Aromatase deficiency caused by a novel P450(arom) gene mutation: Impact ofabsent estrogen production on serum gonadotropin concentration in a boy

We identified a new point mutation in the CYP19 gene responsible for aromat ase (P450(arom)) deficiency in a 46,XY male infant with unremarkable clinic al findings at birth. This boy is homozygote for a l-bp (C) deletion in exo n 5 of the aromatase gene causing a frame-shift mutation. The frame-shift r esults in a prematurely terminated protein that is inactive due to the abse nce of the functional regions of the enzyme. Aromatase deficiency was suspected prenatally because of the severe viriliz ation of the mother during the early pregnancy, and the diagnosis was confi rmed shortly after birth. Four weeks after birth, the baby boy showed extre mely low levels of serum estrogens, but had a normal level of serum free te stosterone; in comparison with the high serum concentration of androstenedi one at birth, a striking decrease occurred by 4 weeks postnatally. We previ ously reported elevated basal and stimulated FSH levels in a female infant with aromatase deficiency in the first year of life. In contrast, in the ma le infant, basal FSH and peak FSH levels after standard GnRH stimulation te sts were normal. This finding suggests that the contribution of estrogen to the hypothalamic-pituitary gonadotropin-gonadal feedback mechanism is diff erent in boys and girls during infancy and early childhood. In normal girls , serum estradiol concentrations strongly correlate with circulating inhibi n levels, and thus, low inhibin levels may contribute to the striking eleva tion of FSH in young girls with aromatase deficiency. In contrast, estradio l levels are physiologically about a 7-fold lower in boys than in girls, an d serum inhibin levels remain elevated even though levels of FSH, LH, and t estosterone are decreased.