X-Linked Adrenal Hypoplasia Congenita: A Mutation in DAX1Expands the Phenotypic Spectrum in Males and Females

X-linked adrenal hypoplasia congenita (AHC) is a disorder associated with primary adrenal insufficiency and hypogonadotropic hypogonadism (HH).The gene responsible for X-linked AHC, DAX1, encodes a member of the nuclear hormone receptor superfamily.We studied an extended kindred with AHC and HH in which two males (the proband and his nephew) were affected with a nucleotide deletion (501delA).The proband's mother, sister, and niece were heterozygous for this frameshift mutation.At age 27 yr, after 7 yr of low dose hCG therapy, the proband underwent a testicular biopsy revealing rare spermatogonia and Leydig cell hyperplasia.Despite steadily progressive doses of hCG and Pergonal administered over a 3-yr period, the proband remained azoospermic.The proband's mother, sister (obligate carrier), and niece all had a history of delayed puberty, with menarche occurring at ages 17-18 yr.Baseline patterns of pulsatile gonadotropin secretion and gonadotropin responsiveness to exogenous pulsatile GnRH were examined in the affected males.LH, FSH, and free ␣-subunit were determined during 12.5-24 h of frequent blood sampling (every 10 min).Both patients then received pulsatile GnRH (25 ng/kg) sc every 2 h for 6 -7 days.Gonadotropin responses to a single GnRH pulse iv were monitored daily to assess the pituitary responsiveness to exogenous GnRH.In the proband, FSH and LH levels demonstrated a subtle, but significant, response to GnRH over the week of pulsatile GnRH therapy.Free ␣-subunit levels demonstrated an erratic pattern of secretion at baseline and no significant response to pulsatile GnRH.We conclude that 1) affected males with AHC/HH may have an intrinsic defect in spermatogenesis that is not responsive to gonadotropin therapy; 2) female carriers of DAX1 mutations may express the phenotype of delayed puberty; and 3) although affected individuals display minimal responses to pulsatile GnRH, as observed in other AHC kindreds, subtle differences in gonadotropin patterns may nevertheless exist between affected individuals within a kindred.