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Next-generation sequencing and CYP21A2 molecular testing confirmed simple virilizing CAH, while reticence and repeated imaging misinterpretation contributed to the delay.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/case-report-challenges-of-an-extremely-delayed-diagnosis-of-classic-congenital-adrenal-hyperplasia/410250/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/case-report-challenges-of-an-extremely-delayed-diagnosis-of-classic-congenital-adrenal-hyperplasia/410250.png","ImageObject",300,407,{"name":42,"@type":43},"Margaret","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-01","2026-09-28",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",8,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why was the diagnosis delayed in this 46,XX case?","Question",{"text":63,"@type":64},"The patient’s hormonal results were initially interpreted as consistent with hypogonadotropic hypogonadism, and clinicians focused on a presumed prostate hyperplasia. Repeated failure to recognize Müllerian remnants on imaging and the patient’s reticent attitude also contributed to the prolonged delay.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What genetic and molecular findings confirmed the condition?",{"text":68,"@type":64},"Next-generation sequencing identified heterozygous variants relevant to sex development differences, and CYP21A2 molecular analysis demonstrated compound heterozygosity for two pathogenic variants (p. I173N and p. R357W), confirming simple virilizing CAH.",{"name":70,"@type":61,"acceptedAnswer":71},"What key clinical features prompted further evaluation?",{"text":72,"@type":64},"The patient was under follow-up for prostate hyperplasia and was referred after finding giant bilateral adrenal myelolipomas, which led to more comprehensive biochemical and genetic testing.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},410250,1790765999,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":111,"show_sort_weight":112,"slug":113},"Research & Report",30,"research-report",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},9,"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":107,"language":139,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":12,"update_tm":143,"read_time":144,"preview_page_count":4},137451207643,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","TYPE Case Report  \nPUBLISHED 18 December 2025 DOI 10.3389/fendo.2025.1726368  \nOPEN ACCESS  \nEDITED BY  \nRita Bertalan,  \nSemmelweis University, Hungary  \nREVIEWED BY  \nPeter Igaz,  \nSemmelweis University, Hungary Dr Anirban Sinha,  \nMedical College and Hospital, India Manjiri Karlekar,  \nKing Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, India  \n*CORRESPONDENCE  \nIrene Campi  \n [i.campi@auxologico.it](i.campi@auxologico.it)  \nRECEIVED 16 October 2025  \nREVISED 17 November 2025  \nACCEPTED 25 November 2025  \nPUBLISHED 18 December 2025  \nCITATION  \nCasiraghi A, Campi I, Federici S, Cernigliaro F, Menabò S and Persani L (2025) Case Report: Challenges of an extremely delayed diagnosis of classic congenital adrenal hyperplasia in a completely virilized 46,XX patient.  \nFront. Endocrinol. 16:1726368 .  \ndoi: 10.3389/fendo.2025.1726368  \nCOPYRIGHT  \n© 2025 Casiraghi, Campi, Federici, Cernigliaro, Menabò and Persani. This is an open-access article distributed under the terms of the  \nCreative Commons Attribution License (CC BY) .  \nThe use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.  \nCase Report: Challenges of an extremely delayed diagnosis of classic congenital adrenal hyperplasia in a completely virilized 46,XX patient  \nAlice Casiraghi 1, Irene Campi 2*, Silvia Federici 1,2,  \nFranco Cernigliaro 3, Soara Menabò 4 and Luca Persani 1,2  \n1 Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy, 2 Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy, 3 Department of Radiology, IRCCS Istituto Auxologico Italiano, Milan, Italy, 4 Medical Genetics Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy  \nClassic Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency is typically diagnosed in early life. We report a 46,XX completely virilized 46,XX patient who was diagnosed with classic CAH at the age of 73 years. He was under follow-up for prostate hyperplasia and referred after the finding of giant bilateral adrenal myelolipomas. He presented with hormonal values initially interpreted as suggestive of hypogonadotropic hypogonadism, prompting further biochemical and genetic analysis. Next-generation sequencing identified heterozygous variants in X-linked genes, uncovering a 46,XX difference of sex development (DSD) . Then, CYP21A2 molecular analysis revealed compound heterozygosity for two pathogenic variants (p. I173N, p. R357W), confirming simple virilizing CAH. The patient’s reticent attitude contributed to the diagnostic delay. However, this unique case reveals the challenges generated by the paraurethral glands hyperplasia - mimicking a prostate due to prolonged untreated hyperandrogenism - as well as the repeated failure to recognize Müllerian remnants on imaging and the critical issues related to diagnostic communication.  \nKEYWORDS  \ncongenital adrenal hyperplasia, diagnostic delay, 46,XX disorder of sex development, adrenal myelolipoma, skene gland hyperplasia, case report  \n1 Introduction  \nCongenital adrenal hyperplasia (CAH) encompasses a group of recessive disorders of adrenal steroidogenesis leading to impaired cortisol biosynthesis. Defective cortisol feedback results in chronic ACTH stimulation of the adrenals, leading to accumulation of upstream precursors and gland hyperplasia (1) . These precursors are shunted into the androgen synthesis pathway, leading to hyperandrogenism.  \nFrontiers in Endocrinology 01 [frontiersin.org](frontiersin.org)  \nOver 95% of CAH cases result from biallelic loss-of-function mutations in the CYP21A2 gene encoding 21-hydroxylase, which converts 17-OH-progesterone (17OH-P) ","cbCaidGz0wfVryPx","https://ap.wps.com/l/cbCaidGz0wfVryPx","pdf",8641956,"English","# Introduction\n## CAH overview and CYP21A2 deficiency\n## Clinical presentation of classic CAH (SW-CAH vs SV-CAH)\n## Typical timing of diagnosis and reasons for missed cases\n# Case description (patient history and diagnostic workup)","[{\"question\":\"Why was the diagnosis delayed in this 46,XX case?\",\"answer\":\"The patient’s hormonal results were initially interpreted as consistent with hypogonadotropic hypogonadism, and clinicians focused on a presumed prostate hyperplasia. Repeated failure to recognize Müllerian remnants on imaging and the patient’s reticent attitude also contributed to the prolonged delay.\"},{\"question\":\"What genetic and molecular findings confirmed the condition?\",\"answer\":\"Next-generation sequencing identified heterozygous variants relevant to sex development differences, and CYP21A2 molecular analysis demonstrated compound heterozygosity for two pathogenic variants (p. I173N and p. R357W), confirming simple virilizing CAH.\"},{\"question\":\"What key clinical features prompted further evaluation?\",\"answer\":\"The patient was under follow-up for prostate hyperplasia and was referred after finding giant bilateral adrenal myelolipomas, which led to more comprehensive biochemical and genetic testing.\"}]","Case Report - Challenges of an Extremely Delayed Diagnosis of Classic Congenital Adrenal Hyperplasia | PDF",1790584776,18]