{ "@context": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/context/doc", "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151", "id": "CG-AC:AC151", "type": "ClinicalActionabilityReport", "metadata": { "schemaLabel": "AC-Sepio.Beta-1 (Unofficial)", "contentVersionId": "28154", "producedAtUTC": "Thu, 10 Sep 2026 19:38:36 -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/AC151/co", "id": "CG-AC:AC151/co", "type": "GeneticCondition", "label": "Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency" }, "outcome": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/ou/Infertility%2Fsubfertility%20in%20females", "id": "CG-AC:AC151/ou/Infertility/subfertility in females", "type": "Outcome", "label": "Infertility/subfertility in females" } ], "intervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/intv/Glucocorticoid%20therapy", "id": "CG-AC:AC151/intv/Glucocorticoid therapy", "type": "Intervention", "label": "Glucocorticoid therapy" } ], "clinicalActionabilityProfile": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/cap", "id": "CG-AC:AC151/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": "Wed, 09 Feb 2022 00:00:00 -0000", "releaseNum": "1.2.4", "media": "call" }, "evidenceStatements": { "evidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/en/potgd", "id": "CG-AC:AC151/en/potgd", "type": "EvidenceNarrative", "narrative": "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.", "evidenceDomainTag": "Nature of the Threat.Prevalence of the Genetic Disorder", "publication": [ "CG-AC:RF000811" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/en/cf", "id": "CG-AC:AC151/en/cf", "type": "EvidenceNarrative", "narrative": "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.", "evidenceDomainTag": "Nature of the Threat.Clinical Features", "publication": [ "CG-AC:RF000811", "CG-AC:RF000812", "CG-AC:RF000813", "CG-AC:RF000814", "CG-AC:RF000810" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/en/nh", "id": "CG-AC:AC151/en/nh", "type": "EvidenceNarrative", "narrative": "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.", "evidenceDomainTag": "Nature of the Threat.Natural History", "publication": [ "CG-AC:RF000811", "CG-AC:RF000812", "CG-AC:RF000813", "CG-AC:RF000814" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/en/ACMI2693", "id": "CG-AC:AC151/en/ACMI2693", "type": "EvidenceNarrative", "narrative": "Autosomal Recessive", "evidenceDomainTag": "Threat Materialization Chances.Modes of Inheritance" } ], "tieredEvidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/ten/NOI2853", "id": "CG-AC:AC151/ten/NOI2853", "type": "TieredEvidenceNarrative", "narrative": "Glucocorticoid overtreatment may cause Cushing syndrome. As such, glucocorticoids are recommended in only a subset of patients with NCCAH and require monitoring.", "evidenceDomainTag": "Acceptability of Intervention.Natures of Intervention", "publication": [ "CG-AC:RF000812" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/ten/CDEC2845", "id": "CG-AC:AC151/ten/CDEC2845", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "NCCAH is often not diagnosed until adolescence when the first symptoms appear. Reduced fertility may be the only symptom of disease.", "evidenceDomainTag": "Condition Escape Detection.Chances to Escape Clinical Detection", "publication": [ "CG-AC:RF000814" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/ten/ACPE4105", "id": "CG-AC:AC151/ten/ACPE4105", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "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", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000811", "CG-AC:RF000812" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/ten/EN2854", "id": "CG-AC:AC151/ten/EN2854", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "The NCCAH phenotype may be highly variable even with a family sharing the same CYP21A2 genotype.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF000811" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/ten/EN2853", "id": "CG-AC:AC151/ten/EN2853", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "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.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF000812" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/ten/PGM2803", "id": "CG-AC:AC151/ten/PGM2803", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "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.", "evidenceDomainTag": "Threat Materialization Chances.Prevalences of the Genetic Mutation", "publication": [ "CG-AC:RF000811" ] } ], "tieredRecommendations": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/tr/REC2939", "id": "CG-AC:AC151/tr/REC2939", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "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).", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF000811" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/tr/ACPM5625", "id": "CG-AC:AC151/tr/ACPM5625", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "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.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF000811", "CG-AC:RF000812", "CG-AC:RF000815" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/tr/ACPM5624", "id": "CG-AC:AC151/tr/ACPM5624", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Treatment is suggested for NCCAH only in adults with patient-important hyperandrogenism with the option of discontinuing treatment once symptoms resolve.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF000811", "CG-AC:RF000812", "CG-AC:RF000815" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/tr/ACPM5626", "id": "CG-AC:AC151/tr/ACPM5626", "type": "TieredRecommendation", "evidenceSourceTier": "Not provided", "recommendation": "The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet algorithm to help clinical decision-making following newborn screening for congenital adrenal hyperplasia (Elevated 17-OHP): https://www.acmg.net/PDFLibrary/Elevated-17-OHP-Algorithm.pdf", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements" } ] }, "evidenceCategory": { "outcomeEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/oei", "id": "CG-AC:AC151/oei", "type": "EvidenceItem", "natureOfTheThreat": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/oei/nott", "id": "CG-AC:AC151/oei/nott", "type": "EvidenceLine", "prevalenceOfTheGeneticDisorder": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/oei/pgd", "id": "CG-AC:AC151/oei/pgd", "type": "EvidenceItem", "keyText": ">1-2 in 100", "sourceOfPopulation": "General population", "evidenceNarrative": { "@id": "CG-AC:AC151/en/potgd" } }, "clinicalFeatures": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/oei/cf", "id": "CG-AC:AC151/oei/cf", "type": "EvidenceItem", "evidenceNarrative": { "@id": "CG-AC:AC151/en/cf" } }, "naturalHistory": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/oei/nh", "id": "CG-AC:AC151/oei/nh", "type": "EvidenceItem", "evidenceNarrative": { "@id": "CG-AC:AC151/en/nh" } } }, "threatMaterializationChances": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/oei/tmc", "id": "CG-AC:AC151/oei/tmc", "type": "EvidenceLine", "modeOfInheritance": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/oei/moi", "id": "CG-AC:AC151/oei/moi", "type": "EvidenceItem", "keyText": "Autosomal Recessive", "evidenceNarrative": { "@id": "CG-AC:AC151/en/ACMI2693" } }, "prevalenceOfTheGeneticMutation": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/oei/pgm", "id": "CG-AC:AC151/oei/pgm", "type": "EvidenceItem", "keyText": ">1-2 in 100", "sourceOfPopulation": "General population", "tieredEvidenceNarrative": { "@id": "CG-AC:AC151/ten/PGM2803" } }, "penetrance": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/oei/pe/ACPE4105", "id": "CG-AC:AC151/oei/pe/ACPE4105", "type": "EvidenceItem", "keyText": "Unknown", "tieredEvidenceNarrative": { "@id": "CG-AC:AC151/ten/ACPE4105" } } ], "expressivity": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/oei/ex/EN2853", "id": "CG-AC:AC151/oei/ex/EN2853", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC151/ten/EN2853" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/oei/ex/EN2854", "id": "CG-AC:AC151/oei/ex/EN2854", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC151/ten/EN2854" } } ] } }, "interventionEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/iei", "id": "CG-AC:AC151/iei", "type": "EvidenceItem", "acceptabilityOfIntervention": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/iei/aoi", "id": "CG-AC:AC151/iei/aoi", "type": "EvidenceLine", "natureOfIntervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/iei/noi/NOI2853", "id": "CG-AC:AC151/iei/noi/NOI2853", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC151/ten/NOI2853" } } ] }, "effectivenessOfIntervention": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/iei/eoi", "id": "CG-AC:AC151/iei/eoi", "type": "EvidenceLine", "patientManagement": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/iei/pm/ACPM5626", "id": "CG-AC:AC151/iei/pm/ACPM5626", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC151/tr/ACPM5626" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/iei/pm/ACPM5624", "id": "CG-AC:AC151/iei/pm/ACPM5624", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC151/tr/ACPM5624" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/iei/pm/REC2939", "id": "CG-AC:AC151/iei/pm/REC2939", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC151/tr/REC2939" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/iei/pm/ACPM5625", "id": "CG-AC:AC151/iei/pm/ACPM5625", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC151/tr/ACPM5625" } } ] }, "conditionEscapeDetection": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/iei/ced", "id": "CG-AC:AC151/iei/ced", "type": "EvidenceLine", "chanceToEscapeDetection": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC151/iei/cted/CDEC2845", "id": "CG-AC:AC151/iei/cted/CDEC2845", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC151/ten/CDEC2845" } } ] } } }, "references": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF000810", "id": "CG-AC:RF000810", "type": "Publication", "publicationType": "OMIM", "citation": "Online Medelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency. MIM: 2019102016 Aug 04. ", "webUrl": "https://www.omim.org/entry/201910", "xdbref": [ "OMIM:201910" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF000811", "id": "CG-AC:RF000811", "type": "Publication", "publicationType": "PMID", "citation": "Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R. Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women. Hum Reprod Update. (2017) 23(5):580-599.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=28582566", "xdbref": [ "PMID:28582566" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF000812", "id": "CG-AC:RF000812", "type": "Publication", "publicationType": "PMID", "citation": "Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. (2010) 95(9):4133-60.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=20823466", "xdbref": [ "PMID:20823466" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF000813", "id": "CG-AC:RF000813", "type": "Publication", "publicationType": "GeneReview", "citation": "S Nimkarn, PK Gangishetti, M Yau, MI New. 21-hydroxylase-deficient congenital adrenal hyperplasia. 2002 Feb 26[Updated 2016 Feb 04]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washingtom, Seattle; 1993-2026. ", "webUrl": "https://www.ncbi.nlm.nih.gov/books/NBK1171/", "xdbref": [ "GeneReview:NBK1171", "PMID:20301350" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF000814", "id": "CG-AC:RF000814", "type": "Publication", "publicationType": "Orphanet", "citation": "Congenital adrenal hyperplasia. Orphanet encyclopedia [Internet]", "xdbref": [ "Orphanet:418" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF000815", "id": "CG-AC:RF000815", "type": "Publication", "publicationType": "PMID", "citation": "Clayton PE, Miller WL, Oberfield SE, Ritzen EM, Sippell WG, Speiser PW. Consensus statement on 21-hydroxylase deficiency from the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society. Horm Res. (2002) 58(4):188-95.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=12324718", "xdbref": [ "PMID:12324718" ] } ] }