Aromatase Deficiency in a Female Who Is Compound Heterozygote for Two New Point Mutations in the P450arom Gene: Impact of Estrogens on Hypergonadotropic Hypogonadism, Multicystic Ovaries, and Bone Densitometry in Childhood1

Abstract

We report on a female who is compound heterozygote for two new point mutations in the CYP19 gene. The allele inherited from her mother presented a base pair deletion (C) occurring at P408 (CCC, exon 9), causing a frameshift that results in a nonsense codon 111 bp (37 aa) further down in the CYP19 gene. The allele inherited from her father showed a point mutation from G-->A at the splicing point (canonical GT to mutational AT) between exon and intron 3. This mutation ignores the splice site and a stop codon 3 bp downstream occurs. Aromatase deficiency was already suspected because of the marked virilization occurring prepartum in the mother, and the diagnosis was confirmed shortly after birth. Extremely low levels of serum estrogens were found in contrast to high levels of androgens. Ultrasonographic follow-up studies revealed persistently enlarged ovaries (19.5-22 mL) during early childhood (2 to 4 yr) which contained numerous large cysts up to 4.8 x 3.7 cm and normal-appearing large tertiary follicles already at the age of 2 yr. In addition, both basal and GnRH-induced FSH levels remained consistently strikingly elevated. Low-dose estradiol (E2) (0.4 mg/day) given for 50 days at the age of 3 6/12 yr resulted in normalization of serum gonadotropin levels, regression of ovarian size, and increase of whole body and lumbar spine (L1-L4) bone mineral density. The FSH concentration and ovarian size returned to pretreatment levels shortly (150 days) after cessation of E2 therapy. Therefore, we recommend that affected females be treated with low-dose E2 in amounts sufficient to result in physiological prepubertal E2 concentrations using an ultrasensitive estrogen assay. However, E2 replacement needs to be adjusted throughout childhood and puberty to ensure normal skeletal maturation and adequate adolescent growth spurt, normal accretion of bone mineral density, and, at the appropriate age, female secondary sex maturation.

Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene

“…These findings are similar to those previously reported for both ArKO-deficient male and female humans (6,9,19,20), as well as the estrogen receptor-deficient male (21), and for the ERKO mice in which the estrogen receptor is inactivated by targeted disruption (10), except that in the latter, serum estradiol levels are markedly elevated (12). However, there are several important differences between the phenotype of the ArKO mice and that of the ERKO mice.…”

“…A number of cases of aromatase deficiency in humans caused by mutations in the cyp19 gene have been reported (3)(4)(5)(6)(7)(8)(9). In the case of the females this condition leads to an autosomal-recessive form of female pseudohermaphroditism and virilization of the mother during pregnancy, as a consequence of impaired or absent conversion of fetal and maternal androgens to estrogens by the placental syncytiotrophoblasts.…”

The Aromatase Cytochrome P-450 and Its Clinical Impact

“…As already indicated above, FSH promotes the proliferation of granulosa cells and induces the expression of genes involved in estradiol biosynthesis [15]. The absence of estrogen synthesis in 1 of our patients because of a complete deficiency of aromatase activity resulted, therefore, in a high concentration of basal FSH and in a brisk gonadotropin-releasing hormone induced gonadotropin response combined with highly FSH-stimulated and enlarged multicystic ovaries in childhood [11]. On a low dose of estradiol (between 0.05 and 0.4 mg) adapted according to the normal values measured in young girls (newborn, childhood until start of pubertal development) using an ultrasensitive recombinant cell bioassay for estradiol determination, we were able to keep the gonadotropin at a normal level and the ovaries without any cystic stimulation.…”

“…In more detail, 3 mol of NADPH and 3 mol of oxygen are required to convert each mole of androstenedione or testosterone to estrone or estradiol, respectively. In addition, reports of patients with P450arom deficiency confirm that the biologically significant estrogen synthesis derives entirely from this enzyme, although some estrogenic effect in animals with aromatase deficiency can derive from phytoestrogens [8, 9, 10, 11, 12, 13]. …”

Aromatase and Intracrinology of Estrogen in Hormone-Dependent Tumors

“…This raises the question of what physiological functions estrogen exerts in various tissues. Analysis of aromatase-deficient patients [34, 35, 36, 37]and aromatase knockout (ArKO) mice [38, 39]partly answered this question. Various abnormalities in extragonadal tissues as well as gonadal tissues were detected.…”