Late-Onset NR0B1-Related Adrenal Hypoplasia Congenita Presenting With Primary Adrenal Insufficiency and Pubertal Delay
Year: 2025
Type: article
Study design: Case Report
Abstract: Primary 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.
Source: Cureus
DOI: 10.7759/cureus.98859
Authors: João Filipe Nico, Rita Cardoso, Alice Mirante
Institution: Unidade Local de Saúde de Coimbra
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4417181752