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.

BELGOROSKY, A; PEPE C,; MARINO R,; GUERCIO G,; SARACO N,; VAIANI E,; RIVAROLA MA,

Review Series Gynecology

Informa Healthcare

Año: 2005 p. 1 - 1

1652-845X

Case report A 46,XX baby, who was born with ambiguous external genitalia but without palpable gonads, had normal serum 17?¿-hydroxy-progesterone and 11-desoxycortisol levels in her first week after birth. These findings ruled out the diagnosis of congenital adrenal hyperplasia secondary to 21-hydroxylase and 11?À-hydroxylase deficiencies, respectively. No rise in serum testosterone was detected after a human chorionic gonadotropin test, indicating the absence of functional Leydig cells. She was assigned the female sex for rearing. Aromatase-deficiency was suspected because her mother had begun progressive virilization at about the second trimester of pregnancy. Gene analysis showed that the baby was a compound heterozygote for 2 new CYP19 aromatase point mutations. In her father?fs allele, a consensus 5?f splice donor sequence mutation was found, GAA-AAA at cDNA position bp 655 in exon 5, which probably resulted in a cryptic donor site. In her mother?fs allele, there was a base A deletion in exon 9 (DA GLU 412X) causing a frame shift mutation, as well as a stop codon after 98 bp (33 codons) downstream, altering the critical heme-binding region.             The follow up of this patient provided us with a natural experiment to study the role of estrogens on gonadotropin regulation during infancy and childhood. At 5 months of age, a laparoscopy and plastic surgery of the external genitalia were performed. Basal serum LH and FSH levels were high (42.9 and 51.3 U/L, respectively) at 8 days of age, and at 26 days (76.2 and 119 U/L) and 60 days (58.7 and 150 U/L). Both gonadotropins decreased dramatically between the second and fifth month of age (to 1.79 and 14.9 U/L, respectively), but remained higher than in normal control girls (0.64 and 8.5 U/L, respectively). Basal serum FSH, but not LH, remained elevated throughout the whole follow-up period during infancy and childhood, and the basal serum estrogen level remained below the detection limit of the assay.             Serum testosterone and androstenedione (?¢4A) levels were high during the first month, but ?¢4A was normal at 2 months of age. However, at 5 months, along with significant decreases in serum LH and FSH levels and increments in serum ?¢4A and testosterone levels, a large ovarian cyst (4 ?L 2 cm) was removed from each gonad. Relatively high levels of testosterone were found in the follicular fluid (27.3 ng/mL or 94.6 nmol/L, compared with 34.9 ng/mL or 121 nmol/L for controls), as well as a high testosterone/estradiol ratio (15.2, compared with <1 for controls). However, estradiol levels were lower than normal (1.8 ng/mL or 6.6 nmol/L, compared with 62.9 ng/mL or 231 nmol/L for controls). Serum ?¢4A and testosterone levels remained normal from one to 5 years of age, but were high at the last visit (late prepuberty). A GnRH test was performed at 3.9, 6 and 7.1 years of age. At 3.9 years, a low prepubertal serum LH peak (2.12 U/L) was found, but higher LH peaks (8.25 and 22.5 U/L) were observed at 6 and 7.1 years, respectively.             The patient?fs growth pattern and body mass index were normal, but after the age of 5.2 years, over 2-year delays in bone age were observed.