# Unmasking Isolated Glucocorticoid Deficiency: Clinical Insights From 2 Cases

## TL;DR

This paper presents two cases of rare familial glucocorticoid deficiency, highlighting genetic causes and clinical features for better diagnosis.

## Contribution

The study identifies novel genetic variants in AFF2 and CYP11A1 associated with familial glucocorticoid deficiency.

## Key findings

- Whole-exome sequencing revealed a biallelic variant in the melanocortin 2 receptor gene in one patient.
- Compound heterozygous variants in the CYP11A1 gene were found in the second patient.
- Both patients improved with glucocorticoid replacement therapy.

## Abstract

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by unresponsiveness to adrenocorticotropin (ACTH) with preserved mineralocorticoid secretion. We describe 2 patients who presented with FGD. The first patient was born to a third-degree consanguineous marriage, and suffered from global developmental delay and recurrent seizures since childhood. He presented to us at age 22 years with severe hyponatremia. Laboratory investigations showed subclinical hypothyroidism, low cortisol, high ACTH, and normal plasma renin activity. After exclusion of common causes of primary adrenal insufficiency (PAI), we undertook whole-exome sequencing (WES) that revealed 2 variants—a hemizygous deletion involving exons 10 to 21 of the AFF2 gene known to cause X-linked intellectual developmental disorder-109 and a biallelic variant in the melanocortin 2 receptor gene (NM_000529.2: c.437G > A; p.Arg146His). The second patient presented at age 25 years with severe hyponatremia and seizures. Investigations revealed isolated glucocorticoid deficiency, and WES yielded compound heterozygous variants in the CYP11A1 gene (c.940G > A; p.Glu314Lys and c.359G > A; p.Arg120Gln). Both patients were put on glucocorticoid replacement and are doing well on follow-up. FGD should be suspected in young individuals with PAI and can be caused by a spectrum of genetic abnormalities.