Hypothalamic-pituitary-ovarian axis during infancy, early and late prepuberty in an aromatase-deficient girl who is a compound heterocygote for two new point mutations of the CYP19 gene

A loss of function mutation of the CYP19 aromatase gene leads to excess circulating androgens in the fetus and in the mother, resulting in ambiguous genitalia in the female fetus. Later on, lack of aromatase is responsible for sexual infantilism, primary amenorrhea, tall stature, and multicystic ovaries, even in preadolescent girls. Up to now, 11 CYP19 aromatase point mutations and 10 well-documented cases have been reported. In the present case, we are reporting the clinical and hormonal follow-up, from birth to 7 yr of age, of an affected girl with ambiguous genitalia. Gene analysis showed that she was a compound heterozygote for two new CYP19 aromatase point mutations. In the father's allele, there was a consensus 5' splice donor sequence mutation, GAA-AAA at cDNA position bp 655 in exon 5, which probably results in a cryptic donor site. In the mother's allele, there was a base A deletion in exon 9 (DeltaA GLU 412X), causing a frame shift mutation, and a stop codon after 98 bp (33 codons) downstream, altering the critical heme-binding region. Basal serum LH and FSH levels were high at 8 d of age (42.9 and 51.3 U/liter), 26 d of age (76.2 and 119 U/liter), and 60 d of age (58.7 and 150 U/liter, respectively). Both gonadotropins dropped dramatically between the second and fifth months of age (to 1.79 and 14.9 U/liter) but remained higher than in normal control girls (0.64 and 8.5 U/liter, respectively). Serum testosterone (T) and androstenedione (Delta(4)A) levels were high during the first month, but (4)A was normal at 2 months of age. However, at 5 months of age, along with significant decrements of serum LH and FSH levels and increments in serum Delta(4)A and T levels, a large ovarian cyst was removed from each gonad. Relatively high levels of T [27.3 ng/ml (94.6 nmol/liter); control, 34.9 ng/ml (121 nmol/liter)], but not of estradiol [1.8 ng/ml (6.6 nmol/liter); control 62.9 ng/ml (231 nmol/liter)], and a high T/estradiol ratio [15.2; control <1] were found in the follicular fluid. Serum Delta(4)A and T levels remained normal from 1-5 yr of age, but they were high at the last visit (late prepuberty). A GnRH test was performed at 3.9, 6, and 7.1 yr of age. At 3.9 yr, a low prepubertal serum LH peak (2.12 U/liter) was found, but at the older ages, higher serum LH peaks (8.25 and 22.5 U/liter, respectively) were observed. Growth pattern and body mass index were normal, but after the age of 5.2 yr, delays in bone age greater than 2 yr were observed. We concluded that: 1) these two new CYP19 aromatase gene mutations are responsible for the phenotype of aromatase deficiency; 2) in girls, aromatase deficiency results in a decrease of the negative feedback of both serum LH and FSH, which can be detected as early as the second week after birth and persists up to the sixth month of life, and of FSH during the rest of prepuberty; and 3) because large ovarian cysts developed when serum LH and FSH dropped, aromatization of androgens might be required to prevent formation of cystic ovaries.