{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:03:41Z","timestamp":1789621421954,"version":"build-2803163510"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>17\u03b1-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\u2013phenotype patterns are scarce.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>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\u2013subtype trends, and document rare incidental manifestations to inform clinical care and genetic counseling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2019s pathogenicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The homozygous c.985_987delTACinsAA (p.Y329Kfs\n                      <jats:sup>*<\/jats:sup>\n                      90) variant predominated in complete-type patients. A novel nonsense variant c.1218G&amp;gt;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\u2011M\u00fcllerian 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This cohort extends the Chinese pathogenic CYP17A1 variant spectrum and reveals tentative genotype\u2013subtype 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1824733","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:29:23Z","timestamp":1789619363000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Extended genotype\u2013phenotype spectrum of 17\u03b1-hydroxylase\/17,20-lyase deficiency: a nine-case series featuring a novel mutation, suspected TART-like lesions, and multisystem involvement"],"prefix":"10.3389","volume":"17","author":[{"given":"Hemeng","family":"Chong","sequence":"first","affiliation":[{"name":"Department of Pediatrics, the Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Pathology, the Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, the Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, the Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, the Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalei","family":"Pi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, the Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgac029","article-title":"Phenotypic heterogeneity and fertility potential of patients with 17-hydroxylase\/17,20-lyase deficiency","volume":"107","author":"Xu","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-016-0957-y","article-title":"Clinical and molecular manifestation of fifteen 17OHD patients: a novel mutation and a founder effect","volume":"53","author":"Han","year":"2016","journal-title":"Endocrine"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2016.02.002","article-title":"Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic","volume":"165","author":"Auchus","year":"2017","journal-title":"J Steroid Biochem Mol Biol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1210\/jc.2003-031021","article-title":"Two prevalent CYP17 mutations and genotype-phenotype correlations in 24 Brazilian patients with 17-hydroxylase deficiency","volume":"89","author":"Costa-Santos","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"B5","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1210\/edrv-12-1-91","article-title":"17 alpha-hydroxylase\/17,20-lyase deficiency: from clinical investigation to molecular definition","volume":"12","author":"Yanase","year":"1991","journal-title":"Endocr Rev"},{"key":"B6","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.mce.2006.01.003","article-title":"A novel compound heterozygous mutation of K494_V495 deletion plus R496L and D487_F489 deletion in extreme C-terminus of cytochrome P450c17 causes 17alpha-hydroxylase deficiency","volume":"249","author":"Lee","year":"2006","journal-title":"Mol Cell Endocrinol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2013.11.011","article-title":"Fertility in patients with genetic deficiencies of cytochrome P450c17 (CYP17A1): combined 17-hydroxylase\/17,20-lyase deficiency and isolated 17,20-lyase deficiency","volume":"101","author":"Marsh","year":"2014","journal-title":"Fertil Steril"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-024-03962-6","article-title":"17\u03b1 hydroxylase\/17,20 lyase deficiency: clinical features and genetic insights from a large Turkey cohort","volume":"85","author":"Siklar","year":"2024","journal-title":"Endocrine"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23626","article-title":"Recommendations for interpreting the loss of function PVS1 ACMG\/AMP variant criterion","volume":"39","author":"Abou Tayoun","year":"2018","journal-title":"Hum Mutat"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgae773","article-title":"17\u03b1-hydroxylase\/17,20-lyase deficiency (17-OHD): a meta-analysis of reported cases","volume":"110","author":"Willemsen","year":"2025","journal-title":"J Clin Endocrinol Metab"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/s0015-0282(00)00500-8","article-title":"Induction of endometrial cycles and ovulation in a woman with combined 17alpha-hydroxylase\/17,20-lyase deficiency due to compound heterozygous mutations on the p45017alpha gene","volume":"73","author":"Matsuzaki","year":"2000","journal-title":"Fertil Steril"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3109\/09513590.2014.895980","article-title":"CYP17A1 gene mutations and hypertension variations found in 46, XY females with combined 17\u03b1-hydroxylase\/17, 20-lyase deficiency","volume":"30","author":"Wang","year":"2014","journal-title":"Gynecol Endocrinol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.4158\/EP161610.OR","article-title":"17\u03b1-hydroxylase\/17, 20-lyase deficiency: clinical and molecular characterization of eight Chinese patients","volume":"23","author":"Wu","year":"2017","journal-title":"Endocr Pract"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.978026","article-title":"Clinical characteristics and molecular etiology of partial 17\u03b1-hydroxylase deficiency diagnosed in 46,XX patients","volume":"13","author":"Zhang","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-21-0152","article-title":"The broad phenotypic spectrum of 17\u03b1-hydroxylase\/17,20-lyase (CYP17A1) deficiency: a case series","volume":"185","author":"Sun","year":"2021","journal-title":"Eur J Endocrinol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1387\/ijdb.082758ea","article-title":"Estrogen regulation of placental angiogenesis and fetal ovarian development during primate pregnancy","volume":"54","author":"Albrecht","year":"2010","journal-title":"Int J Dev Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/s0960-0760(01)00158-3","article-title":"The ovarian phenotype of the aromatase knockout (ArKO) mouse","volume":"79","author":"Britt","year":"2001","journal-title":"J Steroid Biochem Mol Biol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1186\/s13048-024-01448-7","article-title":"Ovarian fibrosis: molecular mechanisms and potential therapeutic targets","volume":"17","author":"Gu","year":"2024","journal-title":"J Ovarian Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2022.109041","article-title":"Whole exome sequencing applied to 42 Han Chinese patients with posterior hypospadias","volume":"184","author":"Shaomei","year":"2022","journal-title":"Steroids"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1210\/mend-2-6-564","article-title":"Structural characterization of normal and mutant human steroid 17 alpha-hydroxylase genes: molecular basis of one example of combined 17 alpha-hydroxylase\/17,20 lyase deficiency","volume":"2","author":"Kagimoto","year":"1988","journal-title":"Mol Endocrinol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-68-2-309","article-title":"Combined 17-hydroxylase and 17,20-desmolase deficiencies: evidence for synthesis of a defective cytochrome P450c17","volume":"68","author":"Winter","year":"1989","journal-title":"J Clin Endocrinol Metab"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/BF03260061","article-title":"17alpha-hydroxylase deficiency: biochemical and molecular findings in two sisters and their family","volume":"8","author":"Perez","year":"2004","journal-title":"Mol Diagn"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.989695","article-title":"Ovarian gonadoblastoma with dysgerminoma in a girl with 46,XX karyotype 17a-hydroxylase\/17, 20-lyase deficiency: a case report and literature review","volume":"13","author":"Yin","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2653","article-title":"A novel point mutation in P450c17 (CYP17) causing combined 17alpha-hydroxylase\/17,20-lyase deficiency","volume":"91","author":"Brooke","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3109\/09513590.2015.1116509","article-title":"Gonadal Malignancy in 202 female patients with disorders of sex development containing Y-chromosome material","volume":"32","author":"Jiang","year":"2016","journal-title":"Gynecol Endocrinol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-2036","article-title":"Molecular characterization of testicular adrenal rest tumors in congenital adrenal hyperplasia: lesions with both adrenocortical and Leydig cell features","volume":"100","author":"Smeets","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1210\/er.2018-00258","article-title":"Testicular adrenal rest tumors: current insights on prevalence, characteristics, origin, and treatment","volume":"40","author":"Manon","year":"2019","journal-title":"Endocr Rev"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehx545","article-title":"Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy","volume":"38","author":"Sedaghat-Hamedani","year":"2017","journal-title":"Eur Heart J"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2016.207","article-title":"Left ventricular noncompaction cardiomyopathy: cardiac, neuromuscular, and genetic factors","volume":"14","author":"Finsterer","year":"2017","journal-title":"Nat Rev Cardiol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1016\/j.jmb.2008.09.070","article-title":"Ubiquitin-proteasome system impairment caused by a missense cardiac myosin-binding protein C mutation and associated with cardiac dysfunction in hypertrophic cardiomyopathy","volume":"384","author":"Bahrudin","year":"2008","journal-title":"J Mol Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-17-1012","article-title":"Late gadolinium enhancement for prediction of mutation-positive hypertrophic cardiomyopathy on the basis of panel-wide sequencing","volume":"82","author":"Teramoto","year":"2018","journal-title":"Circ J"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4065\/83.6.630","article-title":"Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy","volume":"83","author":"Olivotto","year":"2008","journal-title":"Mayo Clin Proc"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/antiox13070842","article-title":"Hearing loss and oxidative stress: a comprehensive review","volume":"13","author":"Maniaci","year":"2024","journal-title":"Antioxidants (Basel)"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00473.x","article-title":"Glucocorticoid-stimulated, transcription-independent release of annexin A1 by cochlear Hensen cells","volume":"158","author":"Kalinec","year":"2009","journal-title":"Br J Pharmacol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.4103\/ijem.IJEM_10_17","article-title":"Endocrine glands and hearing: auditory manifestations of various endocrine and metabolic conditions","volume":"21","author":"Cherian","year":"2017","journal-title":"Indian J Endocrinol Metab"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s12070-021-02378-2","article-title":"Hearing loss and hypertension: a literature review","volume":"74","author":"Umashankar","year":"2022","journal-title":"Indian J Otolaryngol Head Neck Surg"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1824733\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:29:24Z","timestamp":1789619364000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1824733\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":37,"alternative-id":["10.3389\/fendo.2026.1824733"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1824733","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]},"article-number":"1824733"}}