A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism

Mutations in the DAX1 gene cause X-linked adrenal hypoplasia congenita (AHC ) and hypogonadotropic hypogonadism (HHG). In affected boys, primary adrena l insufficiency occurs soon after birth or during early childhood; HHG is r ecognized at the expected time of puberty. In this report, we describe the novel phenotype of a man who presented with apparently isolated adrenal ins ufficiency at 28 years of age. Examination revealed partial pubertal develo pment and undiagnosed incomplete HHG. Gonadotropin therapy did not improve his marked oligospermia, suggesting a concomitant primary testicular abnorm ality. Genomic analysis revealed a novel missense mutation, I439S, in DAX1. The mutant DAX-1 protein was studied for its ability to function as a tran scriptional repressor of target genes. Consistent with the patient's mild c linical phenotype, the I439S mutation conferred intermediate levels of repr essor activity of DAX-1 when compared with mutations associated with classi c AHC. This unique case extends the clinical spectrum of AHC to include del ayed-onset primary adrenal insufficiency in adulthood and milder forms of H HG. Furthermore, in accordance with findings in Ahch (Dax1) knockout mice, the clinical features in this patient suggest that DAX-1 function is requir ed for spermatogenesis in humans, independent of its known effects on gonad otropin production.