consultation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000337"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU631","properties":{"Key Text":{"value":"Monitoring by expert team"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Regular clinical monitoring by a physician or medical team with expertise in treatment of hereditary PGL/PCC syndromes."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000337"}}]}}}},{"Surveillance":{"value":"ACSU630","properties":{"Key Text":{"value":"Biochemical and clinical surveillance"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Lifelong biochemical and clinical surveillance beginning at age 10 years or ≥10 years before the earliest age of diagnosis in the family is recommended. The type and timing of the surveillance should be based on which gene is affected and take into account known genotype-phenotype relationships, with special attention for patients with pathogenic variants in SDHB due to the high risk of malignant disease."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000766"}},{"Reference":{"value":"/coll/reference_model/doc/RF000767"}}]}}}},{"Surveillance":{"value":"ACSU632","properties":{"Key Text":{"value":"Gene-specific biochemical and clinical surveillance"},"Tier":{"value":"4"},"Recommendation Text":{"value":"The following gene-specific monitoring has been proposed based on penetrance data suggesting that if lifelong screening were to begin at age 10, disease would be detected in all persons with a pathogenic variant in SDHD and 96% of persons with a pathogenic variant in SDHB:\n• Individuals should undergo 24-hour urinary excretion of fractionated metanephrines and catecholamines with follow-up imaging as needed\n• For SDHD or SDHC, periodic (e.g., every 2 years) MRI or CT of the skull base and neck to detect PGLs and periodic (e.g., every 4 years) body MRI or CT and 123-I-MIBG scintigraphy to detect PGLs or metastatic disease that may occur beyond the neck and skull base\n•For SDHB, periodic (e.g., every 2 years) MRI or CT of the abdomen, thorax, and pelvis to detect PGLs and periodic (e.g., every 4 years) 123-I-MIBG scintigraphy to detect PGLs or metastatic disease that may not be detected with MRI or CT."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000337"}},{"Reference":{"value":"/coll/reference_model/doc/RF000763"}}]}}}},{"Surveillance":{"value":"ACSU633","properties":{"Key Text":{"value":"Surveillance and Surgery"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Early detection of tumors through surveillance and removal of tumors may prevent or minimize complications related to mass effects, catecholamine hypersecretion, and malignant transformation or metastasis. In addition, factors associated with longer survival seems to be an early diagnosis and excision of the primary tumor, and, whenever possible, aggressive excision of any recurrence or soft-tissue metastases. Surgical resection is the mainstay for treatment for both benign and malignant PGL/PCCs."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000763"}},{"Reference":{"value":"/coll/reference_model/doc/RF000767"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC046","properties":{"Recommendation":{"value":"Though there is no available evidence specific to HPPS-related surveillance and surgery, a meta-analysis of 7 studies (N= 2,634) indicated that risk of recurrent disease after complete resection was 2.24 events/100 person-years (95% CI: 1.62, 2.87) for studies that include a majority of patients with genetic or syndromic disease (e.g., von Hippel Lindau)."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000768"}}]}}}}]}}}}]},"Family Managements":{"value":null,"items":[{"Family Management":{"value":"ACFM419","properties":{"Key Text":{"value":"Genetic testing"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Because early diagnosis and treatment is very likely to change the outcome for individuals, it is recommended that relatives at risk be offered genetic testing as early as possible when the family mutation is known. Relatives at risk who have not undergone DNA-based testing need regular clinical monitoring by a physician or medical team with expertise in treatment of hereditary PGL/PCC syndromes."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000337"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA532","properties":{"Key Text":{"value":"Avoidance of high altitudes and exposure to hypoxic conditions"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Penetrance of hereditary PGL/PCC syndromes may be increased in those who live in high altitudes or are chronically exposed to hypoxic conditions. Avoidance of habitation at high altitudes and activities that promote long-term exposure to hypoxia should be considered. In one study, individuals with SDHD pathogenic variants diagnosed with single tumors at their first clinical evaluation lived at lower average altitudes and were exposed to lower altitude-years than those with multiple tumors (p<0.012)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000337"}}]}}}},{"Circumstance to Avoid":{"value":"ACCA531","properties":{"Key Text":{"value":"Avoidance of cigarette smoking"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Activities, such as cigarette smoking, that predispose to chronic lung disease should be discouraged in individuals who have a pathogenic variant in SDHD, SDHA, SDHAF2, SDHC, SDHB, or MAX."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000337"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Tier":{"value":"3"},"Notes":{"value":"Among hereditary PGL/PCC, approximately 30% of cases are attributed to pathogenic variants in SDHD, 4-8% are attributed to SDHC, 22-38% are attributed to SDHB, and 0.6-3% with SDHA. The proportions attributed to SDHAF2, MAX, and TMEM127 are unclear."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000337"}}]}}},"Penetrances":{"value":6,"items":[{"Penetrance":{"value":"ACPE605","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Though data is limited, pathogenic variants in SDHD, SDHAF2, SDHA, SDHC, and SDHB appear to have a high but age-related penetrance."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000337"}}]}}}},{"Penetrance":{"value":"ACPE606","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"For SDHD, penetrance of any outcome is 48% by age 30 and 86% by age 50. The penetrance of skull base and neck PGLs is 68% by age 40, while the penetrance of extra-adrenal abdominal or thoracic tumors is 35% by age 60. For SDHB, penetrance of any outcome is 29% by age 30, <50-77% by age 50, and 100% by age 80. The penetrance of skull base and neck PGLs by age 40 is 15%, while the penetrance of extra-adrenal abdominal or thoracic tumors by age 60 is 69%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000337"}}]}}}},{"Penetrance":{"value":"ACPE603","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"1"},"Notes":{"value":"The pooled risk based on prevalence studies malignant PGL for SDHD and SDHB is estimated to be 4% (95% CI: 2-7%) and 13% (95% CI: 4-34%), respectively."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000171"}}]}}}},{"Penetrance":{"value":"ACPE607","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"In a large Dutch family, out of 45 individuals with a variant in SDHAF2, 33 with paternal inheritance of the variant developed the disease, 5 (median age 42 years) with paternal inheritance of the variant had not developed overt PGL, and 7 (median age 74 years) with maternal inheritance of the variant were unaffected."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000758"}}]}}}},{"Penetrance":{"value":"ACPE602","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"5"},"Notes":{"value":"A summary of 62 individuals with SDHC pathogenic variants noted that 77% had developed at least one tumor, though all were index cases. A study focused on 8 index cases indicated that none of the first-degree relatives had developed tumors, suggesting lower penetrance for all carriers."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000769"}}]}}}},{"Penetrance":{"value":"ACPE604","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"5"},"Notes":{"value":"A prospective study of 11 individuals with MAX pathogenic variants (8 index patients and 3 relatives), 37 individuals with SDHA pathogenic variants (29 index patients and 8 relatives), and 29 individuals with TMEM127 pathogenic variants (20 index patients and 9 relatives) estimated penetrance by age 40 years as 73% (95% CI: 28-90%) for MAX, 39% (95% CI: 21-53%) for SDHA, and 41% (95% CI: 20-57%) for TMEM127. The penetrance in relatives with an SDHA variant was significantly lower compared with index patients by age 40 (13% versus 45%, p<0.001). However, a difference in penetrance between index patients compared with relatives was not identified for MAX (50% vs 22%, p=0.26) or TMEM127 (88% vs 33%, p=0.69], but these results have to be interpreted with caution owing to the low case numbers in these subgroups."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000770"}}]}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN278","properties":{"Key Text":{"value":"Variation in the prevalence, penetrance, and phenotypic expression of pathogenic variants of the SDH subunits (SDHD, SDHA, SDHC, SDHB) may be population specific. In addition, phenotypes vary among individuals and even among family members with the same pathogenic variant."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000337"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC030","properties":{"Recommendation":{"value":"The age-dependent penetrance and variable expressivity of SDHA, SDHD, SDHAF2, SDHC, SDHD, and MAX pathogenic variants, as well as the parent-of-origin effects associated with SDHD, SDHAF2, and MAX pathogenic variants, predict that a substantial number of individuals who have inherited these variants will be simplex cases."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000337"}}]}}}},{"RecommendationID":{"value":"REC031","properties":{"Recommendation":{"value":"An individual who inherits an SDHD, SDHAF2, or MAX pathogenic variant from his/her mother is at low but not negligible risk of developing disease, though exceptions do occur. An individual who inherits an SDHD, SDHAF2, or MAX pathogenic variant from his/her father is at high risk of manifesting PGL and PCC."},"Tier":{"value":"4"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000337"}}]}}}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI283","properties":{"Key Text":{"value":"Interventions include regular biochemical monitoring with subsequent imaging as indicated (MRI or CT and 123-I-MIBG scintigraphy)."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC276","properties":{"Key Text":{"value":"PCCs and extra-adrenal sympathetic PGLs in hereditary PGL/PCC syndromes present in a manner similar to those in persons with sporadic tumors, most often coming to medical attention due to the signs and symptoms associated with catecholamine hypersecretion or signs and symptoms related to mass effects from the neoplasm. Diagnosis may be delayed due to the rarity of the tumors, absence of symptoms due to inactivated catecholamine, and non-specificity of signs and symptoms. The average time lag from the onset of hypertension to the diagnosis of the tumor is 3 years, with the tumors often diagnosed incidentally. Regular screening is recommended beginning at diagnosis, or earlier for family members. These screenings are above and beyond general population recommendations."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000337"}},{"Reference":{"value":"/coll/reference_model/doc/RF000763"}}]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2018-04-02"},"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"slavotineka"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"srego"}},{"Scorer":{"value":"sobreiran"}}]},"Notes":{"value":""}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Overall Score":{"value":"11CB"},"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":7,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3B"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"sobreiran","properties":{"First Name":{"value":"Nara Lygia"},"Last Name":{"value":"Sobreira"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":7,"items":[{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"One could invent scenarios with sudden death b/o catecholamine release but this  would be highly unusual"}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"The evidence levels are all over the map."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"slavotineka","properties":{"First Name":{"value":"Anne"},"Last Name":{"value":"Slavotinek"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"Averaged the level of evidence"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"Surveillance probably doesn't stop them developing, but getting them early could be effective"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3B","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"as you know, I continue to have difficulty calling imaging of any type an intervention.  The intervention is the surgery in my mind."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"as you know, I continue to have difficulty calling imaging of any type an intervention.  The intervention is the surgery in my mind."}}}}}}]}}}}]}}}},{"Scorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"Could go with a 2 or 3 here."}}}}}}]}}}}]}}}},{"Scorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"sobreiran","properties":{"First Name":{"value":"Nara Lygia"},"Last Name":{"value":"Sobreira"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Paraganglioma development","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Surveillance","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.1","properties":{"Notes":{"value":"This release is actually 2.0.0 - the merged version of HPPS from the four prior reports. Because there's not yet ACI features for merging reports, the 1.0 versions of the report will be retracted on this date.\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36183},"ReasonCode":{"value":"Q0","properties":{"Reason":{"value":"Initial Release"}}},"Date":{"value":"2018-09-07"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC151","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"CYP21A2","properties":{"HGNCId":{"value":"HGNC:2600"},"GeneOMIM":{"value":"613815"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"201910"}}]}}}}]},"Syndrome":{"value":"Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"201910"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"418"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":2,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2018-05-09"},"Notes":{"value":""},"Label":{"value":""}}}}]}}}},{"Source":{"value":"National Guideline Clearinghouse","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"dilated cardiomyopathy","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2018-07-10"},"Notes":{"value":""},"Label":{"value":""}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":"This report required clarification of the scope of the AAWG. It was decided that infertility was an important outcome, and that because management was different for NCCAH patients than non-NCCAH patients, the condition fell within our scope. However, it wasn't a traditional \"exception\" need."},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"No"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Unknown"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"},"Notes":{"value":"This report required clarification of the scope of the AAWG. It was decided that infertility was an important outcome, and that because management was different for NCCAH patients than non-NCCAH patients, the condition fell within our scope. However, it wasn't a traditional \"exception\" need."},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"No"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Unknown"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"FullName":{"value":"Glucocorticoid therapy"}}}}]},"FullName":{"value":"Infertility/subfertility in females"}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Notes":{"value":"Hyperandrogenism is estimated to affect approximately 10% of the female population. Among these women, the prevalence of non-classic congenital hyperplasia (NCCAH) due to 21-hydroxylase deficiency is estimated to range between 1-10% depending on the ethnicity, with a worldwide estimate of 4.2% of hyperandrogenic women. While it is expected that NCCAH would occur equally in men and women, only a few case reports and small series have been reported in men."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000811"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"In NCCAH there is mild deficiency (30-50%) of the activity of the 21-hydroxylase enzyme resulting in androgen excess. These individuals have postnatal onset with signs of hyperandrogenism.\\n\\nFemales are not virilized at birth (as in the classic form), though postnatal virilization can occur. Symptoms of androgen excess may include acne, premature development of pubic hair, accelerated growth, advanced bone age, and reduced adult stature due to premature epiphyseal fusion. Other symptoms in females can include hirsutism, frontal baldness, delayed menarche, ovulatory and menstrual dysfunction, and infertility. Polycystic ovarian morphology is a frequent finding in females with NCCAH. Most women with NCCAH will conceive spontaneously; however, between 10-30% of NCCAH women or reproductive age complain of infertility or subfertility, mainly due to anovulation. Affected adult females are more likely to have gender dysphoria, experience less heterosexual interest, and reduced satisfaction with the assignment to the female sex.  \\n\\nData regarding adult males with NCCAH are extremely limited, therefore it appears that the great majority of male patients are asymptomatic with most identified during genetic screening. Males with NCCAH may have early beard growth, gynecomastia, and an enlarged phallus with relatively small testes. Typically, men have normal sperm counts and do not have impaired gonad function. Testicular adrenal rest tumors are quite uncommon but may occur. Males do not show a general alteration in gender identity or sexual orientation. \\n\\nThere is limited data to suggest an association with adrenal hyperplasia and adenoma, insulin resistance, obesity, metabolic syndrome, and exercise intolerance, and cardiovascular events with both classic CAH and NCCAH."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000811"}},{"Reference":{"value":"/coll/reference_model/doc/RF000812"}},{"Reference":{"value":"/coll/reference_model/doc/RF000813"}},{"Reference":{"value":"/coll/reference_model/doc/RF000814"}},{"Reference":{"value":"/coll/reference_model/doc/RF000810"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"NCCAH may present any time postnatally. Most children with NCCAH are asymptomatic in the prepubertal years with premature pubarche, menstrual irregularities (females), and gynecomastia (males) often occurring as the first presentation. Women who present with NCCAH symptoms as adults typically present with hirsutism, acne, androgenic alopecia, and/or clitoromegaly."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000811"}},{"Reference":{"value":"/coll/reference_model/doc/RF000812"}},{"Reference":{"value":"/coll/reference_model/doc/RF000813"}},{"Reference":{"value":"/coll/reference_model/doc/RF000814"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1189","properties":{"Key Text":{"value":"Treatment for patient-important hyperandrogenism"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Treatment is suggested for NCCAH only in adults with patient-important hyperandrogenism with the option of discontinuing treatment once symptoms resolve."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000811"}},{"Reference":{"value":"/coll/reference_model/doc/RF000812"}},{"Reference":{"value":"/coll/reference_model/doc/RF000815"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC276","properties":{"Recommendation":{"value":"In adult women with NCCAH, ovarian androgen suppression or peripheral androgen blockade are more effective than glucocorticoids for reducing circulating androgens and their effects. One controlled randomized trial on a series of 30 patients compared the effectiveness of cyproterone acetate (CPA) versus hydrocortisone. Based on the hirsutism score, CPA was more effective than hydrocortisone (hirsutism improved in 54% and 24% patients, respectively). In another randomized trial including 28 patients, CPA associated with ethinylestradiol was found to be superior to dexamethasone (hirsutism improved in 66% and 31% patients, respectively)."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000811"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1190","properties":{"Key Text":{"value":"Infertility/subfertility treatment"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Women should be counseled regarding an increased risk of infertility. Treatment is suggested in adults with NCCAH with patient-important infertility. Adult women with NCCAH who have not conceived spontaneously and who demonstrate overt or subclinical ovulatory dysfunction may benefit from glucocorticoids or from ovulation induction. In a recent study of 38 patients who presented with oligo-amenorrhea before treatment, 27 achieved regular menstrual cycles with hydrocortisone treatment (average dose: 17.5 ± 7.5mg/day). Among the 11 patients presenting with amenorrhea before treatment, only three still had amenorrhea after glucocorticoid-only treatment. Plasma testosterone and androstenedione concentrations decreased significantly in all patients. In one study the rate of singleton live birth was higher in NCCAH women diagnosed and treated for their disorder prior to conceiving that in those patients who conceived spontaneously (86% versus 69%); there were no difference in the rate of ectopic pregnancy, preterm birth, stillbirths, twins or multiple pregnancies. Evidence is mixed regarding the continuation of glucocorticoid treatment during pregnancy to potentially reduce pregnancy loss and there are no clear guidelines concerning treatment during pregnancy."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Infertility/subfertility in females"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000811"}},{"Reference":{"value":"/coll/reference_model/doc/RF000812"}},{"Reference":{"value":"/coll/reference_model/doc/RF000815"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":">1-2 in 100"},"Tier":{"value":"3"},"Notes":{"value":"The vast majority of NCCAH patients seeking medical attention are associated with CYP21A2 pathogenic variants. As such, it can be estimated that the prevalence of CYP21A2 variants resulting in NCCAH is near the population prevalence of the disease cited above."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000811"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE608","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"Adult Women:\\n-Overt ovulatory and menstrual dysfunction: 30-50%\\n-Polycystic ovarian morphology: 24-44%\\n-Infertility: 10-30%\\n-Subfertility: ~50%\\n-Spontaneous miscarriage: 25% of pregnancies \\n-Hirsutism: 60-80% \\n-Acne: ~33% \\n-Clitoromegaly: 6-20%\\n-Alopecia: 2-8%\\n\\nAdult Men:\\n-Testicular adrenal rest tumors: Unknown; rare"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Infertility/subfertility in females"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000811"}},{"Reference":{"value":"/coll/reference_model/doc/RF000812"}}]}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN280","properties":{"Key Text":{"value":"Because many patients are compound heterozygotes for two or more different mutant CYP21A2 alleles with varying impacts on enzyme function, a wide spectrum of phenotypes may be observed."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000812"}}]},"Tier":{"value":"3"}}}},{"Expressivity Note":{"value":"EN279","properties":{"Key Text":{"value":"The NCCAH phenotype may be highly variable even with a family sharing the same CYP21A2 genotype."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000811"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI284","properties":{"Key Text":{"value":"Glucocorticoid overtreatment may cause Cushing syndrome. As such, glucocorticoids are recommended in only a subset of patients with NCCAH and require monitoring."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000812"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC277","properties":{"Key Text":{"value":"NCCAH is often not diagnosed until adolescence when the first symptoms appear. Reduced fertility may be the only symptom of disease."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000814"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2018-07-16"},"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"jenniferposey"}},{"Scorer":{"value":"alexanderkatz"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"srego"}}]},"Notes":{"value":""}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Overall Score":{"value":"7CB"},"Effectiveness":{"value":"1B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":10,"items":[{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"jvengoe","properties":{"First Name":{"value":"Jaime"},"Last Name":{"value":"Vengoechea"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"jenniferposey","properties":{"First Name":{"value":"Jennifer"},"Last Name":{"value":"Posey"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"alexanderkatz","properties":{"First Name":{"value":"Alexander"},"Last Name":{"value":"Katz"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":10,"items":[{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"would prefer to call this moderate morbidity rather than modest, which sounds more minimal, but we have a category for this"}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"A bit of a judgment call regarding whether the morbidity is modest or major. Worth a discussion. \\n\\nAs I read this I'm also thinking that perhaps males and females should have been scored separately...the implications seem much, much more significant for females and I'm thinking the scores between M and F would be quite different..."}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"Again, see my note above about scoring males and females separately. I'm doing this basically as though a female was discovered with a relevant variant..."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":"With appropriate monitoring Cushing syndrome should be readily avoided"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"With appropriate monitoring Cushing syndrome should be readily avoided"}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"Trying to balance the apparent ineffectiveness c/w CPA with some level of benefit from comparing glucocorticoids to no treatment."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"jvengoe","properties":{"First Name":{"value":"Jaime"},"Last Name":{"value":"Vengoechea"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"0","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"jenniferposey","properties":{"First Name":{"value":"Jennifer"},"Last Name":{"value":"Posey"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"I considered Infertility + subfertility"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"alexanderkatz","properties":{"First Name":{"value":"Alexander"},"Last Name":{"value":"Katz"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Small sample size"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"I could also see scoring this a 0"}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"Could go with a 2 depending how you would administer therapy and how often one would have side effects."}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"0-1 ?"}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"based on range of PCOS and Infertility"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":"1-2 based on 86% vs 69%"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Infertility/subfertility in females","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Glucocorticoid therapy","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.1","properties":{"Notes":{"value":"Initial release\nInternal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36185},"ReasonCode":{"value":"Q0","properties":{"Reason":{"value":"Initial Release"}}},"Date":{"value":"2018-07-17"},"ReleasedBy":{"value":"mittendorfkf","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Mittendorf"}}}}}}}},
{"ActionabilityDocID":{"value":"AC152","properties":{"Status":{"value":"Released"},"Genes":{"value":2,"items":[{"Gene":{"value":"POLE","properties":{"HGNCId":{"value":"HGNC:9177"},"GeneOMIM":{"value":"174762"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"615083"}}]}}}},{"Gene":{"value":"POLD1","properties":{"HGNCId":{"value":"HGNC:9175"},"GeneOMIM":{"value":"174761"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"612591"}}]}}}}]},"Syndrome":{"value":"POLE and POLD1 associated susceptibility to CRC","properties":{"OmimIDs":{"value":2,"items":[{"OmimID":{"value":"615083"}},{"OmimID":{"value":"612591"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"447877"}}]},"Overview":{"value":""},"Acronyms":{"value":0,"items":[]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"POLD1","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2018-07-05"},"Notes":{"value":""},"Label":{"value":"POLD1"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"No"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"No"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Colorectal Cancer (POLE)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy"}}]}}}},{"Outcome":{"value":"Colorectal Cancer (POLD1)","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy"}}]}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"The prevalence of colorectal cancer (CRC) cases associated variants in POLE and POLD1 is unclear. An estimated 3-5% of CRC cases are caused by high-penetrance germline mutations and only a small proportion of these would be expected to be associated with pathogenic variants in POLE or POLD1. A study of 858 familial/early-onset CRC cases and polyposis, one POLE and one POLD1 pathogenic variant were identified."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000830"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"POLE and POLD1 associated susceptibility to CRC is characterized by a predisposition to the development of colorectal polyposis, adenomas, carcinomas. Available data suggest a phenotype characterized by attenuated or oligoadenomatous colorectal polyposis with a reported range of 0-68 adenomas upon examination. The histologic features of the tumors may be unremarkable or show microsatellite instability. The phenotype appears to overlap with that of Lynch syndrome and attenuated adenomatous polyposis. A broader extracolonic spectrum of cancers has been noted as additional carrier families are identified, including cancers of the endometrium, ovaries, pancreas, brain, and small intestine. However, evidence on these associations is still limited. Thus, the recommendations in this report are focused on CRC."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000830"}},{"Reference":{"value":"/coll/reference_model/doc/RF000226"}},{"Reference":{"value":"/coll/reference_model/doc/RF000831"}},{"Reference":{"value":"/coll/reference_model/doc/RF000828"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"A study of 47 individuals (from 20 families) with a POLE pathogenic variant reported that 30 individuals developed CRC with a mean age of onset of 40.7 years. In 22 individuals (from 8 families) with a POLD1 pathogenic variant, 13 developed CRC with a mean age of onset of 35.9 years."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000830"}},{"Reference":{"value":"/coll/reference_model/doc/RF000832"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1191","properties":{"Key Text":{"value":""},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"No recommendations for patient management were identified."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU634","properties":{"Key Text":{"value":"Colonoscopy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Colonoscopy should be performed every 1-3 years starting at ages 20-30 with the interval based on the finding of polyps and with consideration of surgery if the polyp burden becomes unmanageable by colonoscopy. Data to support the surveillance recommendations are currently evolving, therefore colonoscopy regimens should consider patient preferences and new knowledge that may emerge."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal Cancer (POLE)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000832"}},{"Reference":{"value":"/coll/reference_model/doc/RF000833"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC047","properties":{"Recommendation":{"value":"Evidence on the effectiveness of colonoscopy in individuals with a POLE and POLD1 associated susceptibility to CRC was not identified. However, evidence indicates that screening in individuals with Lynch Syndrome and familial adenomatous polyposis (FAP) decreases the risk of CRC. In a systematic review of individual with Lynch Syndrome, five out of six studies found a significantly reduced incidence rate of CRC with surveillance (OR estimates ranged from 0.11 to 0.35), while the sixth study reporting an OR of 0.93 was not significant. Two out of four studies showed a significant reduction in CRC-related mortality with surveillance (OR estimates range from 0.04 to 0.17), while three of the four studies reported no mortality in the study arm with surveillance. Among individuals with FAP, 26 of 27 studies showed a statistically significant reduction in CRC incidence with surveillance (ORs ranged from 0.01 to 0.37) in screened patients compared to those who presented symptomatically with polyposis/CRC outside of a screening program. Eight studies examined CRC mortality, all of which showed a significant reduction in CRC mortality (ORs ranged from <0.01 to 0.16) in screened (N= 1028) versus symptomatic groups (N= 947). Two studies provided evidence for complete prevention of CRC-related deaths during surveillance, although the duration of follow-up was short (2-4 years)."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000114"}}]}}}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA533","properties":{"Key Text":{"value":""},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"No recommendations related to circumstances to avoid were identified."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"No information on the prevalence of pathogenic variants in POLD1 or POLE was identified."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]}}},"Penetrances":{"value":2,"items":[{"Penetrance":{"value":"ACPE609","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"1"},"Notes":{"value":"A systematic review of pedigree studies of families with a germline POLE or POLD1 variant modeled the cumulative risk of CRC based on segregation analysis adjusted for ascertainment of families. Not all individuals in these pedigrees were genotyped. \\nThe cumulative risk of CRC to age 70 years for individuals with a POLE pathogenic variant was estimated to be 28% (95% CI: 10-42%) for males and 21% (95% CI: 7-33%) for females. For those specifically with the c.1270C >G, p.Leu424Val variant (19 families) the estimated risk of CRC by age 70 was 97% (95% CI: 85-99%) for males and 92% (95% CI: 75-99%) for females.\\nThe cumulative risk of CRC to age 70 years for individuals with a POLD1 pathogenic variant was estimated to be 90% (95% CI: 33-99%) for males and 82% (95% CI: 26-99%) for females."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal Cancer (POLE)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000830"}}]}}}},{"Penetrance":{"value":"ACPE610","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"5"},"Notes":{"value":"A smaller study with genotypic information on all participants found that among 47 individuals (from 20 families) with a POLE pathogenic variant, CRC was identified in 30/47 carriers (63.8%). Among 22 individuals (from 8 families) with a POLD1 pathogenic variant, CRC was identified in 13/22 carriers (59.1%)."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000832"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR250","properties":{"Key Text":{"value":">3"},"Notes":{"value":"Compared with the general population the hazard ratios (HR) for development of CRC for individuals with a pathogenic variant in POLE was estimated to be 12.2 (95% CI: 7.35-20.2) with the HR decreasing with age: 38.7 (95% CI: 17.5-85.4) before age 50 and 8.21 (95% CI: 4.24-15.9) for ages ≥50. The estimated HR for pathogenic variants in POLD1 was 87.2 (95% CI: 15.3-495): 201 (95% CI: 62.0-651) before age 50 and 3.34 (95% CI: 0.22-50.1) for ages ≥50. No differences in hazard ratios were identified by sex."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000830"}}]},"Tier":{"value":"1"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN281","properties":{"Key Text":{"value":"No information on expressivity was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI285","properties":{"Key Text":{"value":"The recommended interventions include colonoscopy with polypectomy."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC278","properties":{"Key Text":{"value":"The age recommended to begin screening for CRC is earlier than that currently recommended for the general population. 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The disease is more frequent in the Ashkenazi Jewish population, with heterozygosity in 8-9% and homozygosity in 0.2-0.5%."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000743"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000835"}},{"Reference":{"value":"/coll/reference_model/doc/RF000671"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"FXI deficiency is a bleeding disorder due to reduced plasma FXI levels. Spontaneous bleeding is rare even with low factor levels, with bleeding usually occurring after circumcision, dental extractions, trauma, or surgery. Hemorrhages are usually moderate and can occur at sites rich in fibrinolytic activity, such as the oral and nasal mucosa, and genitourinary system. Women are at risk for menorrhagia, bleeding during childbirth and miscarriage, as well as post-partum hemorrhage (PPH). Intracranial bleeding is very uncommon."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000743"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000835"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000276"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"FXI deficiency affects both sexes equally and manifests at any age. Severely low FXI levels are typically seen in homozygotes or compound heterozygotes and partial deficiency in heterozygotes. Most heterozygotes are asymptomatic, but patients with even mild reductions in FXI may have a bleeding tendency. Plasma levels of FXI show poor correlation with bleeding symptoms. The condition is associated with a variable bleeding tendency even in the same individual. The unpredictable nature of FXI deficiency makes management more difficult. The risk of PPH in women is highest in those with a bleeding phenotype and of blood group O (26.4% in blood group O vs 6.3% in non-O group)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000835"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000276"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1194","properties":{"Key Text":{"value":"Assessment for additional risk factors"},"Tier":{"value":"2"},"Recommendation Text":{"value":"It is likely that other clotting factors, such as VWF and platelet function, play a role in determining the bleeding tendency. Thus, patients with FXI deficiency should be assessed for the presence of other potentially confounding factors, such as low VWF levels and platelet dysfunction."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000743"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000691"}}]}}}},{"Patient Management":{"value":"ACPM1195","properties":{"Key Text":{"value":"Therapeutic options"},"Tier":{"value":"2"},"Recommendation Text":{"value":"As spontaneous bleeding is uncommon in FXI deficiency, management usually comprises treatment of traumatic bleeds and prevention of surgical or obstetric bleeding. Therapeutic options include incrementing FXI levels by administration of fresh frozen plasma (FFP) or the administration of FXI concentrates and through use of antifibrinolytic agents (such as tranexamic acid). Cases with FXI deficiency should be identified as at a higher risk of bleeding if the FXI activity is <0.1 IU/ml or if there is another coagulopathy, a personal history of bleeding or if surgery comprises dental extraction or involves the oropharyngeal or genitourinary mucosa. Consider tranexamic acid for minor bleeds or minor surgery in higher bleeding risk cases, and for all bleeds or surgery in low bleeding risk cases. Consider FXI concentrate without additional tranexamic acid for severe bleeds or major surgery in high bleeding risk cases."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000743"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000276"}},{"Reference":{"value":"/coll/reference_model/doc/RF000691"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC279","properties":{"Recommendation":{"value":"One study evaluated 86 patients over 242 treatment episodes of FXI concentrate for emergency or elective situations. There were eight (3.3%) episodes of persistent bleeding post-concentrate."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000836"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1193","properties":{"Key Text":{"value":"Dental Management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Dental management in patients with inherited bleeding disorders should involve a liaison between a hemophilia center, hospital dentist, and general dental practice regarding the nature of the disorder, treatment plans, and risk of transfusion-transmitted infection. Each hemophilia follow-up visit should document the oral health status and advice about preventive care. Treatment planning during dental procedures is essential for good outcome.  Coagulation factors should be provided for inferior dental block, lingual infiltration, and invasive dental procedures."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000276"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC280","properties":{"Recommendation":{"value":"One study evaluated 19 patients with severe factor XI deficiency who had previously bled following dental extractions (14 patients) or other trauma (5 patients). Tranexamic acid was given from 12 h before surgery, until 7 days afterwards. No excessive bleeding was observed following dental extractions. One patient had slight oozing after 3 days which ceased spontaneously."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000837"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1197","properties":{"Key Text":{"value":"Pregnancy Management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Pregnancy in women with FXI deficiency requires specialized and individualized care provided collaboratively by an obstetrician, hematologist and anesthetist.  Pregnancy management recommendations include:\n• Treatment plans around labor and delivery plans should be individualized and made in advance due to the unpredictable nature of bleeding. Factors to consider are: personal history of bleeding, family history of bleeding, mode of delivery, previous obstetric history, blood group, FXI level (if low)\n• Delivery should occur at a unit with expertise in the management of this disorder and resources for laboratory testing and clotting factor treatments readily available\n• Though FXI levels usually remain constant during pregnancy, they can change; thus, levels should be checked at booking, third trimester, and prior to invasive procedures\n• Patients with low FXI levels or a bleeding history should be given prophylaxis to cover invasive procedures\n• Central neuraxial anesthesia should not be given to women with low FXI levels with a known bleeding phenotype, where the phenotype is not clear, or when there is a severe reduction in level given the risk of a spinal hematoma with compression of the spinal cord; in those with a nonbleeding phenotype, discussion and counseling should be given regarding the risks and benefits of neuraxial anesthesia with or without factor replacement \n• Active management of third stage should be practiced, with prophylactic treatment with tranexamic acid considered post-delivery"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC278","properties":{"Recommendation":{"value":"Among 61 pregnancies and 49 live births in 30 women with FXI deficiency there was no significant change in FXI levels during pregnancy. Among women with a history of bleeding, PPH occurred after 3/19 deliveries when prophylaxis was given and after 3/3 deliveries when prophylaxis was not given. Of the 38 pregnancies where the woman was known to have FXI deficiency prior to delivery, intrapartum prophylaxis with FXI concentrate or tranexamic acid was given in 19 deliveries where the mother had a positive bleeding history, with no PPH in 16, primary PPH in 1 case, and secondary PPH in 2. Three cases had a bleeding history, but did not have prophylaxis, and all 3 had a primary PPH. The remaining 16 cases had no bleeding history and prophylaxis was given; PPH occurred after 4/16 of these deliveries."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000838"}}]}}}},{"RecommendationID":{"value":"REC277","properties":{"Recommendation":{"value":"Within a retrospective study of 62 women with low FXI levels, PPH occurred in 24% (32/132) not covered by FFP and in 14% (2/14) of vaginal deliveries covered by FFP. In none of the 34 vaginal deliveries associated with bleeding was this complication life-threatening, and in only 12 deliveries (35.5%) was blood transfusion or plasma replacement therapy given. PPH occurred in 16.7% (2/12) of cesarean deliveries not covered by FFP and in none of the six cesarean deliveries covered by FFP. Overall, 43 women (69%) never experienced PPH during 164 deliveries."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000839"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1196","properties":{"Key Text":{"value":"Menorrhagia management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Management of menorrhagia in women with inherited bleeding disorders should be provided by a multidisciplinary team including a hematologist and gynecologist to ensure optimal outcomes. Specific hemostatic therapy will be required in some women to control menorrhagia. Medical treatment of menorrhagia in women with inherited bleeding disorders include tranexamic acid, combined oral contraceptive pills, DDAVP (desmopressin), cyclical 21-days oral progesterone, and the levonorgestrel intrauterine device. The treatment choice depends on the type of bleeding disorder, and patient’s age, childbearing status and preferences in terms of the perceived efficacy and side effects."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000749"}}]}}}},{"Patient Management":{"value":"ACPM1192","properties":{"Key Text":{"value":"Other gynecological bleeding management"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Women with inherited bleeding disorders are more likely to be symptomatic from gynecological problems that are associated with bleeding. Awareness of an underlying bleeding disorder will allow appropriate management."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000294"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU635","properties":{"Key Text":{"value":"Not available"},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"Information on surveillance in individuals with FXI deficiency was not available."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA534","properties":{"Key Text":{"value":"Avoidance of NSAIDs"},"Tier":{"value":"2"},"Recommendation Text":{"value":"NSAID (nonsteroidal anti-inflammatory drugs) use is contraindicated in individuals with inherited bleeding disorders due to their anti-aggregation effect on platelet function."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000294"}},{"Reference":{"value":"/coll/reference_model/doc/RF000840"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"},"Notes":{"value":"Autosomal Dominant"},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Tier":{"value":"5"},"Notes":{"value":"One study performed molecular testing in 25 index cases with FXI plasma levels below 50 IU dL. They identified disease-associated variants in F11 in 24 of the 25 cases. Of these 24 cases with disease-associated variants in F11, 22 patients were heterozygous, and two patients were homozygous."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000841"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC070","properties":{"Recommendation":{"value":"These results indicate that pathogenic variants in F11 are likely to have a similar prevalence as that estimated for FXI deficiency, or 1 to 33 per 1,000,000."},"Tier":{"value":"Not provided"},"References":{"value":null,"items":[]}}}}]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE612","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"In two UK series of 128 cases with FXI deficiency (based on FXI levels and not genotype), approximately 65% were asymptomatic. In the remainder, the most common symptoms were bleeding after surgery and trauma."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000743"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC081","properties":{"Recommendation":{"value":"Most studies of heterozygotes suggest that 20-50% of partially FXI deficient individuals bleed excessively."},"Tier":{"value":"3"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000834"}}]}}}}]}}}},{"Penetrance":{"value":"ACPE613","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"Pregnant female patients with FXI levels <15 IU dL have a 16–30% risk of excessive bleeding during delivery."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000294"}}]}}}},{"Penetrance":{"value":"ACPE611","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"3"},"Notes":{"value":"The risk of PPH is increased in women with FXI deficiency, in both homozygotes and heterozygotes, with an overall risk of 16-22%."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR251","properties":{"Key Text":{"value":">3"},"Notes":{"value":"This risk of PPH is increased in those with a bleeding phenotype, with a relative risk of 7.2 (95% CI 1.99 - 25.90)."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000679"}}]},"Tier":{"value":"3"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN282","properties":{"Key Text":{"value":"There is intra- and inter-individual variation in bleeding phenotype. Clinical phenotypes vary even among individuals with the same factor level, and the bleeding tendency can also be variable in the same individual in response to different hemostatic challenges."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}}]},"Tier":{"value":"3"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI286","properties":{"Key Text":{"value":"Interventions identified for FXI include treatment for bleeding episodes or prophylactic coverage for surgery using FXI concentrate, FFP, and antifibrinolytic agents (such as tranexamic acid). Issues with FXI concentrate are the risk of thrombosis and (rarely) inhibitor development in patients with very low FXI levels. There is also a very rare risk of transfusion-transmitted infection or allergic reactions. Tranexamic acid is generally well tolerated, with nausea and diarrhea as the most common side effects."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000743"}},{"Reference":{"value":"/coll/reference_model/doc/RF000679"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC011","properties":{"Recommendation":{"value":"One study evaluated 86 patients over 242 treatment episodes of FXI concentrate for emergency or elective situations. There were 4 (1.7%) non-bleeding adverse events: two recorded inhibitors, one thrombotic event (central retinal artery occlusion), and one transfusion reaction. No patient suffering an adverse event had long-term morbidity."},"Tier":{"value":"Not provided"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000836"}}]}}}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC279","properties":{"Key Text":{"value":"Bleeding episodes in patients with FXI are unpredictable and vary in response to different hemostatic challenges. Undiagnosed and untreated patients with FXI deficiency can develop significant hematomas after a surgical procedure."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000835"}},{"Reference":{"value":"/coll/reference_model/doc/RF000294"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2018-10-01"},"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"evansjames"}},{"Scorer":{"value":"murugumanickam"}},{"Scorer":{"value":"jenniferposey"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"srego"}},{"Scorer":{"value":"odanielj"}}]},"Notes":{"value":""}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Overall Score":{"value":"10CN"},"Effectiveness":{"value":"3N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":8,"items":[{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"murugumanickam","properties":{"First Name":{"value":"Murugu"},"Last Name":{"value":"Manickam"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"jenniferposey","properties":{"First Name":{"value":"Jennifer"},"Last Name":{"value":"Posey"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"3N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"3B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"2C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"2B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":8,"items":[{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"3N","properties":{"Notes":{"value":"I could go with a 2 or 3 here."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"I could go with a 2 or 3 here."}}}}}}]}}}}]}}}},{"Scorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last Name":{"value":"Evans"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"One could imagine sudden death due to bleeding during a procedure or childbirth but this would be very unusual."}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"One could argue for the efficacy being moderate but I took into account not only the diminished tendency to bleed with prophylaxis but alsot he fact that when patients do bleed it would not come as a surprise. I did not see much about bad outcomes occurring. So I went with highly effective though we can legitimately argue about that."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"Part of my reasoning for a high score was that the prevention of bad outcomes is only with procedures...in other words, there isn't a need for ongoing, chronic treatment."}}}}}}]}}}}]}}}},{"Scorer":{"value":"murugumanickam","properties":{"First Name":{"value":"Murugu"},"Last Name":{"value":"Manickam"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"jenniferposey","properties":{"First Name":{"value":"Jennifer"},"Last Name":{"value":"Posey"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":"Went with 5-39% based on specific refs (rather than OMIM)"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"Hard to tell the severity of bleeding when it does occur - could go with 2 if sometimes severe.\nAlso, last sentence of Clinical Features could use a tweak, even though women are indeed at risk of childbirth."}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":"I based my score of 3 on the first case since it seemed most inclusive, but would be find going to a 2 as well."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"Not enough info. PPH could be 2, \"moderate hemorrahge\" might be 1. Later PPH is described as mostly not life-threatening."}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":"should evidence be higher given prof guidelines?"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Bleeding complications with pregnancy, procedures or trauma","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team","properties":{"Effectiveness":{"value":"2B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.1","properties":{"Notes":{"value":"Internal system migration related to score text replacement from E to N"},"Public Notes":{"value":"Internal system migration related to score text replacement from E to N"},"kbRevision-PairedKB":{"value":36189},"ReasonCode":{"value":"Q0","properties":{"Reason":{"value":"Initial Release"}}},"Date":{"value":"2018-10-15"},"ReleasedBy":{"value":"marianjgilmore","properties":{"First Name":{"value":"Mari"},"Last Name":{"value":"Gilmore"}}}}}}}},
{"ActionabilityDocID":{"value":"AC154","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"GREM1","properties":{"HGNCId":{"value":"HGNC:2001"},"GeneOMIM":{"value":"603054"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"601228"}}]}}}}]},"Syndrome":{"value":"Hereditary mixed polyposis syndrome 1","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"601228"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"157794"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2018-08-03"},"Notes":{"value":""},"Label":{"value":"OMIM"}}}}]}}}}]},"Status":{"value":"Incomplete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"No"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Unknown"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"webberem","properties":{"First Name":{"value":"Beth"},"Last Name":{"value":"Webber"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"No"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"No"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Unknown"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Colorectal Cancer","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy"}}]}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on the prevalence of hereditary mixed polyposis syndrome (HMPS) was identified. It is unclear what percent of colorectal cancer (CRC) cases are due to a duplication upstream of GREM1.  Screening of 718 familial CRC cases identified 1 individual of Ashkenazi descent with the duplication."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000842"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"HMPS is a genetically heterogeneous condition characterized by the presence of a mixture of hyperplastic, atypical juvenile and adenomatous polyps that are associated with an increased risk of developing colorectal cancer if left untreated. HMPS can be caused by heterozygous upstream duplication on chromosome 15q13-q14 that results in increased ectopic expression of the GREM1 gene, a bone morphogenetic protein (BMP) antagonist. The pathogenesis of polyps in HMPS likely overlaps with juvenile polyposis syndromes caused by inactivating mutations in genes of the BMP pathway. Generally, extra-colonic manifestations have not been noted among families; however, some families have been found to present with clinical features which may overlap with familial adenomatous polyposis (FAP) or Lynch syndrome. Screening within families with an identified duplication upstream of GREM1 have found 1-81 polyps of mixed types."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000842"}},{"Reference":{"value":"/coll/reference_model/doc/RF000843"}},{"Reference":{"value":"/coll/reference_model/doc/RF000844"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"A 40-kb duplication upstream of GREM1 has been identified among a series of Ashkenazi Jewish HMPS families and is considered a potential founder variant. The rearrangement appears to be extremely rare among unselected colonic cancer cases and among non-Ashkenazi patients with multiple hyperplastic polyps. However, additional duplications involving GREM1 have been reported in individuals of unknown or non-Ashkenazi Jewish ancestry.  In general, the age of onset of polyps occurs in the late 20s or older; however, polyps have been reported in individuals as young as 10. Point mutations in GREM1 have also been found to confer an increased risk for CRC; however, this report is focused on individuals with a duplication upstream of GREM1."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000844"}},{"Reference":{"value":"/coll/reference_model/doc/RF000845"}},{"Reference":{"value":"/coll/reference_model/doc/RF000846"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1199","properties":{"Key Text":{"value":"No recommendations for patient management were identified."},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":""},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU637","properties":{"Key Text":{"value":"Colonoscopy"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Colonoscopy should be performed every 1-3 years starting at ages 25-30 with the interval based on the finding of polyps and with consideration of surgery if the polyp burden becomes unmanageable by colonoscopy. Data to support the surveillance recommendations are currently evolving, therefore colonoscopy regimens should consider patient preferences and new knowledge that may emerge."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal Cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000847"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC049","properties":{"Recommendation":{"value":"No evidence was identified related to effectiveness of surveillance in individuals with a GREM1 duplication. However, the cancer risk and age of onset have been stated to be similar to that of attenuated familial adenomatous polyposis. Evidence indicates that screening in individuals with Lynch Syndrome and familial adenomatous polyposis (FAP) decreases the risk of CRC. In a systematic review, five out of six studies found a significantly reduced incidence rate of CRC with surveillance (OR estimates ranged from 0.11 to 0.35), while the sixth study reporting an OR of 0.93 was not significant. Two out of four studies showed a significant reduction in CRC-related mortality with surveillance (OR estimates range from 0.04 to 0.17), while three of the four studies reported no mortality in the study arm with surveillance. Among individuals with FAP, 26 of 27 studies showed a statistically significant reduction in CRC incidence with surveillance (ORs ranged from 0.01 to 0.37) in screened patients compared to those who presented symptomatically with polyposis/CRC outside of a screening program. Eight studies examined CRC mortality, all of which showed a significant reduction in CRC mortality (ORs ranged from <0.01 to 0.16) in screened (N= 1028) versus symptomatic groups (N= 947). Two studies provided evidence for complete prevention of CRC-related deaths during surveillance, although the duration of follow-up was short (2-4 years)."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000114"}}]}}}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA536","properties":{"Key Text":{"value":"No recommendations for circumstances to avoid were identified."},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":""},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":""},"References":{"value":null,"items":[]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"No information was identified on the prevalence of upstream duplications of GREM1."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]}}},"Penetrances":{"value":4,"items":[{"Penetrance":{"value":"ACPE620","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"No studies were identified indicating the percent of individuals with a duplication upstream of GREM1 who develop CRC."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal Cancer"}}]},"References":{"value":null,"items":[]}}}},{"Penetrance":{"value":"ACPE618","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"5"},"Notes":{"value":"Within one large kindred ascertained through a 21-year-old proband with metastatic colon cancer, 18 family members were evaluated within a 3-generation pedigree. Polyps were seen in all 10 family members who tested positive for the duplication upstream of GREM1 (range: 1-40 polyps, mean: 14.1). Multiple polyps were identified in every affected family member over the age of 20."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal Cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000845"}}]}}}},{"Penetrance":{"value":"ACPE621","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"5"},"Notes":{"value":"In a single extended family from an inherited CRC registry, 51 colonoscopies (range per individual: 1-15) were performed among 10 patients with a confirmed GREM1 duplication. Mean age of presentation of patients was 33.3 years (range 9-52) with patients tending to present because of family history of polyposis or rectal bleeding. One patient presented with CRC at age 52 before engaging in surveillance. No other carcinomas were detected during in the cohort surveillance (mean years of follow up 26.2, range 1-59 years). All individuals were found to have polyps (ranging from 4-81) mainly comprised of adenomas and mixed hyperplastic/inflammatory polyp types."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal Cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000848"}}]}}}},{"Penetrance":{"value":"ACPE619","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"5"},"Notes":{"value":"Within a study of 16 individuals from 4 families with a GREM1 duplication, 2 individuals (probands) were identified with CRC (ages 41-49)."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Colorectal Cancer"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000844"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR253","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN284","properties":{"Key Text":{"value":"No information on expressivity was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI288","properties":{"Key Text":{"value":"The recommended interventions include colonoscopy with polypectomy."},"References":{"value":null,"items":[]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC281","properties":{"Key Text":{"value":"The age recommended to begin screening for CRC and precursor lesions is earlier than that currently recommended for the general population. Therefore, it is likely that individuals could develop CRC before general screening would commence."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Colorectal Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Overall Score":{"value":"7DB"},"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"Extrapolated from Lynch Syndrome and familial adenomatous polyposis."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":11,"items":[{"FinalScoreOfScorer":{"value":"evansjames","properties":{"First Name":{"value":"Jim"},"Last 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Given that poor evidence, it looks like the outcome of CRC is low, thus my score of \"1\" for penetrance. Scoring \"excess polyp formation\" would have yielded a higher score..."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":"I rated the intervention as highly efficacious, which I think is likely correct. But I dinged the evidence level because we have very poor data on this condition and we're extrapolating."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"This should be the same burden that we came up with for Lynch, FAP, etc."}}}}}}]}}}}]}}}},{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Colorectal Cancer","properties":{"Severity":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":"For consideration: if lifetime risk for CRC is about 4%, these carriers are greater than that, but not likely >40%."}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"Not Scored","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Colorectal Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"Extrapolated and dropped the evidence level"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"jenniferposey","properties":{"First Name":{"value":"Jennifer"},"Last Name":{"value":"Posey"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Colorectal Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":"Although the likelihood is not really known, I am reluctant to score '0', as the available evidence across the 3 reports (36 individuals in 6 families, with 4 having CA = 11%) suggests the likelihood is not close to 1%"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Colorectal Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"3C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"murugumanickam","properties":{"First Name":{"value":"Murugu"},"Last Name":{"value":"Manickam"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Colorectal Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":"Based on no specific information for GREM1 and unknown penetrance"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Colorectal Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":"How have we scored colonoscopy for nature of intervention in the past? I'm happy to change my score to align with past colonoscopy scores if it's different."}}}}}}]}}}}]}}}},{"Scorer":{"value":"alexanderkatz","properties":{"First Name":{"value":"Alexander"},"Last Name":{"value":"Katz"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Colorectal Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Colorectal Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":"Tier 1 evidence was for FAP, so extrapolate and call it Tier 2?"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Colorectal Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0D","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Extrapolated from APC and degraded the evidence level."}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Colorectal Cancer","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":"Assume penetrance of polyps not CRC"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Colonoscopy with polypectomy","properties":{"Effectiveness":{"value":"3B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.1","properties":{"Notes":{"value":"Reopened this topic to fix an error: Stage 2 updated to \"complete.\""},"Public Notes":{"value":""},"kbRevision-PairedKB":{"value":36511},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffected"}}},"Date":{"value":"2019-01-19"},"ReleasedBy":{"value":"wallkat","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Wallace"}}}}}}}},
{"ActionabilityDocID":{"value":"AC155","properties":{"Status":{"value":"Released"},"Genes":{"value":3,"items":[{"Gene":{"value":"DES","properties":{"HGNCId":{"value":"HGNC:2770"},"GeneOMIM":{"value":"125660"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"601419"}}]}}}},{"Gene":{"value":"BAG3","properties":{"HGNCId":{"value":"HGNC:939"},"GeneOMIM":{"value":"603883"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"612954"}}]}}}},{"Gene":{"value":"FLNC","properties":{"HGNCId":{"value":"HGNC:3756"},"GeneOMIM":{"value":"102565"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"609524"}}]}}}}]},"Syndrome":{"value":"Myofibrillar Myopathy","properties":{"OmimIDs":{"value":3,"items":[{"OmimID":{"value":"612954"}},{"OmimID":{"value":"601419"}},{"OmimID":{"value":"609524"}}]},"OrphanetIDs":{"value":3,"items":[{"OrphanetID":{"value":"171445"}},{"OrphanetID":{"value":"199340"}},{"OrphanetID":{"value":"98909"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"OMIM","properties":{"NumberOfHits":{"value":0},"Date":{"value":"2018-09-06"},"Notes":{"value":""},"Label":{"value":""}}}}]}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Unknown"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"marianjgilmore","properties":{"First Name":{"value":"Mari"},"Last Name":{"value":"Gilmore"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Unknown"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Clinically significant cardiac involvement (DES)","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Cardiology management","properties":{"FullName":{"value":"Cardiology management"}}}},{"Intervention":{"value":"ICD implantation","properties":{"FullName":{"value":"ICD implantation"}}}}]},"FullName":{"value":"Clinically significant cardiac involvement (DES)"}}}},{"Outcome":{"value":"Clinically significant cardiac involvement (FLNC)","properties":{"Interventions":{"value":2,"items":[{"Intervention":{"value":"Cardiology management","properties":{"FullName":{"value":"Cardiology management"}}}},{"Intervention":{"value":"ICD implantation","properties":{"FullName":{"value":"ICD implantation"}}}}]},"FullName":{"value":"Clinically significant cardiac involvement (FLNC)"}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"The overall prevalence of myofibrillar myopathy (MFM) is currently undetermined. The prevalence of DES-related MFM has been estimated to be 0.17 in 100,000. However, the prevalence of BAG3- and FLNC- related MFM was not available."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000852"}},{"Reference":{"value":"/coll/reference_model/doc/RF000853"}},{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"The diagnosis of MFM is traditionally based on common morphologic features on muscle biopsy.  Pathogenic variants in DES, FLNC and BAG3 are responsible for a subset of MFM cases. Cardiac manifestations of MFM include cardiomyopathy (dilated, hypertrophic, restrictive or left ventricular noncompaction) and arrhythmia (atrioventricular conduction block, atrial fibrillation, other tachyarrhythmias and cardiac conduction defects). MFM is characterized by slowly progressive muscle weakness, from distal to proximal lower extremities with eventual involvement of upper extremities, trunk, facial and respiratory muscles as the disease progresses."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000852"}},{"Reference":{"value":"/coll/reference_model/doc/RF000853"}},{"Reference":{"value":"/coll/reference_model/doc/RF000664"}},{"Reference":{"value":"/coll/reference_model/doc/RF000854"}},{"Reference":{"value":"/coll/reference_model/doc/RF000849"}},{"Reference":{"value":"/coll/reference_model/doc/RF000851"}},{"Reference":{"value":"/coll/reference_model/doc/RF000850"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"MFM typically presents in adulthood starting around 30-50 years of age (range 2-77 years); the majority of cases present after age 40 years. However, presentation of BAG3-related MFM characteristically occurs earlier, in the first and second decades of life, and is often fatal. Patients with this subtype typically experience rapid progression and are often severely affected by the second decade and require cardiac transplant, respiratory ventilation, and/or a wheelchair. DES-related MFM can also present as early as the first decade (range: first to sixth decade). In cases of childhood onset, the disease is rapidly progressive and leads to debilitating contractures, cardiomyopathy, and cardiorespiratory failure. Cardiomyopathy is more common in patients with pathogenic variants in DES and BAG3. Cardiac involvement onset in DES-related disease has been observed from first to seventh decades of life, with cardiomyopathy occurring more often in males than females. In DES-related MFM, cardiac involvement often precedes muscle weakness. Respiratory involvement can lead to death. While most cases are heterozygous, some homozygous or compound heterozygous cases have been described with pathogenic variants in DES; these cases manifested earlier and had more rapid progression, while heterozygous carriers in these kindreds were unaffected."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000852"}},{"Reference":{"value":"/coll/reference_model/doc/RF000853"}},{"Reference":{"value":"/coll/reference_model/doc/RF000664"}},{"Reference":{"value":"/coll/reference_model/doc/RF000854"}},{"Reference":{"value":"/coll/reference_model/doc/RF000849"}},{"Reference":{"value":"/coll/reference_model/doc/RF000851"}},{"Reference":{"value":"/coll/reference_model/doc/RF000850"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1214","properties":{"Key Text":{"value":"Multidisciplinary Clinic"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Clinicians should refer patients to a multidisciplinary clinic (including cardiology, physical therapy and occupational therapy) designed specifically to care for patients with neuromuscular diseases (NMDs). This recommendation is based on evidence in the setting of amyotrophic lateral sclerosis (ALS), indicating that a multidisciplinary approach is associated with improved survival, higher quality of life, increased use of treatments and interventions, and increased use of adaptive equipment."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":""}},{"Outcome":{"value":"Clinically significant cardiac involvement (DES)"}},{"Outcome":{"value":"Clinically significant cardiac involvement (FLNC)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000853"}},{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}},{"Patient Management":{"value":"ACPM1210","properties":{"Key Text":{"value":"Baseline Cardiac Evaluation"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Individuals should undergo a baseline cardiac evaluation. Patients may present with cardiac morbidity or sudden cardiac death (SCD), and serious cardiac manifestations are often identified only with cardiology testing. No effectiveness data was presented in the setting of MFM. However, patients with Duchenne muscular dystrophy (DMD) often have improved quality of life following appropriate cardiac interventions."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinically significant cardiac involvement (DES)"}},{"Outcome":{"value":"Clinically significant cardiac involvement (FLNC)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000853"}},{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}},{"Patient Management":{"value":"ACPM1213","properties":{"Key Text":{"value":"Cardiac Evaluation Before Anesthesia"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Cardiac evaluation should be performed before anesthesia/sedation in patients with MFM."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinically significant cardiac involvement (DES)"}},{"Outcome":{"value":"Clinically significant cardiac involvement (FLNC)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000853"}}]}}}},{"Patient Management":{"value":"ACPM1212","properties":{"Key Text":{"value":"ACEI and ARB"},"Tier":{"value":"2"},"Recommendation Text":{"value":"In the setting of reduced ejection fraction (EF), angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) are recommended in combination with beta-adrenergic blockade. Though evidence of the effectiveness of these interventions in MFM were not available, early initiation of ACEIs has been shown to prolong survival relative to late initiation in open-label cross-over trials with DMD. Beta blockade initiated in the pre-symptomatic stages of HF in DMD improved survival over blockade initiated after symptomatic HF onset."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinically significant cardiac involvement (DES)"}},{"Outcome":{"value":"Clinically significant cardiac involvement (FLNC)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000853"}}]}}}},{"Patient Management":{"value":"ACPM1209","properties":{"Key Text":{"value":"ICD Placement"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Consider ICD placement in an individualized manner, with decisions in DES-related MFM not dependent on EF alone."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinically significant cardiac involvement (DES)"}},{"Outcome":{"value":"Clinically significant cardiac involvement (FLNC)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000853"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC286","properties":{"Recommendation":{"value":"In a meta-analysis of 159 DES-related MFM patients, ICD was placed in 7 and pacemaker in 36. Sudden cardiac death occurred in two patients with a pacemaker, suggestive of ventricular tachyarrhythmia, indicating ICD may be a more appropriate consideration in cases due to DES."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000854"}}]}}}},{"RecommendationID":{"value":"REC285","properties":{"Recommendation":{"value":"More data are available on ICDs in the settings of cardiac conduction defects due to LMNA pathogenic variants or of non-ischemic cardiomyopathy. One prospective cohort study of 19 patients with an LMNA pathogenic variant and an ICD showed that 42% (N=8) received appropriate ICD therapy in response to ventricular tachycardia (N=2) and ventricular fibrillation (N=6) across a 34 month period. A meta-analysis of randomized control trials of patients with non-ischemic cardiomyopathy reported an overall reduction in mortality with ICD therapy (RR=0.69, 95% CI=0.56-0.86; p=0.002)."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000005"}},{"Reference":{"value":"/coll/reference_model/doc/RF000218"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1208","properties":{"Key Text":{"value":"Pulmonary Evaluation"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Clinicians should order pulmonary function testing or refer for pulmonary evaluation to identify and treat respiratory insufficiency at the time of diagnosis and if symptoms develop. Patients with respiratory failure from NMDs often do not have symptoms that precede the onset of respiratory failure, which is often identified only with pulmonary function tests. Historically, non-invasive ventilation was recommended in the setting of respiratory failure in MFM. Newer guidelines withhold making a recommendation about non-invasive ventilation, citing more recent evidence that this treatment may increase mortality."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}},{"Patient Management":{"value":"ACPM1211","properties":{"Key Text":{"value":"Glucocorticoid Use"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Glucocorticoid use should be guided by noncardiac indications for treatment. No data are available on glucocorticoid effectiveness in MFM, though daily glucocorticoid treatment has been shown to reduce the risk of scoliosis in DMD and is the recommended standard of care treatment of DMD."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000853"}},{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC287","properties":{"Recommendation":{"value":"Glucocorticoid treatment in pediatric DMD has been shown to improve muscle strength and respiratory function, prolong walking function, and reduce the need for scoliosis surgery, with 13 of 24 (54%) untreated patients requiring spinal stabilization versus 0 of 30 treated patients (0%)."},"Tier":{"value":"5"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000857"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1215","properties":{"Key Text":{"value":"Gastroenterology Evaluation"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Clinicians should refer patients experiencing dysphagia, frequent aspiration, or weight loss for swallowing evaluation and/or gastroenterology evaluation to assess and manage swallowing function and aspiration risk. There is evidence from related conditions (including ALS) that maintenance of nutrition and body weight prolongs survival."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU643","properties":{"Key Text":{"value":"Asymptomatic Evaluation"},"Tier":{"value":"2"},"Recommendation Text":{"value":"In asymptomatic patients, annual cardiac evaluation with examination, ECG and structural evaluation (echocardiography or cardiac MRI) is reasonable."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinically significant cardiac involvement (DES)"}},{"Outcome":{"value":"Clinically significant cardiac involvement (FLNC)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000853"}}]}}}},{"Surveillance":{"value":"ACSU644","properties":{"Key Text":{"value":"Periodic Pulmonary Evaluation"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Clinicians should obtain periodic pulmonary function testing or periodic referral for pulmonary evaluation to identify and treat respiratory insufficiency."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}},{"Surveillance":{"value":"ACSU642","properties":{"Key Text":{"value":"Monitoring for Spine Issues"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Patients should be monitored for the development of spinal deformities to prevent resultant complications and preserve function."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA539","properties":{"Key Text":{"value":"Events to Avoid"},"Tier":{"value":"2"},"Recommendation Text":{"value":"Avoid dehydration, exercising to exhaustion, and supramaximal, high-intensity exercise due to the risk of exercise-induced muscle damage, myoglobinuria, and subsequent overwork weakness."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Dominant"},"Notes":{"value":"There have been reported cases of compound heterozygotes or homozygotes in DES-related MFM."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000852"}},{"Reference":{"value":"/coll/reference_model/doc/RF000853"}},{"Reference":{"value":"/coll/reference_model/doc/RF000664"}},{"Reference":{"value":"/coll/reference_model/doc/RF000854"}},{"Reference":{"value":"/coll/reference_model/doc/RF000849"}},{"Reference":{"value":"/coll/reference_model/doc/RF000851"}},{"Reference":{"value":"/coll/reference_model/doc/RF000850"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"Not provided"},"Notes":{"value":"No data have been reported on the population prevalence of pathogenic variants in these genes."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[]}}},"Penetrances":{"value":3,"items":[{"Penetrance":{"value":"ACPE632","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"3"},"Notes":{"value":"The overall penetrance of pathogenic variants in these genes is not known."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":""}},{"Outcome":{"value":"Clinically significant cardiac involvement (DES)"}},{"Outcome":{"value":"Clinically significant cardiac involvement (FLNC)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000852"}}]}}}},{"Penetrance":{"value":"ACPE631","properties":{"Key Text":{"value":"5-39 %"},"Tier":{"value":"1"},"Notes":{"value":"The frequency of some symptoms has been reported, although it is a combination of clinically and molecularly identified patients (via family studies). Penetrance data on the basis of molecular identification alone is not available:\\n\\nFor individuals with FLNC-related MFM, the following were observed in a systematic review of case series: \\nCardiac involvement: 21/57 (37%)\\nRespiratory involvement: 14/61 (23%)\\nMusculoskeletal involvement: 63/70 (90%)\\n\\nFor individuals with BAG3-related MFM, the following were observed in a systematic review of case series: \\nCardiac involvement: 7/7 (100%)\\nRespiratory involvement: 6/7 (86%)\\nMusculoskeletal involvement: 7/7 (100%)"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":""}},{"Outcome":{"value":"Clinically significant cardiac involvement (FLNC)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}},{"Penetrance":{"value":"ACPE630","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"1"},"Notes":{"value":"For individuals with DES-related MFM, a systematic review of case series and a meta-analysis of cases reported in the literature (each with over 100 patients but containing overlapping studies/patients), report the following: \\nCardiac involvement: 74%-79%\\nRespiratory involvement: 26%-32%\\nMusculoskeletal involvement: 74%-86%"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Clinically significant cardiac involvement (DES)"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}},{"Reference":{"value":"/coll/reference_model/doc/RF000854"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR256","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"Information on relative risk was not available."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN287","properties":{"Key Text":{"value":"Inter- and intra-familial variability in symptoms and age of onset is reported. Genotype–phenotype correlations with DES-related MFM are emerging, but they are not yet useful for guiding clinical decisions."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}},{"Reference":{"value":"/coll/reference_model/doc/RF000854"}}]},"Tier":{"value":"1"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI291","properties":{"Key Text":{"value":"Identified interventions include non-invasive surveillance, pharmacotherapy, possible ICD implantation, and anesthetic precautions."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000853"}},{"Reference":{"value":"/coll/reference_model/doc/RF000664"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC286","properties":{"Key Text":{"value":"Patients with respiratory failure from neuromuscular-related weakness often do not have symptoms that precede the onset of respiratory failure. For DES-related MFM, cardiac involvement can occur prior to the onset of muscle weakness. As such, presenting symptoms can be serious, including sudden cardiac death."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000664"}},{"Reference":{"value":"/coll/reference_model/doc/RF000854"}}]},"Tier":{"value":"Not provided"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Notes":{"value":"DES Outcome – Clinically significant cardiac involvement:\nSeverity: no notes\nLikelihood: differences between A and B – argument that 100 patients is maybe not sufficient even though a SR, but it would seem they were comfortable with an A.\n\nIntervention: Cardiology management\n-a lot of the data is DMD and some scorers note knocking evidence level down because of extrapolation; ALS for the multidisciplinary clinic\n-some debate about effectiveness. Many people wavered between 0 and 1, and Adam wavered between a 1 and 2.  Adam moved to a 1 on reflection about the lack of specificity on the efficacy – no risk or hazard ratio. It’s a qualitative statement. Others felt it was reasonable to score as a 2 and then score the evidence as a different letter for evidence.\n\nIntervention: ICD\nEffectiveness\n-level of evidence originally tied between A and C. Julianne hadn’t scored, and added a D, making it tied between C and A and D. Murugu wanted to move to a C.\n-torn because DES evidence comes from a T1 source, but it’s not really effectiveness. The other evidence is extrapolated and T2.\n\nFLNC Outcome – Clinically sig cardiac involvement:\nSeverity: no notes\nLikelihood: 2A\n\nIntervention: Cardiology management\n-initial consensus is a 2C, which is not consistent with DES so they re-scored \n\nIntervention: ICD\nEffectiveness: split between 0 and 2 initially, a little all over the place on the effectiveness, but Laney hadn’t scored. She scored 2 D, which made the 2 a consensus and the D a consensus."}}},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Clinically significant cardiac involvement (DES)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Cardiology management","properties":{"Overall Score":{"value":"10AD"},"Effectiveness":{"value":"2D","properties":{"Notes":{"value":"Evidence level downgraded due to extrapolation from ALS/DMD and qualitative nature of evidence."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"ICD implantation","properties":{"Overall Score":{"value":"9AC"},"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Evidence level downgraded due to extrapolation from cardiac conduction defect dues to LMNA pathogenic variants. 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Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"ICD implantation","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":2,"items":[{"Outcome":{"value":"Clinically significant cardiac involvement (DES)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3A","properties":{"Notes":{"value":"why is penetrance = unknown?"}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Cardiology management","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"described as \"reasonable\""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"ICD implantation","properties":{"Effectiveness":{"value":"0","properties":{"Notes":{"value":"could say 2, but there is no good data"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}},{"Outcome":{"value":"Clinically significant cardiac involvement (FLNC)","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"2A","properties":{"Notes":{"value":""}}},"Interventions":{"value":2,"items":[{"Intervention":{"value":"Cardiology management","properties":{"Effectiveness":{"value":"1","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}},{"Intervention":{"value":"ICD implantation","properties":{"Effectiveness":{"value":"0","properties":{"Notes":{"value":"could say 2, but there is no good data"}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.0","properties":{"Notes":{"value":"First release of report."},"Public Notes":{"value":""},"kbRevision-PairedKB":{"value":36808},"ReasonCode":{"value":"Q0","properties":{"Reason":{"value":"Initial Release"}}},"Date":{"value":"2019-02-14"},"ReleasedBy":{"value":"marianjgilmore","properties":{"First Name":{"value":"Mari"},"Last Name":{"value":"Gilmore"}}}}}}}},
{"ActionabilityDocID":{"value":"AC156","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"HGD","properties":{"HGNCId":{"value":"HGNC:4892"},"GeneOMIM":{"value":"607474"}}}}]},"Syndrome":{"value":"Alkaptonuria","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"203500"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"56"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"HGD","properties":{"NumberOfHits":{"value":2},"Date":{"value":"2018-10-03"},"Notes":{"value":"203500, 607474"},"searchURL":{"value":"https://omim.org/search/?index=entry&start=1&limit=10&sort=score+desc%2C+prefix_sort+desc&search=hgd"},"Label":{"value":"OMIM"}}}}]}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"No"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"No"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"hunterj","properties":{"First Name":{"value":"Jessica"},"Last Name":{"value":"Hunter"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Yes"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Incomplete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram"}}]}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"The incidence of alkaptonuria (AKU) in the US is estimated at 1:250,000 to 1:1,000,000 live births. Worldwide estimates are similar, around 1:111,000 to 1:1,000,000. AKU occurs with high prevalence in the Dominican Republic and northwestern Slovakia, likely as the result of a founder effect. The prevalence of AKU in Slovakia is estimated as 1:19,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}},{"Reference":{"value":"/coll/reference_model/doc/RF000860"}},{"Reference":{"value":"/coll/reference_model/doc/RF000861"}},{"Reference":{"value":"/coll/reference_model/doc/RF000858"}},{"Reference":{"value":"/coll/reference_model/doc/RF000862"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"AKU is caused by the deficiency of an enzyme which results in the accumulation of homogentisic acid (HGA). AKU has three main features: HGA in urine (oxidation of HGA may cause urine to turn dark on standing), ochronosis (bluish-black pigmentation in connective tissue, such as cartilage, skin, and sclera), and arthritis of the spine and larger joints (ochronic arthropathy). Other manifestations include pigment deposition; aortic or mitral valve calcification or regurgitation and occasionally aortic dilation; stones (renal prostate, gall bladder, and salivary glands); renal failure; respiratory insufficiency; and rupture of tendons, muscles, and ligaments."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}},{"Reference":{"value":"/coll/reference_model/doc/RF000860"}},{"Reference":{"value":"/coll/reference_model/doc/RF000861"}},{"Reference":{"value":"/coll/reference_model/doc/RF000858"}},{"Reference":{"value":"/coll/reference_model/doc/RF000862"}},{"Reference":{"value":"/coll/reference_model/doc/RF000863"}},{"Reference":{"value":"/coll/reference_model/doc/RF000864"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Though elevated plasma and urinary HGA are present during childhood, individuals are typically asymptomatic until early adulthood. Ochronosis occurs only after age 30 years. A systematic review of 40 patients reported an average age of onset for ocular findings of 40.6 years. Arthritis often begins in the third decade, usually in the spine, and resembles ankylosing spondylitis in its large joint distribution. In one large series, low back pain was observed prior to age 30 years in 49% of individuals and prior to age 40 years in 94%. Half of individuals require at least one joint replacement by age 55. Joint disease appears to start earlier and progress more rapidly in males than females. Because the kidneys are responsible for secreting massive quantities of HGA, impaired renal function can accelerate the development of ochronosis and joint destruction. AKU follows a steady progression from early adulthood and leads to motor disabilities requiring physical aids. Pain can be constant, though life span is generally not reduced. Cardiac complications are often life-threatening and may worsen with prognosis."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}},{"Reference":{"value":"/coll/reference_model/doc/RF000860"}},{"Reference":{"value":"/coll/reference_model/doc/RF000861"}},{"Reference":{"value":"/coll/reference_model/doc/RF000858"}},{"Reference":{"value":"/coll/reference_model/doc/RF000863"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1207","properties":{"Key Text":{"value":"Initial evaluations"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with AKU, the following evaluations are recommended:\n• Complete history and physical examination with particular attention to range of motion in the spine and large joints\n• Physical medicine and rehabilitation evaluation if limited range of motion or joint pain occurs\n• Electrocardiogram and echocardiogram in individuals older than age 40 years\n• Renal ultrasound examination or helical abdominal CT to evaluate for the presence of renal calculi\n• Consultation with a clinical geneticist and/or genetic counselor."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}}]}}}},{"Patient Management":{"value":"ACPM1205","properties":{"Key Text":{"value":"Preventive treatment"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Although several therapeutic modalities have been investigated, no preventive or curative treatment is available for AKU."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC283","properties":{"Recommendation":{"value":"However, a recent expert review of AKU treatment modalities proposed the following sequential therapeutic strategy:\n• During childhood: A vegetarian diet with mineral and vitamin supplements if needed. A low protein diet will theoretically decrease HGA production, possibly reducing HGA accumulation. A study of 12 patients with AKU tested a low protein diet for 1 week followed by a high protein diet for 1 week and reported that HGA excretion was significantly lower with the low protein diet, but only among patients younger than 12. However, the long-term clinical effects are not clear. \n• During adulthood: Nitisinone and a mild protein restriction. In trials of adult AKU patients, a daily dose of nitisinone reduced urine and plasma HGA concentrations by 95%, a result sustained during 3 years. No long-term benefit of nitisinone was found on the rheumatologic parameters and, at best, suggested a limited progression of the associated aortic valve disease."},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000863"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1204","properties":{"Key Text":{"value":"Symptomatic treatment"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Joint pain is substantial in individuals with AKU, and close attention to pain control is necessary. Pain management may include physical and occupational therapy and surgical replacement of the large joints. In general, the goal of joint replacement is pain relief rather than increased range of motion."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC284","properties":{"Recommendation":{"value":"A systematic review of 13 AKU cases in the literature reported that most cases had received bilateral arthroplasty, all with satisfactory results. However, the criteria for a satisfactory outcome was not defined and reports of pre- and post-operative outcomes for all cases were not available."},"Tier":{"value":"1"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000864"}}]}}}}]}}}},{"Patient Management":{"value":"ACPM1206","properties":{"Key Text":{"value":"Surgical recommendations"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Specific surgical recommendations include preoperative assessment as well as anesthesia and other considerations. Preoperative assessments should include spinal mobility and cardiovascular system. Degenerative changes of the lumbar spine may complicate regional anesthesia, while calcification of interspinous ligaments make epidural approaches difficult if not impossible.  Additionally, excessive pigment deposition may interfere with pulse oximeter monitoring; and stiffness of cartilage in the chest wall may cause failure to wean from mechanical ventilation or dyspnea."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000862"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU641","properties":{"Key Text":{"value":"Cardiac"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Surveillance for cardiac complications every one to two years is advisable after age 40 years and should include:\n• Echocardiography to detect aortic dilation and aortic or mitral valve calcification and stenosis\n• Surveillance CT scans in affected individuals with coronary artery calcification."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Aortic/cardiac disease"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC051","properties":{"Recommendation":{"value":"No evidence for the effectiveness of cardiac surveillance was available for AKU. However, recommendations for management of valvular heart disease (VHD) from unspecified etiology indicate that echocardiography is key to confirm the diagnosis of VHD and assess its severity and prognosis. In asymptomatic patients with aortic stenosis (AS), the wide variability of the rate of progression heightens the need for patients to be educated about the importance of follow-up with echocardiography and reporting symptoms as soon as they develop. Aortic valve replacement (AVR) is the definitive therapy for severe AS and is the traditional treatment for aortic regurgitation (AR). ARV in symptomatic AS patients has been shown to prolong and improve quality of life, even in patients over 80 years of age. Treatment for AS and AR with concomitant aneurysm/dilatation of the ascending aorta generally consists of combined replacement of the aorta and valve with reimplantation of the coronary arteries"},"Tier":{"value":"2"},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000866"}}]}}}}]}}}},{"Surveillance":{"value":"ACSU640","properties":{"Key Text":{"value":"Urologic"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Urologic complications become more prevalent after age 40 years:\n• Routine surveillance is not recommended, but awareness of this potential complication is advised.\n• Ochronotic prostate stones appear on radiography; renal  stones can be identified by ultrasonography and helical abdominal CT."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA538","properties":{"Key Text":{"value":""},"Tier":{"value":"4"},"Recommendation Text":{"value":"Avoidance of physical stress to the spine and large joints, including heavy manual labor or high impact sports, may reduce the progression of severe arthritis. Specifically, younger individuals with AKU should be directed toward non-contact and lower-impact sports."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"},"Notes":{"value":""},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}},{"Reference":{"value":"/coll/reference_model/doc/RF000861"}},{"Reference":{"value":"/coll/reference_model/doc/RF000858"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"4"},"Notes":{"value":"Pathogenic variants in HGD account for 90% of cases of AKU."},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}}]},"Additional Tiered Statements":{"value":null,"items":[{"RecommendationID":{"value":"REC072","properties":{"Recommendation":{"value":"No information on carrier frequency or prevalence was identified."},"Tier":{"value":"Not provided"},"References":{"value":null,"items":[]}}}}]}}},"Penetrances":{"value":4,"items":[{"Penetrance":{"value":"ACPE628","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"Elevated urinary HGA and ochronotic arthritis occur in all individuals who are homozygous or compound heterozygous for pathogenic variants in HGD."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}}]}}}},{"Penetrance":{"value":"ACPE629","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"1"},"Notes":{"value":"A systematic review of 40 patients indicated that 83% of patients had scleral pigmentation."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000860"}}]}}}},{"Penetrance":{"value":"ACPE626","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"4"},"Notes":{"value":"By age 64 years, 50% of individuals with AKU have a history of renal stones."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}}]}}}},{"Penetrance":{"value":"ACPE627","properties":{"Key Text":{"value":"Unknown"},"Tier":{"value":"5"},"Notes":{"value":"A case series of 76 AKU patients who underwent transthoracic echocardiography found the following results: 6 (8%) had aortic valve replacements, 12 (16%) had aortic sclerosis, 7 (9%) had aortic stenosis ranging from mild to severe, 15 had aortic regurgitation, and 7 had aortic root dilation. Among 40 patients who also underwent CT scans, 17 had coverage suitable for evaluation of coronary or valvular calcification. Among these 17, valvular calcification was present in 8 (47%) and 3 (18%) had evidence of significant coronary calcification. By the age of 60, 100% of individuals had evidence of significant intracardiac calcification. Among 40 patients, 26 (65%) patients had evidence of significant vascular calcification in the aorta."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Aortic/cardiac disease"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000865"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR255","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN286","properties":{"Key Text":{"value":"HGA excretion and disease severity can vary significantly within the same family."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI290","properties":{"Key Text":{"value":"Interventions identified in this report include imaging surveillance, surgical management, avoidance of stressors to spine and large joins, a low protein diet, and nitisinone. The only side effect of nitisonone is the expected rise of plasma tyrosine, and corneal lesions have been observed due to the poor solubility of tyrosine."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000863"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC285","properties":{"Key Text":{"value":"In some individuals, the diagnosis of AKU is identified only after the individual seeks medical attention for chronic joint pain or after black articular cartilage is noted during orthopedic surgery. Urine darkening, though present in infancy, may not occur for several hours after voiding and many individuals never observe any abnormal color to their urine."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000859"}}]},"Tier":{"value":"4"}}}},{"Chance to Escape Clinical Detection":{"value":"CDEC284","properties":{"Key Text":{"value":"In a systematic review of 40 patients with AKU, the initial diagnosis was not determined correctly in six cases."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000860"}}]},"Tier":{"value":"1"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2019-02-04"},"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"jenniferposey"}},{"Scorer":{"value":"murugumanickam"}},{"Scorer":{"value":"weaverm"}},{"Scorer":{"value":"leekristy"}},{"Scorer":{"value":"odanielj"}}]},"Notes":{"value":"Originally scored on 01/07/2019 but decided to postpone scoring the effectiveness in order to add effectiveness evidence for valve replacement in the setting of cardiac calcification. Added extrapolate evidence from general valvular heart disease guidelines. Effectiveness re-scored on 02/04/2019.\n\nScoring notes: \nSeverity: Scorers had a hard time distinguishing between 1 or 2, but the sentence in the last section of NH indicated cardiac disease could be lift-threatening so went with a 2.\nLikelihood: Murugu kept a 0 as penetrance of cardiac disease is unknown, whereas the others accounted for the aortic outcomes noted in the Tier 5 source though there was concern about the “murkiness” of this info.\nEffectiveness: There was concern that we don’t have evidence for the effectiveness of surveillance since we don’t have evidence of improved outcomes from surveillance or repair; Kristy will reach out to Brian Jensen about a similar disorder to pull evidence from; could also use aortic dilation from Marfan and/or repair after calcification in the general population. Update: we will in data from the general population and rescored. However, scorers were still unsure about the effectiveness of surveillance and scored i a 1 and dropped the evidence level since it was extrapolated."}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Overall Score":{"value":"9NC"},"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"Evidence extrapolated from guidelines for valvular heart disease of unspecified etiology."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":9,"items":[{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"Not Scored"},"Likelihood":{"value":"Not Scored"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"Not Scored"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"1"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"jenniferposey","properties":{"First Name":{"value":"Jennifer"},"Last Name":{"value":"Posey"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"murugumanickam","properties":{"First Name":{"value":"Murugu"},"Last Name":{"value":"Manickam"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"0N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"1C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"0C"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"Not Scored"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3N"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"alexanderkatz","properties":{"First Name":{"value":"Alexander"},"Last Name":{"value":"Katz"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3A"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"1B"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}}]}}},"Scorers":{"value":9,"items":[{"Scorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":"I think the term modest would make more sense as moderate, esp with having minimal and major on either side of the scoring options. Modest sounds more like minimal to me but I think it was intended to suggest moderate."}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"Though could go with 3 due to 'cardiac complications are often life-threatening'."}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":"Am also considering AVR's effectiveness for patients with AS but dropping evidence level due to extrapolation."}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":"1 or 2"}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"2","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"jenniferposey","properties":{"First Name":{"value":"Jennifer"},"Last Name":{"value":"Posey"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"0D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"murugumanickam","properties":{"First Name":{"value":"Murugu"},"Last Name":{"value":"Manickam"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"1","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"0C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"leekristy","properties":{"First Name":{"value":"Kristy"},"Last Name":{"value":"Lee"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3N","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"2C","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]}}}},{"Scorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Status":{"value":"Complete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"0N","properties":{"Notes":{"value":"Penetrance data is not given"}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"1C","properties":{"Notes":{"value":"from the add'l info - still not sure about how efficacious: 1 or 2?"}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"follow-up is 3, but the procedures that impact efficacy may be a 2"}}}}}}]}}}}]}}}},{"Scorer":{"value":"alexanderkatz","properties":{"First Name":{"value":"Alexander"},"Last Name":{"value":"Katz"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Aortic/cardiac disease","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3A","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Cardiology follow-up with periodic echocardiogram","properties":{"Effectiveness":{"value":"1B","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":"For scoring purposes, ct surgery not included"}}}}}}]}}}}]}}}}]}}},"Release":{"value":"1.0.1","properties":{"Notes":{"value":"Updated to version 1.0.1, reopened to add literature search date."},"Public Notes":{"value":""},"kbRevision-PairedKB":{"value":36660},"ReasonCode":{"value":"Q1","properties":{"Reason":{"value":"Minor textual or formatting updates (e.g., typos corrected) but scoring pairs unaffected"}}},"Date":{"value":"2019-02-06"},"ReleasedBy":{"value":"wallkat","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Wallace"}}}}}}}},
{"ActionabilityDocID":{"value":"AC157","properties":{"Status":{"value":"Released"},"Genes":{"value":1,"items":[{"Gene":{"value":"CP","properties":{"HGNCId":{"value":"HGNC:2295"},"GeneOMIM":{"value":"117700"},"SyndromeOMIMs":{"value":1,"items":[{"OMIM":{"value":"604290"}}]}}}}]},"Syndrome":{"value":"Aceruloplasminemia","properties":{"OmimIDs":{"value":1,"items":[{"OmimID":{"value":"604290"}}]},"OrphanetIDs":{"value":1,"items":[{"OrphanetID":{"value":"604290"}}]}}},"LiteratureSearch":{"value":null,"properties":{"Sources":{"value":1,"items":[{"Source":{"value":"OMIM","properties":{"SearchStrings":{"value":1,"items":[{"SearchString":{"value":"Aceruloplasminemia","properties":{"NumberOfHits":{"value":1},"Date":{"value":"2019-01-03"},"Notes":{"value":""},"searchURL":{"value":"https://omim.org/entry/604290"},"Label":{"value":"OMIM Search"}}}}]}}}}]},"Status":{"value":"Complete"}}},"Stage 1":{"value":null,"properties":{"Final Stage1 Report":{"value":null,"properties":{"Notes":{"value":""},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Unknown"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}},"Scorers Stage1":{"value":1,"items":[{"Scorer Stage1":{"value":"wallkat","properties":{"First Name":{"value":"Kathleen"},"Last Name":{"value":"Wallace"},"Notes":{"value":"[unknown]"},"Actionability":{"value":null,"properties":{"Practice Guideline":{"value":"Yes"},"Result Actionable":{"value":null,"properties":{"Patient Management":{"value":"Yes"},"Surveillance or Screening":{"value":"Yes"},"Family Management":{"value":"Yes"},"Circumstances to Avoid":{"value":"Yes"},"Yes for 1 or more above":{"value":"Yes"}}},"Result Actionable in undiagnosed":{"value":"Yes"}}},"Penetrance":{"value":null,"properties":{"Moderate Penetrance Variant":{"value":"Unknown"}}},"Significance of Disease":{"value":null,"properties":{"Important Health Problem":{"value":"Yes"}}},"Need for making exception":{"value":"No","properties":{"Exception Made":{"value":"No","properties":{"Note why exception made":{"value":""}}}}},"Status":{"value":"Complete"}}}}]}}},"Stage 2":{"value":null,"properties":{"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation","properties":{"Interventions":{"value":1,"items":[{"Intervention":{"value":"Iron chelation and avoidance of iron supplementation","properties":{"FullName":{"value":"Iron chelation and avoidance of iron supplementation"}}}}]},"FullName":{"value":"Morbidity due to iron accumulation"}}}}]},"Status":{"value":"Complete"},"Nature of the Threat":{"value":null,"properties":{"Prevalence of the Genetic Disorder":{"value":null,"properties":{"Key Text":{"value":"< 1-2 in 100000"},"Notes":{"value":"To date, 56 cases of aceruloplasminemia have been reported and the prevalence has been estimated at about 1/1,000,000-1/1,200,000.  In Japan, the prevalence of aceruloplasminemia in non-consanguineous marriages was estimated at 1/2,000,000."},"Additional Fields":{"value":null,"properties":{"Source of Population":{"value":"General population"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}},{"Reference":{"value":"/coll/reference_model/doc/RF000897"}}]}}},"Clinical Features":{"value":null,"properties":{"Key Text":{"value":"Aceruloplasminemia is a disorder of iron metabolism caused by the complete absence of ceruloplasmin ferroxidase activity. It is characterized by iron accumulation in the brain and viscera leading to a triad of clinical manifestations: retinal degeneration, diabetes mellitus, and various neurologic symptoms. The neurologic findings of movement disorder (blepharospasm, grimacing, facial and neck dystonia, tremors, and chorea) and ataxia (gait ataxia, dysarthria) correspond to regions of iron accumulation in the brain.  Affected individuals often present with anemia prior to onset of diabetes mellitus or neurologic symptoms. Cognitive dysfunction including apathy and forgetfulness occurs in more than half of individuals with this condition."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}},{"Reference":{"value":"/coll/reference_model/doc/RF000897"}},{"Reference":{"value":"/coll/reference_model/doc/RF000895"}}]}}},"Natural History":{"value":null,"properties":{"Key Text":{"value":"Aceruloplasminemia presents in adulthood, from age 25 years to older than 70 years. The prognosis may include heart failure due to cardiac iron overload. At least five patients are known to have died from heart failure, probably due to cardiac iron overload, in their sixties. In the absence of heart failure and with good treatment of diabetes mellitus, the prognosis is good."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}},{"Reference":{"value":"/coll/reference_model/doc/RF000897"}}]}}}}},"Effectiveness of Intervention":{"value":null,"properties":{"Patient Managements":{"value":null,"items":[{"Patient Management":{"value":"ACPM1231","properties":{"Key Text":{"value":"Establish the extent of disease"},"Tier":{"value":"4"},"Recommendation Text":{"value":"To establish the extent of disease and needs in an individual diagnosed with aceruloplasminemia, evaluations for the following are recommended:\n• Iron deposition: serum ferritin concentration, brain and abdomen MRI findings and hepatic iron and copper content by the liver biopsy\n• Neurologic findings: brain MRI\n• Diabetes mellitus: glucose tolerance test, blood concentrations of insulin and HbA1c\n• Retinal degeneration: examination of the optic fundi and fluorescein angiography\n• Anemia: complete blood count\n• Other: consultation with a clinical geneticist and/or genetic counselor"},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}}]}}}},{"Patient Management":{"value":"ACPM1229","properties":{"Key Text":{"value":""},"Tier":{"value":"Not provided"},"Recommendation Text":{"value":"Individual case reports indicate the effectiveness of treatment in patients with aceruloplasminemia; however, no large series of symptomatic patients treated with iron chelators and zinc is available and there is no universally accepted treatment regimen."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}}]}}}},{"Patient Management":{"value":"ACPM1228","properties":{"Key Text":{"value":"Chelation"},"Tier":{"value":"3"},"Recommendation Text":{"value":"Treatment with iron chelating agents can be considered for symptomatic individuals whose blood hemoglobin concentration is higher than 9 g/dL. Treatment can decrease serum ferritin concentration as well as brain and liver iron stores and can prevent progression of the neurologic symptoms. \n• Desferrioxamine: Three case reports indicated improvement following treatment: one patient had increased signal intensity of the basal ganglia on T2-weighted MRI, serum ferritin concentration and hepatic iron concentration was decreased, serum iron concentration was elevated, and anemia and diabetes mellitus were ameliorated; a second patient did not show a change on brain MRI, but excess iron in the liver was removed; and a third patient demonstrated improvement in low-intensity areas in the basal ganglia on brain MRI. \n• Deferasirox: Therapy led to mild improvement in clinical symptoms, including cognitive performance, gait, and balance, in an individual with aceruloplasminemia who had no response to both deferoxamine and fresh-frozen plasma therapy (FFP).\n• Deferiprone: Therapy had no beneficial effects in a patient in a previous report; however, it has been shown to protect against retinal degeneration and neurodegeneration and to increase the life span if initiated early in mice exhibiting knockout for ceruloplasmin and hephaestin."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}}]}}}},{"Patient Management":{"value":"ACPM1230","properties":{"Key Text":{"value":""},"Tier":{"value":"3"},"Recommendation Text":{"value":"After the intravenous administration of FFP containing ceruloplasmin in a single case, serum iron content increased for several hours because of ferroxidase activity of ceruloplasmin. Iron content in the liver decreases more with combined intravenous administration of FFP and desferrioxamine than with FFP administration alone. Neurologic signs/symptoms can improve following repetitive FFP treatment."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}}]}}}},{"Patient Management":{"value":"ACPM1232","properties":{"Key Text":{"value":""},"Tier":{"value":"3"},"Recommendation Text":{"value":"Antioxidants such as vitamin E may be used along with a chelator or oral administration of zinc to prevent tissue damage, particularly to the liver and pancreas."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}}]}}}}]},"Surveillances":{"value":null,"items":[{"Surveillance":{"value":"ACSU653","properties":{"Key Text":{"value":"Glucose tolerance"},"Tier":{"value":"4"},"Recommendation Text":{"value":"All affected individuals should have an annual glucose tolerance test starting at age 15 years to evaluate for the onset of diabetes mellitus."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}}]}}}},{"Surveillance":{"value":"ACSU652","properties":{"Key Text":{"value":"Electrocardiography"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Electrocardiography evaluation should be performed early in the course of the disease."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}}]}}}},{"Surveillance":{"value":"ACSU651","properties":{"Key Text":{"value":""},"Tier":{"value":"4"},"Recommendation Text":{"value":"Evaluation of thyroid, liver function and complete blood count are indicated annually starting at the time of diagnosis."},"Outcomes":{"value":null,"items":[]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}}]}}}}]},"Circumstances to Avoid":{"value":null,"items":[{"Circumstance to Avoid":{"value":"ACCA544","properties":{"Key Text":{"value":"Iron supplementation"},"Tier":{"value":"4"},"Recommendation Text":{"value":"Iron supplements should be avoided, as individuals with aceruloplasminemia erroneously diagnosed as having iron deficiency anemia and treated with iron supplements had accelerated iron accumulation."},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}}]}}}}]}}},"Threat Materialization Chances":{"value":null,"properties":{"Mode of Inheritance":{"value":null,"properties":{"Key Text":{"value":"Autosomal Recessive"},"Notes":{"value":""},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}},{"Reference":{"value":"/coll/reference_model/doc/RF000897"}},{"Reference":{"value":"/coll/reference_model/doc/RF000895"}}]}}},"Prevalence of the Genetic Mutation":{"value":null,"properties":{"Key Text":{"value":"1-2 in 50000"},"Tier":{"value":"3"},"Notes":{"value":"A study screened the serum ceruloplasmin concentrations in nearly 5,000 Japanese adults (with subsequent sequence determination in 31 individuals), found an estimated pathogenic variant frequency of 1/14000.  The frequency of homozygotes and heterozygotes was estimated as 1/2,000,000 and 1/700, respectively, in non-consanguineous marriages with a higher homozygote frequency estimated in consanguineous marriages (1/300,000).  The heterozygote frequency in consanguineous parents was similar to non-consanguineous parents at 1/700"},"Outcomes":{"value":null,"items":[]},"Additional Fields":{"value":null,"properties":{"Source of Population for this Prevalence":{"value":"Other"}}},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}}]}}},"Penetrances":{"value":1,"items":[{"Penetrance":{"value":"ACPE640","properties":{"Key Text":{"value":">= 40 %"},"Tier":{"value":"3"},"Notes":{"value":"A summary of clinical manifestations (age of onset) in 71 Japanese individuals with aceruloplasminemia found the following distribution of symptoms:\n• Anemia - 80% \n• Diabetes mellitus - 70% (<30 yrs: 18%; 30-39 yrs: 35%; 40-49 yrs: 31%; >50 yrs: 16%)\n• Retinal degeneration - 76%  (At least >20 yrs)\n• Neurologic symptoms - 68% (<40 yrs: 7%; 40-49 yrs: 38 %; 50-59 yrs: 42%; >60 yrs: 13%) \n• Ataxia - 71%, including: dysarthria, gait ataxia, limb ataxia, nystagmus \n• Involuntary movement - 64%, including: dystonia (blepharospasm, grimacing, neck dystonia), tremors, chorea\n• Parkinsonism - 20%, including: rigidity, akinesia\n• Cognitive dysfunction - 60%, including:  apathy, forgetfulness"},"Outcomes":{"value":null,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation"}}]},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}}]}}}}]},"Relative Risks":{"value":null,"items":[{"Relative Risk":{"value":"RR260","properties":{"Key Text":{"value":"Unknown"},"Notes":{"value":"No information on relative risk was identified."},"References":{"value":null,"items":[]},"Tier":{"value":"Not provided"}}}}]},"Expressivity Notes":{"value":null,"items":[{"Expressivity Note":{"value":"EN291","properties":{"Key Text":{"value":"Phenotypic expression varies even within families."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}}]},"Tier":{"value":"4"}}}}]}}},"Acceptability of Intervention":{"value":null,"properties":{"Natures of Intervention":{"value":null,"items":[{"Nature of Intervention":{"value":"NOI297","properties":{"Key Text":{"value":"The interventions identified in the report include treatment with intravenous iron chelating agents and FFP, oral iron chelating agents and oral antioxidants. The intravenous iron chelator desferrioxamine is infused during one hour sessions twice a week for six to ten months. Deferasirox is administered orally and daily. Some case reports have shown that high doses of iron chelators can cause severe side effects, particularly aggravated anemia, that may lead to discontinuation of therapy. One report of three patients treated with oral deferasirox indicated that all three discontinued therapy within five months due to side effects, including diarrhea, anemia, and skin rash. Additional case reports have proposed a combination of iron chelating agents along with oral zinc as an antioxidant, as zinc therapy has been shown to ameliorate neurological symptoms with minimal side effects. Additional interventions include surveillance for diabetes mellitus and organ damage due to iron deposition as well as the avoidance of iron supplementation which may accelerate iron accumulation."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}},{"Reference":{"value":"/coll/reference_model/doc/RF000898"}},{"Reference":{"value":"/coll/reference_model/doc/RF000899"}},{"Reference":{"value":"/coll/reference_model/doc/RF000900"}},{"Reference":{"value":"/coll/reference_model/doc/RF000901"}}]}}}}]}}},"Condition Escape Detection":{"value":null,"properties":{"Chances to Escape Clinical Detection":{"value":null,"items":[{"Chance to Escape Clinical Detection":{"value":"CDEC290","properties":{"Key Text":{"value":"Individuals affected with aceruloplasminemia often present with anemia prior to onset of other symptoms, and there is evidence that patients erroneously diagnosed as having iron deficiency anemia and treated with iron supplements had accelerated iron accumulation."},"References":{"value":null,"items":[{"Reference":{"value":"/coll/reference_model/doc/RF000896"}}]},"Tier":{"value":"4"}}}}]}}}}},"Score":{"value":null,"properties":{"Status":{"value":"Complete"},"Final Scores":{"value":null,"properties":{"Metadata":{"value":null,"properties":{"Media":{"value":"call"},"Date":{"value":"2019-03-18"},"Scorers Present":{"value":7,"items":[{"Scorer":{"value":"odagan"}},{"Scorer":{"value":"murugumanickam"}},{"Scorer":{"value":"lindorl"}},{"Scorer":{"value":"buchanana"}},{"Scorer":{"value":"odanielj"}},{"Scorer":{"value":"weaverm"}},{"Scorer":{"value":"srego"}}]},"Notes":{"value":"Severity: Adam was torn between 1 and 2 and went with a 2.\nLikelihood: Already had consensus on scores.\nEffectiveness: Concerns that evidence is based on case reports. A question about how many unique cases across these case reports, which is not clear. Laney pointed out that as a patient would be encouraged by the potential benefits, even though the evidence is limited. Decided to keep the score of a 2, but bump down the evidence to a D. Others followed suit. \nNOI: Some question about how it is administered. Should add method of administration to the NOI section to indicate the burden (could be oral or IV)."}}},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Iron chelation and avoidance of iron supplementation","properties":{"Overall Score":{"value":"10CD"},"Effectiveness":{"value":"2D","properties":{"Notes":{"value":""}}},"Nature Of Intervention":{"value":"3","properties":{"Notes":{"value":""}}}}}}]}}}}]},"FinalScoreOfScorers":{"value":7,"items":[{"FinalScoreOfScorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Iron chelation and avoidance of iron supplementation","properties":{"Effectiveness":{"value":"2N"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"murugumanickam","properties":{"First Name":{"value":"Murugu"},"Last Name":{"value":"Manickam"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Iron chelation and avoidance of iron supplementation","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"lindorl","properties":{"First Name":{"value":"Laney"},"Last Name":{"value":"Lindor"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Iron chelation and avoidance of iron supplementation","properties":{"Effectiveness":{"value":"2D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"buchanana","properties":{"First Name":{"value":"Adam"},"Last Name":{"value":"Buchanan"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Iron chelation and avoidance of iron supplementation","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"odanielj","properties":{"First Name":{"value":"Julliane"},"Last Name":{"value":"O'Daniel"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Iron chelation and avoidance of iron supplementation","properties":{"Effectiveness":{"value":"0D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"weaverm","properties":{"First Name":{"value":"Meredith"},"Last Name":{"value":"Weaver"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Iron chelation and avoidance of iron supplementation","properties":{"Effectiveness":{"value":"1D"},"Nature Of Intervention":{"value":"3"}}}}]}}}}]}}}},{"FinalScoreOfScorer":{"value":"srego","properties":{"First Name":{"value":"Shannon"},"Last Name":{"value":"Rego"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation","properties":{"Severity":{"value":"2"},"Likelihood":{"value":"3C"},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Iron chelation and avoidance of iron supplementation","properties":{"Effectiveness":{"value":"2C"},"Nature Of Intervention":{"value":"2"}}}}]}}}}]}}}}]}}},"Scorers":{"value":7,"items":[{"Scorer":{"value":"odagan","properties":{"First Name":{"value":"Orit"},"Last Name":{"value":"Dagan"},"Status":{"value":"Incomplete"},"Outcomes":{"value":1,"items":[{"Outcome":{"value":"Morbidity due to iron accumulation","properties":{"Severity":{"value":"2","properties":{"Notes":{"value":""}}},"Likelihood":{"value":"3C","properties":{"Notes":{"value":""}}},"Interventions":{"value":1,"items":[{"Intervention":{"value":"Iron chelation and avoidance of iron supplementation","properties":{"Effectiveness":{"value":"2N","properties":{"Notes":{"value":""}}},"Nature Of 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