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NR0B1-related adrenal hypoplasia congenita (AHC) is an X-linked disorder that can appear after infancy and may mimic congenital adrenal hyperplasia (CAH). A 13-year-old boy previously diagnosed with CAH had low ACTH and absent puberty; switching to hydrocortisone improved labs, but adrenal androgens remained suppressed. A hemizygous NR0B1 pathogenic variant was identified, and testosterone induced pubertal onset. The case broadens the late-onset spectrum and highlights low adrenal androgens despite elevated ACTH as a diagnostic clue.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/late-onset-nr0b1-related-adrenal-hypoplasia-congenita-presenting-with-primary-adrenal-insufficiency-and-pubertal-delay/460777/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/late-onset-nr0b1-related-adrenal-hypoplasia-congenita-presenting-with-primary-adrenal-insufficiency-and-pubertal-delay/460777.png","ImageObject",300,407,{"name":92,"@type":93},"Margaret","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why can NR0B1-related adrenal hypoplasia congenita be misdiagnosed as congenital adrenal hyperplasia (CAH)?","Question",{"text":113,"@type":114},"The case describes late-onset presentation where clinical symptoms and initial endocrine patterns can resemble CAH. A key distinguishing finding is persistently low adrenal androgens despite high ACTH, prompting genetic evaluation.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What genetic finding confirmed the diagnosis in the reported patient?",{"text":118,"@type":114},"Genetic testing revealed a hemizygous NR0B1 pathogenic variant: c.1292del, p.(Ser431Ilefs*6), previously reported only in early-onset disease.",{"name":120,"@type":111,"acceptedAnswer":121},"How did treatment affect the patient’s condition and puberty?",{"text":122,"@type":114},"Switching from prednisolone to hydrocortisone improved biochemical parameters, but adrenal androgen precursors stayed suppressed and puberty did not progress by age 15. Testosterone therapy induced pubertal onset.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},460777,1791027891,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":24,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},137451207643,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","Review began 11/16/2025  \nReview ended 12/04/2025  \nPublished 12/09/2025  \n© Copyright 2025  \nNico et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0. , which permits unrestricted use , distribution , and reproduction in any medium , provided the original author and source are credited.  \nDOI: 10.7759/cureus.98859  \nOpen Access Case Report  \nLate-Onset NR0B 1-Related Adrenal Hypoplasia Congenita Presenting With Primary Adrenal Insufficiency and Pubertal Delay  \nJoão Filipe Nico 1, Rita Cardoso 1, Alice Mirante 1  \n1. Pediatric Endocrinology, Diabetes and Growth Unit, Ambulatory Pediatric Department, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, PRT  \nCorresponding author: João Filipe Nico, [joaoffnico@gmail.com](joaoffnico@gmail.com)  \nAbstract  \nPrimary adrenal insufficiency (PAI) in childhood is a rare condition most often caused by genetic defects rather than autoimmune disease. Among these, NR0B1-related adrenal hypoplasia congenita (AHC) is a distinctive X-linked disorder that may present beyond infancy and occasionally mimic congenital adrenal hyperplasia (CAH) . We report the case of a 13-year-old boy previously diagnosed with CAH at the age of four because of chronic fatigue. On referral, he was receiving prednisolone and fludrocortisone and presented with short stature, absent puberty, and low adrenocorticotropic hormone (ACTH) levels. Switching to hydrocortisone improved biochemical parameters, but adrenal androgen precursors remained suppressed, and no pubertal development occurred by 15 years. AHC was suspected, and genetic testing revealed a hemizygous NR0B1 pathogenic variant (c. 1292del, p.(Ser431Ilefs*6)), previously reported only in early-onset disease. Testosterone therapy induced pubertal onset. Family history identified a maternal half-brother diagnosed in infancy with presumed CAH and a similar biochemical profile, and another asymptomatic infant half-brother, both referred for genetic evaluation. This case expands the clinical spectrum of NR0B1-related AHC, demonstrating that it can present as late as adolescence and be misdiagnosed as CAH. Persistently low adrenal androgens despite elevated ACTH serve as a diagnostic clue. Early genetic testing allows accurate diagnosis, individualized therapy, and appropriate counseling of at-risk families.  \nCategories: Genetics, Pediatrics, Endocrinology/Diabetes/Metabolism  \nKeywords: adrenal hypoplasia congenita, delayed puberty (dp), hypogonadotropic hypogonadism, nr0b1, primary adrenal insufficiency  \nIntroduction  \nPrimary adrenal insufficiency (PAI) in childhood is a rare but potentially life-threatening condition caused by deficient production of glucocorticoids, mineralocorticoids, or both. Unlike adults, in whom autoimmune adrenalitis predominates, most pediatric cases are genetic in origin [1] . Among these, NR0B1-related adrenal hypoplasia congenita (AHC) represents a distinctive X-linked disorder characterized by combined adrenal insufficiency and hypogonadotropic hypogonadism (HH) due to loss-of-function variants in the NR0B1 gene encoding the DAX-1 protein [2,3] .  \nThe clinical spectrum of NR0B1-related AHC is remarkably heterogeneous. While most affected males present in infancy with salt-wasting crises, some develop adrenal failure later in childhood or adolescence, often with subtle symptoms such as fatigue, growth impairment, or delayed puberty [1,2,4,5] . This variability often delays diagnosis and can lead to misclassification as 21-hydroxylase deficiency, the most common  \ncause of congenital adrenal hyperplasia (CAH) [1,6] .  \nBiochemically, low adrenal androgens despite elevated adrenocorticotropic hormone (ACTH) contrast with the androgen excess typical of CAH [6] . Recognition of this discrepancy is crucial for prompting genetic investigation. Advances in molecular diagnostics have improved identification of the underlying defects, allowing accu","cbCaitffMevTsVX9","https://ap.wps.com/l/cbCaitffMevTsVX9","pdf",221639,"English","# Abstract\n# Introduction\n# Case Presentation","[{\"question\":\"Why can NR0B1-related adrenal hypoplasia congenita be misdiagnosed as congenital adrenal hyperplasia (CAH)?\",\"answer\":\"The case describes late-onset presentation where clinical symptoms and initial endocrine patterns can resemble CAH. A key distinguishing finding is persistently low adrenal androgens despite high ACTH, prompting genetic evaluation.\"},{\"question\":\"What genetic finding confirmed the diagnosis in the reported patient?\",\"answer\":\"Genetic testing revealed a hemizygous NR0B1 pathogenic variant: c.1292del, p.(Ser431Ilefs*6), previously reported only in early-onset disease.\"},{\"question\":\"How did treatment affect the patient’s condition and puberty?\",\"answer\":\"Switching from prednisolone to hydrocortisone improved biochemical parameters, but adrenal androgen precursors stayed suppressed and puberty did not progress by age 15. Testosterone therapy induced pubertal onset.\"}]","Late-Onset NR0B1-Related Adrenal Hypoplasia Congenita Presenting With Primary Adrenal Insufficiency and Pubertal Delay | PDF",1790759516,13]