Extended genotype-phenotype spectrum of 17α-hydroxylase/17,20-lyase deficiency: a nine-case series featuring a novel mutation, suspected TART-like lesions, and multisystem involvement.
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CONTEXT: 17α-hydroxylase/17,20-lyase deficiency (17-OHD), a rare congenital adrenal hyperplasia driven by biallelic CYP17A1 variants, shows extensive clinical and molecular heterogeneity; data on rare phenotypes and genotype-phenotype patterns are scarce. OBJECTIVE: To characterize clinical, hormonal, gonadal pathological, and genetic features of nine Chinese patients with 17-OHD from a single center, expand the population-specific CYP17A1 variant spectrum, explore genotype-subtype trends, and document rare incidental manifestations to inform clinical care and genetic counseling. METHODS: A retrospective case series included nine genetically verified patients (seven 46,XY, two 46,XX). SWISS-MODEL homology modeling and American College of Medical Genetics and Genomics (ACMG) criteria were applied to assess the novel variant's pathogenicity. RESULTS: The homozygous c.985_987delTACinsAA (p.Y329Kfs*90) variant predominated in complete-type patients. A novel nonsense variant c.1218G>A, p.W406X, predicted to truncate 103 C-terminal amino acids, was tentatively classified as pathogenic based on PVS1/PM2/PM3/PM4 evidence in one partial-type case. We observed a descriptive trend: biallelic truncating loss-of-function variants correlated with complete 17-OHD, while partial forms carried missense variants with residual enzyme activity. The two 46,XX complete-type patients had bilateral ovarian atrophy and low anti‑Müllerian hormone (AMH); two 46,XY patients presented with incidental unilateral sensorineural hearing loss. One 46,XY patient harbored gonadal steroidogenic cell nests resembling testicular adrenal rest tumors (TART), without adrenal-specific immunohistochemistry (IHC) to confirm cellular origin. One proband had two independent monogenic diseases: 17-OHD and left ventricular non-compaction cardiomyopathy, carrying concurrent CYP17A1 and sarcomeric gene (MYBPC3/ACTN2/TTN) variants. All patients had elevated adrenocorticotropic hormone (ACTH), most had low cortisol, and 11-deoxycorticosterone (11-DOC) and corticosterone levels were variably elevated. CONCLUSIONS: This cohort extends the Chinese pathogenic CYP17A1 variant spectrum and reveals tentative genotype-subtype associations plus rare co-occurring phenotypes. Larger multicenter cohorts and functional experiments are needed to validate causal links between atypical manifestations and 17-OHD. Early adrenal steroid profiling and CYP17A1 sequencing are recommended for patients with hypertension, hypokalemia, and disorders of sex development. Serial ovarian reserve testing is required for 46,XX patients, and long-term gonadal imaging follow-up for 46,XY patients with gonadal dysgenesis.