NR0B1 Gene Variants as Rare Forms of Primary Adrenal Insufficiency in Children: Case Report and Narrative Review

Primary adrenal insufficiency (PAI) is a severe and potentially life-threatening condition characterised by the inability of the adrenal cortex to produce enough glucocorticoids and/or mineralocorticoids. The clinical signs of PAI are primarily due to deficient steroid hormone synthesis and include weight loss, orthostatic hypotension secondary to dehydration, hyponatremia, hyperkalaemia, and hypoglycaemia. In the paediatric population, PAI is most commonly associated with inherited monogenic disorders, particularly enzyme deficiencies. X-linked adrenal hypoplasia congenita (AHC) is a rare condition caused by deletions or single-nucleotide variants in the NR0B1 (DAX1) gene, which encodes the DAX1 protein expressed in the adrenal cortex, gonads, hypothalamus and pituitary gland. Although molecular genetics has significantly expanded our understanding of the aetiology of PAI, clinical diagnosis remains challenging when the initial hormonal findings are atypical, often delaying recognition and treatment. Pathogenic variants of DAX1 can lead to a spectrum of phenotypes, ranging from isolated adrenal insufficiency (AI) to complex syndromic presentations combining AI with hypogonadotropic hypogonadism and impaired spermatogenesis. Here, we report a case of a male patient with AI due to a de novo pathogenic variant in the NR0B1 gene. Furthermore, we provide a non-systematic review of the available literature on the diagnostic challenges facing and clinical variability in AHC, with a particular focus on the paediatric population. This case highlights the importance of a stepwise, comprehensive diagnostic approach to suspected PAI, particularly when initial biochemical and genetic testing is inconclusive. Considering rare causes—such as NR0B1 pathogenic variants in men—can be crucial for establishing a definitive diagnosis, with significant implications for the management of patients and their families.