Late-onset X-linked adrenal hypoplasia (DAX-1, NR0B1): two new adult-onset cases from a single center

DAX-1 (NR0B1) is an orphan nuclear receptor, which plays a critical role in development and regulation of the adrenal gland and hypothalamo-pituitary-gonadal axis. Mutations in NR0B1 lead to adrenal hypoplasia congenita (AHC), hypogonadotropic hypogonadism (HH) and azoospermia in men. Presentation is typically with adrenal insufficiency (AI) during infancy or childhood. To date only eight cases/kindreds are reported to have presented in adulthood. We describe two new cases of men with DAX-1 mutations who presented in adulthood and who were diagnosed at a large University Hospital. Case 1 presented with AI at 19 years. At 38 years he was diagnosed with HH. Detailed history revealed a brother diagnosed with AI at a similar age. Sequencing of the DAX-1 (NR0B1) gene revealed a heterozygous c.775T > C substitution in exon 1, which changes codon 259 from serine to proline (p.Ser259Pro). Case 2 was diagnosed with AI at 30 years. Aged 37 years he presented with HH and azoospermia. He was treated with gonadotropin therapy but remained azoospermic. Testicular biopsy showed maturational arrest and hypospermatogenesis. Analysis of the NR0B1 gene showed a heterozygous c.836C > T substitution in exon 1, resulting in a change of codon 279 from proline to leucine (p.Pro279Leu). This change alters the structure of the repression helix domain of DAX-1 and affects protein complex interactions with NR5A family members. We describe two missense mutations within the putative carboxyl-terminal ligand binding domain of DAX-1, presenting with AHC and HH in adulthood, from a single center. DAX-1 mutations may be more frequent in adults than previously recognized. We recommend testing for DAX-1 mutations in all adults with primary AI and HH or impaired fertility where the etiology is unclear.