Combined hypothalamic-pituitary-gonadal defect in a hypogonadic man with anovel mutation in the DAX-1 gene

We have studied a 20-yr-old male patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism (HH) due to a C to A transversion at nucl eotide 825 in the DAX-1 gene, resulting in a stop codon at position 197. Th e same mutation was detected in his affected first cousin (adrenal hypoplas ia congenita and HH) and in a heterozygous state in their carrier mothers. The patient had had acute adrenal insufficiency at the age of 2 yr and 6 mo nths, bilateral cryptorchidism corrected surgically at the age of 12 yr, an d failure of spontaneous puberty. Plasma testostereone (T) was undetectable (<0.30 nmol/L), gonadotropin levels were low (LH, <0.4 IU/L; FSH, 1.5 IU/L ) and not stimulated after iv injection of 100 mu g GnRH. The endogenous LH secretory pattern was apulsatile, whereas free alpha-subunit (FAS) levels depicted erratic pulses, suggesting an incomplete deficiency of hypothalami c GnRH secretion. During iv pulsatile GnRH administration(10 mu g/pulse eve ry 90 min for 40 h), each GnRH pulse induced a LH response of low amplitude (0.54 +/- 0.05 UI/L), whereas mean LH (0.45 +/- 0.01 IU/L) and FAS (63 +/- 8 mU/L) levels remained low. Amplitude of LH peaks (0.83 +/- 0.09 IU/L), m ean LH (0.53 +/- 0 02 IU/L), and FAS (161 +/- 18 mU/L) levels increased (P < 0.01), whereas the T concentration remained low (0.75 nmol/L) when the pu lsatile GnRH regimen was raised to 20 mu g/pulse for a 40-h period, suggest ing a partial pituitary resistance to GnRH. Thereafter, plasma T levels rem ained in prepubertal value after three daily im injections of 5000 IU hCG ( 3.6 nmoL/L) and after 1-yr treatment with weekly im injections of 1500 IU h CG (1.2 nmol/L), implying Leydig cell resistance to hCG. The patient had a growth spurt, bone maturation, progression of genital and pubic hair stages , and normalization of plasma T level (16.8 nmol/L) after a 12-month treatm ent with twice weekly injections of hCG and human menopausal gonadotropin ( 75 IU International Reference Preparation 2) preparations, suggesting that, in presence of FSH, a Sertoli cell-secreted factor stimulated Leydig cell production of T. In conclusion, we report a novel mutation in the DAX-1 gen e in patients with AHC and HH. Our results suggest that the hypogonadism is due to a combined hypothalamic-pituitary gonadal defect and imply that the DAX-1 gene may play a critical role in human testicular function.