{ "@context": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/context/doc", "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150", "id": "CG-AC:AC150", "type": "ClinicalActionabilityReport", "metadata": { "schemaLabel": "AC-Sepio.Beta-1 (Unofficial)", "contentVersionId": "30975", "producedAtUTC": "Wed, 28 Oct 2026 00:18:04 -0000", "note": "DISCLAIMER: The SEPIO-inspired schema presented here is an initial prototype for Clinical Actionability curation summaries and has not been reviewed nor finalized by the ClinGen Data Exchange Modeling Team. We expect it to differ significantly from the final schema." }, "description": "JSON-LD representation of ClinGen Actionability Stage 2 report modeled with SEPIO. The hierarchically structured document will include:\n1. Contextual & topic information, such as the **conditions/diseases** and the **genes**.\n2. Categorized **evidence narratives**, with references.\n\t* This content corresponds to the texts within the *Actionability Summary Report*\n4. **Outcome & Intervention** pairs, with **consensus scoring** in 5 dimensions:\n\t1. Outcome Severity\n\t2. Outcome Likelihood\n\t3. Intervention Effectiveness\n\t4. Nature of the Intervention\n\t5. Total (Overall) Score\n\n*( Note: The summary report does not include the **Screening Survey** which led to preparation of the actionability report. )", "condition": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/co", "id": "CG-AC:AC150/co", "type": "GeneticCondition", "label": "Hereditary Paraganglioma-Pheochromocytoma Syndromes", "description": "Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues symmetrically distributed along the paravertebral axis from the base of the skull to the pelvis) and by pheochromocytomas (paragangliomas that are confined to the adrenal medulla)." }, "outcome": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/ou/Morbidity%20and%20mortality%20due%20to%20hereditary%20pheochromocytoma%20and%20paraganglioma%20syndromes%20%28SDHB%29", "id": "CG-AC:AC150/ou/Morbidity and mortality due to hereditary pheochromocytoma and paraganglioma syndromes (SDHB)", "type": "Outcome", "label": "Morbidity and mortality due to hereditary pheochromocytoma and paraganglioma syndromes (SDHB)" }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/ou/Morbidity%20and%20mortality%20due%20to%20hereditary%20pheochromocytoma%20and%20paraganglioma%20syndromes%20%28MAX%2C%20SDHC%2C%20SDHD%29", "id": "CG-AC:AC150/ou/Morbidity and mortality due to hereditary pheochromocytoma and paraganglioma syndromes (MAX, SDHC, SDHD)", "type": "Outcome", "label": "Morbidity and mortality due to hereditary pheochromocytoma and paraganglioma syndromes (MAX, SDHC, SDHD)" }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/ou/Morbidity%20and%20mortality%20due%20to%20hereditary%20pheochromocytoma%20and%20paraganglioma%20syndromes%20%28SDHA%2C%20SDHAF2%2C%20TMEM127%29", "id": "CG-AC:AC150/ou/Morbidity and mortality due to hereditary pheochromocytoma and paraganglioma syndromes (SDHA, SDHAF2, TMEM127)", "type": "Outcome", "label": "Morbidity and mortality due to hereditary pheochromocytoma and paraganglioma syndromes (SDHA, SDHAF2, TMEM127)" } ], "intervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/intv/Surveillance%20by%20specialists%20to%20facilitate%20early%20identification%20and%20guide%20decision-making%20for%20surgical%20intervention", "id": "CG-AC:AC150/intv/Surveillance by specialists to facilitate early identification and guide decision-making for surgical intervention", "type": "Intervention", "label": "Surveillance by specialists to facilitate early identification and guide decision-making for surgical intervention" }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/intv/Surveillance%20by%20specialists%20to%20facilitate%20early%20identification%20and%20guide%20decision-making%20for%20surgical%20intervention", "id": "CG-AC:AC150/intv/Surveillance by specialists to facilitate early identification and guide decision-making for surgical intervention", "type": "Intervention", "label": "Surveillance by specialists to facilitate early identification and guide decision-making for surgical intervention" }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/intv/Surveillance%20by%20specialists%20to%20facilitate%20early%20identification%20and%20guide%20decision-making%20for%20surgical%20intervention", "id": "CG-AC:AC150/intv/Surveillance by specialists to facilitate early identification and guide decision-making for surgical intervention", "type": "Intervention", "label": "Surveillance by specialists to facilitate early identification and guide decision-making for surgical intervention" } ], "clinicalActionabilityProfile": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/cap", "id": "CG-AC:AC150/cap", "type": "Assertion", "assertionMethod": "The ClinGen AWG developed a standardized protocol to generate evidence-based profiles of clinical actionability of genes and associated disorders in the form of summary reports and semiquantitative metric (SQM) scores.", "releaseDate": "Thu, 22 Oct 2026 00:00:00 -0000", "releaseNum": "2.0.0", "media": "call" }, "evidenceStatements": { "evidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/en/nh", "id": "CG-AC:AC150/en/nh", "type": "EvidenceNarrative", "narrative": "The risk for malignant transformation is greater for extra-adrenal sympathetic PGLs than for PCCs or skull base and neck PGLs. 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 ~75% presenting as multiple tumors and a <5% metastatic risk. SDHAF2 is associated with PGLs of the skull base and neck, with ~90% presenting as multiple tumors and a low metastatic risk. SDHA is associated with PGLs generally presenting as single tumors with a low metastatic risk. SDHC is associated with parasympathetic skull base and neck paragangliomas, with ~20% presenting as multiple tumors and a low metastatic risk. SDHB is associated with extra-adrenal sympathetic PGLs, with ~20% presenting as multiple tumors and a 34-97% metastatic 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% metastatic 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\\nPGL/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. Pediatric patients with metastatic PGL/PCC have disease-related 5-year and 10-year survival rates of 78% and 31%, respectively. No reliable pathology studies are available to distinguish a primary benign PGL/PCC from a primary malignant PGL/PCC.", "evidenceDomainTag": "Nature of the Threat.Natural History", "publication": [ "CG-AC:RF004102", "CG-AC:RF000337", "CG-AC:RF004103", "CG-AC:RF004104", "CG-AC:RF004105", "CG-AC:RF004106", "CG-AC:RF004108", "CG-AC:RF004109" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/en/potgd", "id": "CG-AC:AC150/en/potgd", "type": "EvidenceNarrative", "narrative": "The incidence of hereditary paraganglioma-pheochromocytoma syndromes (HPPS) has not been well established. The incidence of pheochromocytoma (PCC) is approximately 0.6 in 100,000 per year. About 25% of all PCC arise in individuals with a hereditary predisposition. The incidence of paragangliomas (PGL) is lower, but these tumors are more often associated with a hereditary predisposition. Up to 80% of children who develop PGL/PCC (collectively referred to as PPGL) carry an identifiable germline pathogenic variant in a PPGL predisposition gene, with almost half of these variants in one of the SDH subunit genes (SDHA, SDHB, SDHC, and SDHD).", "evidenceDomainTag": "Nature of the Threat.Prevalence of the Genetic Disorder", "publication": [ "CG-AC:RF004102", "CG-AC:RF000337", "CG-AC:RF004103", "CG-AC:RF004104" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/en/cf", "id": "CG-AC:AC150/en/cf", "type": "EvidenceNarrative", "narrative": "HPPS are a set of disorders characterized by predisposition to PGLs and PCCs. 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 (GIST) may also occur in individuals with a pathogenic variant in SDHD, SDHA, SDHC, or SDHB. Renal clear cell carcinoma (RCC) has been reported in individuals with a pathogenic variant in SDHA, SDHB, SDHC, SDHD or TMEM127, and papillary thyroid carcinoma has 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). It has been established that a secreting PPGL during pregnancy is associated with an elevated risk of pre-eclampsia and gestational diabetes and severe cardiac complications for the pregnant person. Additional pregnancy complications including miscarriage, intrauterine fetal loss and death of baby at delivery.", "evidenceDomainTag": "Nature of the Threat.Clinical Features", "publication": [ "CG-AC:RF004102", "CG-AC:RF000337", "CG-AC:RF004103", "CG-AC:RF004104", "CG-AC:RF004105", "CG-AC:RF004106", "CG-AC:RF004107", "CG-AC:RF004108", "CG-AC:RF004109", "CG-AC:RF004110" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/en/ACMI2895", "id": "CG-AC:AC150/en/ACMI2895", "type": "EvidenceNarrative", "narrative": "Autosomal Dominant", "evidenceDomainTag": "Threat Materialization Chances.Modes of Inheritance", "publication": [ "CG-AC:RF004106", "CG-AC:RF004107", "CG-AC:RF004113" ] } ], "tieredEvidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/ten/NOI3087", "id": "CG-AC:AC150/ten/NOI3087", "type": "TieredEvidenceNarrative", "narrative": "Surgery is the only curative treatment option for PPGL. The surgical approach is a high-risk procedure requiring perioperative management by a specialized multidisciplinary team in centers with broad expertise. Hemodynamic instability and hypoglycemia are the two specific complications of postsurgical PPGL. Severe hypoglycemia can occur in 13% of patients, usually 2 to 4.5 hours after tumor resection.", "evidenceDomainTag": "Acceptability of Intervention.Natures of Intervention", "publication": [ "CG-AC:RF004115" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/ten/NOI3088", "id": "CG-AC:AC150/ten/NOI3088", "type": "TieredEvidenceNarrative", "narrative": "Cumulative radiation exposure from imaging examinations should be limited for genetically predisposed asymptomatic young individuals as they will need lifelong monitoring. It should also aim to minimize anxiety in and inconvenience to patients and families.", "evidenceDomainTag": "Acceptability of Intervention.Natures of Intervention", "publication": [ "CG-AC:RF004103", "CG-AC:RF004110", "CG-AC:RF004111" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/ten/CDEC3183", "id": "CG-AC:AC150/ten/CDEC3183", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "Not provided", "narrative": "PCCs and extra-adrenal sympathetic PGLs in HPPS 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 excess or signs and symptoms related to mass effects from the neoplasm. In children the signs and symptoms of catecholamine excess are often overlooked. Clinical presentation can overlap with those of other disorders often encountered among pediatric patients, such as ADHD. Autopsy studies have shown that up to 50% of all PGL are clinically undetected. PPGL in children remains underdiagnosed. Due to the slow-growing nature of the tumors and usual delays in diagnosis, the true prevalence of PPGL in childhood is likely to be much higher than currently estimated.", "evidenceDomainTag": "Condition Escape Detection.Chances to Escape Clinical Detection", "publication": [ "CG-AC:RF004103", "CG-AC:RF004108" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/ten/RR2816", "id": "CG-AC:AC150/ten/RR2816", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "Not provided", "evidenceDomainTag": "Threat Materialization Chances.Relative Risks" }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/ten/ACPE4780", "id": "CG-AC:AC150/ten/ACPE4780", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "1", "narrative": "Penetrance of PPGLs for nonproband/nonindex individuals with SDHB pathogenic variants by age 20 was 4%, 11% by age 40, 24% by age 60, and 35% by age 80. The overall risk of metastatic disease for nonproband/nonindex carriers with PPGLs was 9% per lifetime. In all affected cases (combining both proband/index and nonproband/nonindex carriers with tumors), the risk of a second tumor was 24% and all-cause 5-year mortality was 18%.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF004114" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/ten/ACPE4783", "id": "CG-AC:AC150/ten/ACPE4783", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Penetrance estimates of PGL/PCC by gene are as follows: \\n•SDHA (200+ reported carriers): \\n-penetrance of non-probands 0% at 25 years, ≤ 10% at 70 years\\n-penetrance of all affected 7% at 25 years and 50% at 70 years \\n-rate of metastatic PGL/PCC: 12% \\n-median age of initial PGL/PCC: 28-43 years (range 8-81 years) \\n•SDHAF2 (few reported patients/families): \\n-unknown penetrance\\n-rate of metastatic PGL/PCC: <5%\\n-median age of initial PGL/PCC: 33 years (range 22-47 years) \\n•SDHB (1500 + reported carriers): \\n-penetrance of non-probands 2.2% at age 18 years \\n-penetrance of non-probands 22-26% at 60 years\\n-penetrance of all affected 24-58% at 60 years \\n-rate of metastatic PGL/PCC: 25-50%\\n-median age of initial PGL/PCC: 25-30 years (range 6-77 years) \\n•SDHC (100+ reported carriers):\\n-penetrance of 25% at 60 years\\n-rate of metastatic PGL/PCC: <5%\\n-median age of initial PGL/PCC: 33-38 years (range 12-73 years) \\n•SDHD (500+ reported carriers):\\n-penetrance of non-probands 6.4% at age 18 years \\n-penetrance of 43% at 60 years\\n-rate of metastatic PGL/PCC: 5%\\n-median age of initial PGL/PCC: 28-36 years (range 7-68 years)\\n•MAX (140+ reported carriers):\\n-penetrance of 73% at 40 years\\n-rate of metastatic PGL/PCC: 10%\\n-median age of initial PGL/PCC: 33-36 years (range 13-58 years) \\n•TMEM127 (70+ reported carriers):\\n-penetrance of 41% at 40 years \\n-rate of metastatic PGL/PCC: <5% \\n-median age of initial PGL/PCC: 45 years (range 21-84 years)", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF004102", "CG-AC:RF004104", "CG-AC:RF004108", "CG-AC:RF004111", "CG-AC:RF004113" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/ten/ACPE4781", "id": "CG-AC:AC150/ten/ACPE4781", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "For the SDHAF2, SDHD and MAX genes, tumor penetrance is primarily present in pathogenic variants on the paternal allele. Tumors have only rarely been reported in individuals with maternally inherited variants in these genes.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF004102" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/ten/ACPE4782", "id": "CG-AC:AC150/ten/ACPE4782", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Penetrance estimates vary. Penetrance was initially believed to be quite high, but larger studies with less bias from probands suggest a much lower penetrance.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF004113" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/ten/PGM3117", "id": "CG-AC:AC150/ten/PGM3117", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Among HPPS, approximately 20-25% of cases are attributed to pathogenic variants in SDHD, 8% are attributed to SDHC, 50-55% are attributed to SDHB, 4% with SDHA, 5% are attributed to TMEM127, 4% are attributed to MAX and 1% are attributed to SDHAF2.", "evidenceDomainTag": "Threat Materialization Chances.Prevalences of the Genetic Mutation", "publication": [ "CG-AC:RF004113" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/ten/EN3213", "id": "CG-AC:AC150/ten/EN3213", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "In the same family with all individuals carrying the same variant, it is possible to see lifelong asymptomatic carriers, individuals with a single head and/or neck paraganglioma, and others with metastatic PPGL.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF004110" ] } ], "tieredRecommendations": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/tr/ACPM7290", "id": "CG-AC:AC150/tr/ACPM7290", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Transition from pediatric to adult care is essential and should be initiated sometime after individuals turn 16 years of age.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF004103" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/tr/ACPM7291", "id": "CG-AC:AC150/tr/ACPM7291", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "A treatment algorithm focusing on clinical characteristics like multiple and extra-adrenal lesions and the risk of metastasis from certain HPPS pathogenic variants can enhance PPGL care.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF004104" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/tr/ACSU4176", "id": "CG-AC:AC150/tr/ACSU4176", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Screening in asymptomatic individuals with HPPS should be performed before planning a pregnancy.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF004110" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/tr/ACSU4174", "id": "CG-AC:AC150/tr/ACSU4174", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Children with a germline pathogenic or probable pathogenic variant in a PPGL predisposition gene should be offered lifelong follow-up. One guideline recommended decreasing the frequency of screening to every 5 years after 70 years of age and stopping follow-up at 80 years of age. One guideline suggests that if a person is asymptomatic and without a prior history of elevation, annual follow-up and testing can be omitted or done with imaging every 2-3 years.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF004103", "CG-AC:RF004106", "CG-AC:RF004110" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/tr/ACSU4175", "id": "CG-AC:AC150/tr/ACSU4175", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Early diagnosis and therapeutic intervention are expected to reduce morbidity and mortality. Surgery remains the only curative treatment. One study found that long-term surveillance leads to the early detection of PPGL, reduced risk of metastasis, and improved prognosis in individuals with SDHB pathogenic variants. This multi-center study included 181 SDHB pathogenic variant carriers (33 probands, 148 non-probands) with at least 1 surveillance episode (clinical, biochemical, imaging). Median duration of follow-up was 6 years. Tumors were found in 20% of non-probands undergoing surveillance (age range 9-76 years). Estimated 10-year metastasis-free survival was 66% for probands and 84% for non-probands with surveillance-detected tumors (P = .027). Surveillance-detected tumors were smaller than those in probands (median 27 mm vs 45 mm respectively, P = .001). Tumor size ≥40 mm was associated with progression to metastatic disease (OR 16.9, 95% CI 2.3-187.9, P = .001). Patients with surveillance-detected tumors had lower mortality compared to probands: 10-year overall survival was 79% for probands and 100% for non-probands (P = .029).", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF004103", "CG-AC:RF004104", "CG-AC:RF004112" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/tr/ACSU4177", "id": "CG-AC:AC150/tr/ACSU4177", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Multiple guidelines recommend gene-specific HPPS surveillance, though specific intervals and ages to start recommendations differ slightly. The main aim of surveillance programs in asymptomatic individuals with pathogenic variants in HPPS genes, is to identify disease at an early stage to allow a successful intervention at the appropriate time, improve cure rates and limit the chance of malignant transformation and metastasis. Surveillance includes the following (specific intervals listed are from most recent guideline): \\n•Medical visits (including symptom and sign questionnaire) with blood pressure measurement\\n-Repeat annually for SDHA, SDHAF2, SDHB, SDHC, TMEM127, MAX and SDHD if paternally inherited, de novo or cannot establish inheritance.\\n•Plasma fractionated metanephrines or 24-hour urine fractionated metanephrines\\n-Repeat annually for SDHA, SDHAF2, SDHB, SDHC, TMEM127, MAX, and SDHD if paternally inherited, de novo or cannot establish inheritance\\n•Whole body MRI and neck MRI (concurrently)\\n-Repeat every 2 years for SDHA, SDHAF2, SDHB, MAX, TMEM127\\n-Repeat every 3 years for SDHC, SDHD if paternally inherited, de novo or cannot establish inheritance. \\n•Complete blood count\\n-Repeat annually for SDHA, SDHB, SDHC, SDHD if paternally inherited, de novo or cannot establish inheritance.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF004102", "CG-AC:RF004103", "CG-AC:RF004104", "CG-AC:RF004105", "CG-AC:RF004106", "CG-AC:RF004107", "CG-AC:RF004108", "CG-AC:RF004109", "CG-AC:RF004110", "CG-AC:RF004111" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/tr/ACCA3867", "id": "CG-AC:AC150/tr/ACCA3867", "type": "TieredRecommendation", "evidenceSourceTier": "Not provided", "recommendation": "None identified", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid" }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/tr/ACPM7289", "id": "CG-AC:AC150/tr/ACPM7289", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Given the appreciable risk for bilateral tumors in HPPS, consideration should be given to cortical-sparing adrenalectomy. Smaller, less aggressive renal tumors may be eligible for partial nephrectomy, while those with larger, more aggressive tumors should undergo radical nephrectomy.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF004103", "CG-AC:RF004106" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/tr/ACPM7284", "id": "CG-AC:AC150/tr/ACPM7284", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Tumor resection by surgery is the first-line treatment. Surgery is the only curative treatment option for PPGL. The decision to undertake surgery and the surgical approach should be discussed at a specialist multidisciplinary team meeting and surgery should be performed by a surgeon experienced in PPGL surgery.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF004103", "CG-AC:RF004104", "CG-AC:RF004105", "CG-AC:RF004109" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/tr/ACPM7287", "id": "CG-AC:AC150/tr/ACPM7287", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Patients with a confirmed diagnosis of HPPS should have blood and/or urine screening for tumors prior to any surgical procedures.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF004106", "CG-AC:RF004107" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/tr/ACPM7286", "id": "CG-AC:AC150/tr/ACPM7286", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "The management of patients with PPGL requires specialist multidisciplinary input and should ideally be performed in a center with expertise in managing PPGL.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF004103", "CG-AC:RF004105" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/tr/ACPM7285", "id": "CG-AC:AC150/tr/ACPM7285", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "During adulthood a combination of MRI and PET-CT should be used as first-line imaging for initial tumor screening.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF004110" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/tr/ACPM7288", "id": "CG-AC:AC150/tr/ACPM7288", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Multiple guidelines recommend gene-specific HPPS tumor surveillance, though specific ages to initiate surveillance differ slightly. The following assessments are recommended (specific ages to start by HPPS-associated gene are from most recent guideline): \\n•Medical visits (including symptom and sign questionnaire) with blood pressure measurement\\n-Start at time of diagnosis for SDHA, SDHAF2, SDHB, SDHC, TMEM127, SDHD if paternally inherited, de novo or cannot establish inheritance\\n-Start at age 10 y for MAX\\n•Plasma fractionated metanephrines or 24-hour urine fractionated metanephrines\\n-Start at age 10 y for SDHA, SDHC, MAX, SDHD if paternally inherited, de novo or cannot establish inheritance\\n-Start at age 6 y for SDHB\\n-Start at 21 y for SDHAF2, TMEM127\\n•Whole body MRI and neck MRI (concurrently)\\n-Start at age 6 y for SDHB\\n-Start at age 10 y for SDHA, SDHC, SDHD if paternally inherited, de novo or cannot establish inheritance\\n-Start at age 15 y for MAX\\n-Start at age 21 for SDHAF2, TMEM127\\n•Complete blood count\\n-Start at age 6 y for SDHB\\n-Start at age 10 y for SDHA, SDHC, SDHD if paternally inherited, de novo or cannot establish inheritance", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF004102", "CG-AC:RF004103", "CG-AC:RF004104", "CG-AC:RF004106", "CG-AC:RF004107", "CG-AC:RF004108", "CG-AC:RF004109", "CG-AC:RF004110", "CG-AC:RF004111" ] } ] }, "evidenceCategory": { "outcomeEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei", "id": "CG-AC:AC150/oei", "type": "EvidenceItem", "natureOfTheThreat": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei/nott", "id": "CG-AC:AC150/oei/nott", "type": "EvidenceLine", "prevalenceOfTheGeneticDisorder": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei/pgd", "id": "CG-AC:AC150/oei/pgd", "type": "EvidenceItem", "keyText": "< 1-2 in 100000", "sourceOfPopulation": "General population", "evidenceNarrative": { "@id": "CG-AC:AC150/en/potgd" } }, "clinicalFeatures": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei/cf", "id": "CG-AC:AC150/oei/cf", "type": "EvidenceItem", "evidenceNarrative": { "@id": "CG-AC:AC150/en/cf" } }, "naturalHistory": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei/nh", "id": "CG-AC:AC150/oei/nh", "type": "EvidenceItem", "evidenceNarrative": { "@id": "CG-AC:AC150/en/nh" } } }, "threatMaterializationChances": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei/tmc", "id": "CG-AC:AC150/oei/tmc", "type": "EvidenceLine", "modeOfInheritance": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei/moi", "id": "CG-AC:AC150/oei/moi", "type": "EvidenceItem", "keyText": "Autosomal Dominant", "evidenceNarrative": { "@id": "CG-AC:AC150/en/ACMI2895" } }, "prevalenceOfTheGeneticMutation": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei/pgm", "id": "CG-AC:AC150/oei/pgm", "type": "EvidenceItem", "keyText": ">1-2 in 100", "sourceOfPopulation": "General population", "tieredEvidenceNarrative": { "@id": "CG-AC:AC150/ten/PGM3117" } }, "penetrance": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei/pe/ACPE4782", "id": "CG-AC:AC150/oei/pe/ACPE4782", "type": "EvidenceItem", "keyText": "Unknown", "tieredEvidenceNarrative": { "@id": "CG-AC:AC150/ten/ACPE4782" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei/pe/ACPE4781", "id": "CG-AC:AC150/oei/pe/ACPE4781", "type": "EvidenceItem", "keyText": "Unknown", "tieredEvidenceNarrative": { "@id": "CG-AC:AC150/ten/ACPE4781" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei/pe/ACPE4783", "id": "CG-AC:AC150/oei/pe/ACPE4783", "type": "EvidenceItem", "keyText": "5-39 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC150/ten/ACPE4783" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei/pe/ACPE4780", "id": "CG-AC:AC150/oei/pe/ACPE4780", "type": "EvidenceItem", "keyText": "5-39 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC150/ten/ACPE4780" } } ], "relativeRisk": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei/rr/RR2816", "id": "CG-AC:AC150/oei/rr/RR2816", "type": "EvidenceItem", "keyText": "Unknown", "tieredEvidenceNarrative": { "@id": "CG-AC:AC150/ten/RR2816" } } ], "expressivity": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/oei/ex/EN3213", "id": "CG-AC:AC150/oei/ex/EN3213", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC150/ten/EN3213" } } ] } }, "interventionEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei", "id": "CG-AC:AC150/iei", "type": "EvidenceItem", "acceptabilityOfIntervention": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/aoi", "id": "CG-AC:AC150/iei/aoi", "type": "EvidenceLine", "natureOfIntervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/noi/NOI3088", "id": "CG-AC:AC150/iei/noi/NOI3088", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC150/ten/NOI3088" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/noi/NOI3087", "id": "CG-AC:AC150/iei/noi/NOI3087", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC150/ten/NOI3087" } } ] }, "effectivenessOfIntervention": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/eoi", "id": "CG-AC:AC150/iei/eoi", "type": "EvidenceLine", "patientManagement": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/pm/ACPM7288", "id": "CG-AC:AC150/iei/pm/ACPM7288", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC150/tr/ACPM7288" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/pm/ACPM7285", "id": "CG-AC:AC150/iei/pm/ACPM7285", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC150/tr/ACPM7285" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/pm/ACPM7286", "id": "CG-AC:AC150/iei/pm/ACPM7286", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC150/tr/ACPM7286" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/pm/ACPM7287", "id": "CG-AC:AC150/iei/pm/ACPM7287", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC150/tr/ACPM7287" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/pm/ACPM7284", "id": "CG-AC:AC150/iei/pm/ACPM7284", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC150/tr/ACPM7284" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/pm/ACPM7289", "id": "CG-AC:AC150/iei/pm/ACPM7289", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC150/tr/ACPM7289" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/pm/ACPM7291", "id": "CG-AC:AC150/iei/pm/ACPM7291", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC150/tr/ACPM7291" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/pm/ACPM7290", "id": "CG-AC:AC150/iei/pm/ACPM7290", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC150/tr/ACPM7290" } } ], "circumstanceToAvoid": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/cta/ACCA3867", "id": "CG-AC:AC150/iei/cta/ACCA3867", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC150/tr/ACCA3867" } } ], "surveillance": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/su/ACSU4177", "id": "CG-AC:AC150/iei/su/ACSU4177", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC150/tr/ACSU4177" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/su/ACSU4175", "id": "CG-AC:AC150/iei/su/ACSU4175", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC150/tr/ACSU4175" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/su/ACSU4174", "id": "CG-AC:AC150/iei/su/ACSU4174", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC150/tr/ACSU4174" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/su/ACSU4176", "id": "CG-AC:AC150/iei/su/ACSU4176", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC150/tr/ACSU4176" } } ] }, "conditionEscapeDetection": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/ced", "id": "CG-AC:AC150/iei/ced", "type": "EvidenceLine", "chanceToEscapeDetection": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC150/iei/cted/CDEC3183", "id": "CG-AC:AC150/iei/cted/CDEC3183", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC150/ten/CDEC3183" } } ] } } }, "references": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF000337", "id": "CG-AC:RF000337", "type": "Publication", "publicationType": "GeneReview", "citation": "S Kirmani, WF Young. 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