AROMATASE DEFICIENCY IN MALE AND FEMALE SIBLINGS CAUSED BY A NOVEL MUTATION AND THE PHYSIOLOGICAL-ROLE OF ESTROGENS

The aromatase enzyme complex catalyzes the conversion of androgens to estrogens in a wide variety of tissues, including the ovary, testis, placenta, brain, and adipose tissue. Only a single human gene encoding aromatase P450 (CYP19) has been isolated; tissue-specific regulation is controlled in part by alternative promoters in a tissue-specific manner. We report a novel mutation in the CYP19 gene in a sister and brother. The 28-yr-old XX proband, followed since infancy, exhibited the cardinal features of the aromatase deficiency syndrome as recently defined. She had nonadrenal female pseudohermaphrodism at birth and underwent repair of the external genitalia, including a clitorectomy. At the age of puberty, she developed progressive signs of virilization, pubertal failure with no signs of estrogen action, hypergonadotropic hypogonadism, polycystic ovaries on pelvic sonography, and tall stature. The basal concentrations of plasma testosterone, androstenedione, and 17-hydroxyprogesterone were elevated, whereas plasma estradiol was low. Cyst fluid from the polycystic ovaries had a strikingly abnormal ratio of androstenedione and testosterone to estradiol and estrone. Hormone replacement therapy led to breast development, menses, resolution of ovarian cysts, and suppression of the elevated FSH and LH values. Her adult height is 177.6 cm (+2.5 SD). Her only sibling, an XY male, was studied at 24 yr of age. During both pregnancies, the mother exhibited signs of progressive virilization that regressed postpartum The height of the brother was 204 cm (+3.7 SD) with eunuchoid skeletal proportions, and the weight was 135.1 kg (+2.1 SD). He was sexually fully mature and had macroorchidism. The plasma concentrations of testosterone (2015 ng/dL), 5 alpha-dihydrotestosterone (125 ng/dL), and androstenedione (335 ng/dL) were elevated; estradiol and estrone levels were less than 7 pg/mL. Plasma FSH and LH concentrations were more than 3 times the mean value. Plasma PRL was low; serum insulin-like growth factor I and GH-binding protein were normal. The bone age was 14 yr at a chronological age of 24 3/12 yr. Striking osteopenia was noted at the wrist. Bone mineral densitometric indexes of the lumbar spine (cancellous bone) and distal radius (cortical bone) were consistent with osteoporosis; the distal radius was -4.7 SD below the mean value for age- and sex-matched normal men; indexes of bone turnover were increased. Hyperinsulinemia, increased serum total and low density lipoprotein cholesterol, and triglycerides and decreased high density lipoprotein cholesterol were detected. Analysis of genomic DNA in transformed lymphoblasts from both the sister and brother indicated a homozygous single base change at base pair 1123 (C-->T) in exon IX of the CYP19 gene, a highly conserved region, that results in a cysteine instead of an arginine at position 375 (R375C). The parents are obligate heterozygotes in this consanguineous pedigree. Expression of the mutant complementary DNA showed that the R375C mutation had 0.2% the aromatase activity of the wild-type enzyme. The clinical features in the affected female were similar to those described previously due to generalized aromatase deficiency. The affected 24-yr-old brother, who grew normally during childhood, has tall stature, normal male secondary sex characteristics, macroorchidism, osteoporosis, elevated plasma FSH, LH, and androgen values, but estradiol and estrone concentrations below 7 pg/mL. In addition, hyperinsulinism and an abnormal blood lipid profile were detected. The psychosexual orientation of both brother and sister was appropriate for their phenotypic sex. These observations are consistent with the following interpretations: 1) estrogens are essential for normal skeletal maturation and proportions (but not linear growth) in men as in women, the accretion and maintenance of bone mineral density and mass, and the control of the rate of bone turnover; 2) estrogens have a significant role in the sex steroid-gonadotropin feedback mechanism in the male, even in the face of high circulating testosterone; 3) deficient estrogens in the adult male appear to be associated with hyperinsulinemia and abnormal plasma lipids; 4) and placental aromatase has a critical role in protecting the female fetus from fetal masculinization and the pregnant woman from virilization. The findings suggest again that estrogen synthesis in the blastocyst, fetus, and placenta is not essential for normal embryonic and fetal development and reinforce the concept that placental estrogen has no essential role in the physiology of the pregnant woman.