Late-Onset NR0B1-Related Adrenal Hypoplasia Congenita Presenting With Primary Adrenal Insufficiency and Pubertal Delay

Primary adrenal insufficiency (PAI) in childhood is a rare condition most often caused by genetic defects rather than autoimmune disease. Among these, <i>NR0B1</i>-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 <i>NR0B1</i> 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 <i>NR0B1</i>-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.