# Delayed Diagnosis of X-Linked Adrenal Hypoplasia Congenita in a Boy with a Novel NR0B1 Variant: A Case Report

## TL;DR

A 14-year-old boy with a new NR0B1 gene variant was diagnosed with adrenal and gonadal issues, highlighting the need for early genetic testing to prevent severe complications.

## Contribution

A novel NR0B1 variant (c.833_835dup) is identified in a patient with X-linked adrenal hypoplasia congenita.

## Key findings

- The patient had adrenal insufficiency and hypogonadotropic hypogonadism due to a new NR0B1 variant.
- Delayed diagnosis led to an adrenal crisis, emphasizing the need for early genetic testing.
- Treatment with hormone replacement improved symptoms and reduced ACTH levels.

## Abstract

What are the main findings?
We report a pediatric male patient with adrenal insufficiency and hypogonadotropic hypogonadism caused by a novel NR0B1 variant (c.833_835dup p.(Leu278dup)).The case highlights delayed diagnosis despite neonatal symptoms, ultimately leading to adrenal crisis and hypogonadotropic hypogonadism.

We report a pediatric male patient with adrenal insufficiency and hypogonadotropic hypogonadism caused by a novel NR0B1 variant (c.833_835dup p.(Leu278dup)).

The case highlights delayed diagnosis despite neonatal symptoms, ultimately leading to adrenal crisis and hypogonadotropic hypogonadism.

What are the implications of the main findings?
NR0B1 mutations should be considered in boys presenting with adrenal insufficiency and hypogonadotropic hypogonadism, even without a family history.Early genetic testing is essential for timely diagnosis, optimal treatment, and genetic counseling, helping to prevent life-threatening complications.

NR0B1 mutations should be considered in boys presenting with adrenal insufficiency and hypogonadotropic hypogonadism, even without a family history.

Early genetic testing is essential for timely diagnosis, optimal treatment, and genetic counseling, helping to prevent life-threatening complications.

NR0B1 (DAX-1) is an orphan nuclear receptor essential for the development and regulation of the adrenal glands and gonads. Pathogenic variants in NR0B1 cause X-linked adrenal hypoplasia congenita (AHC), which typically presents with adrenal insufficiency and hypogonadotropic hypogonadism (HH) in boys. Delayed diagnosis during adolescence is uncommon but, when it occurs, can lead to preventable adrenal crisis, underscoring the need for early recognition of atypical presentations. We describe a 14-year-old boy who presented with adrenal insufficiency and delayed puberty. Genetic testing revealed a novel hemizygous in-frame duplication variant of NR0B1 (NM_000475.4:c.833_835dup p.(Leu278dup)). This variant has not been previously reported in association with X-linked AHC. The patient received hydrocortisone (10–12 mg/m2/day) and fludrocortisone (0.1 mg/day) as replacement therapy for adrenal insufficiency, along with testosterone supplementation (100–240 mg/day) to induce pubertal progression. Plasma ACTH levels gradually decreased from 10,175 pg/mL at diagnosis to 215 pg/mL during follow-up, accompanied by clinical improvement in skin pigmentation and pubertal development. This case underscores the importance of NR0B1 genetic testing in children with adrenal insufficiency and HH. Early recognition and genetic confirmation are critical for appropriate management and genetic counseling. Identification of novel variants expands the NR0B1 mutational spectrum and enhances our understanding of genotype–phenotype correlations in X-linked AHC.