ADRENAL HYPOPLASIA CONGENITA WITH HYPOGONADOTROPIC HYPOGONADISM - EVIDENCE THAT DAX-1 MUTATIONS LEAD TO COMBINED HYPOTHALAMIC AND PITUITARYDEFECTS IN GONADOTROPIN PRODUCTION

Adrenal hypoplasia congenita (AHC) is an X-linked disorder that typica lly presents with adrenal insufficiency during infancy. Hypogonadotrop ic hypogonadism (HHG) has been identified as a component of this disor der in affected individuals who survive into childhood. Recently, AHC was shown to be caused by mutations in DAX-1, a protein that is struct urally similar in its carboxyterminal region to orphan nuclear recepto rs. We studied two kindreds with clinical features of AHC and HHG. DAX -1 mutations were identified in both families. In the JW kindred, a si ngle base deletion at nucleotide 1219 was accompanied by an additional base substitution that resulted in a frameshift mutation at codon 329 followed by premature termination In the MH kindred, a GCAT duplicati on at codon 418 caused a frameshift that also resulted in truncation o f DAX-1. Baseline luteinizing hormone (LH), follicle-stimulating hormo ne (FSH), and free-cu-subunit (FAS) levels were determined during 24 h of frequent (q10 min) venous sampling. In patient MH, baseline LH lev els were low, but FAS levels were within the normal range, In contrast , in patient JW, the mean LH and FSH were within the normal range duri ng baseline sampling, but LH secretion was erratic rather than showing typical pulses, FAS was apulsatile for much of the day, but a surge w as seen over a 3-4-h period. Pulsatile gonadotropin releasing hormone (GnRH) (25 ng/kg) was administered every 2 h for 7 d to assess pituita ry responsiveness to exogenous GnRH, MH did not exhibit a gonadotropin response to pulsatile GnRH. JW exhibited a normal response to the fir st pulse of GnRH, but there was no increase in FAS, In contrast to the priming effect of GnRH in GnRH-deficient patients with Kallmann syndr ome, GnRH pulses caused minimal secretory responses of LH and no FAS r esponses in patient JW. The initial LH response in patient JW implies a deficiency in hypothalamic GnRH. On the other hand, the failure to r espond to pulsatile GnRH is consistent with a pituitary defect in gona dotropin production These two cases exemplify the phenotypic heterogen eity of AHC/HHG, and suggest that DAX-1 mutations impair gonadotropin production by acting at both the hypothalamic and pituitary levels.