X-linked adrenal hypoplasia congenita and DAX-1

X-linked adrenal hypoplasia congenita (AHC) (OMIM, 300200) is a potentially life-threatening condition that results from mutations in the orphan nuclear receptor, DAX-1. More than 50 different mutations in the DAX1 gene have been reported. DAX1 is expressed in the adrenal gland and at multiple levels throughout the hypothalamic-pituitary gonadal axis. In keeping with this expression pattern, boys with X-linked AHC present with primary adrenal failure in early infancy or childhood and hypogonadotropic hypogonadism (HHG) becomes apparent at the expected time of puberty. This form of HHG reflects combined hypothalamic and pituitary abnormalities, and the gonadotropin response to gonadotropin-releasing hormone is often poor. Impaired spermatogenesis is also observed in Ahch (Dax1) knockout mice. The limited data available to date suggest that DAX-1 may affect Sertoli cell function in humans as well. In this review, we discuss the clinical presentation of patients with X-linked AHC. Several recently reported cases are described that broaden the phenotypic spectrum of this condition and include presentation with adrenal failure in adulthood. The molecular actions of DAX-1 and its pathophysiological role in AHC/HHG are also considered. Finally, future directions for the detection and potential treatment of this condition are proposed.