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

## TL;DR

A 13-year-old boy with symptoms resembling congenital adrenal hyperplasia was found to have a rare genetic disorder causing adrenal insufficiency and delayed puberty.

## Contribution

This case expands the known clinical spectrum of NR0B1-related adrenal hypoplasia congenita to include late-onset presentations.

## Key findings

- NR0B1-related adrenal hypoplasia congenita can present in adolescence and be misdiagnosed as congenital adrenal hyperplasia.
- Persistently low adrenal androgens despite elevated ACTH levels can indicate NR0B1-related disease.
- Early genetic testing enables accurate diagnosis and appropriate treatment for NR0B1-related adrenal hypoplasia congenita.

## 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.