Aromatase deficiency is a rare autosomal recessive disorder in which individuals cannot synthesize endogenous estrogens. If a fetus lacks aromatase activity, dehydroepiandrosterone sulfate produced by the fetal adrenal glands cannot be converted to estrogen by the placenta, and ... Aromatase deficiency is a rare autosomal recessive disorder in which individuals cannot synthesize endogenous estrogens. If a fetus lacks aromatase activity, dehydroepiandrosterone sulfate produced by the fetal adrenal glands cannot be converted to estrogen by the placenta, and is converted to testosterone peripherally and results in virilization of both fetus and mother. Virilization manifests as pseudohermaphroditism in female infants, with hirsutism and acne in the mother; the maternal indicators resolve following delivery. Affected females are usually diagnosed at birth because of the pseudohermaphroditism. Cystic ovaries and delayed bone maturation can occur during childhood and adolescence in these girls, who present at puberty with primary amenorrhea, failure of breast development, virilization, and hypergonadotropic hypogonadism. Affected males do not present with obvious defects at birth. Their clinical symptoms include tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions, and excess adiposity. Estrogen replacement therapy reverses the symptoms in males and females (summary by Jones et al., 2007).
Mango et al. (1978) reported the case of a primigravida who showed low urinary estrogen excretion and demonstrated lack of placental aromatase activity by in vitro assays. The first report of well-substantiated placental aromatase deficiency appears to be ... Mango et al. (1978) reported the case of a primigravida who showed low urinary estrogen excretion and demonstrated lack of placental aromatase activity by in vitro assays. The first report of well-substantiated placental aromatase deficiency appears to be that by Shozu et al. (1991). The deficiency caused maternal virilization during pregnancy and pseudohermaphroditism of the female fetus. Maternal serum levels of estrogens were low and those of androgens were high in the third trimester. The mother delivered vaginally a live, full-term, 46,XX infant who showed male-appearing external genitalia with a greatly enlarged phallus, complete fusion of posterior scrotolabial folds, rugation of the scrotolabial folds, and a single meatus at the base of the phallus. The maternal manifestations of virilization disappeared gradually after delivery and the baby grew uneventfully. Levels of immunologically reactive 17-beta-estradiol in the infant's serum were normal at 2 to 6 months of age. It was unclear whether the aromatization defect existed only in the placenta or in her entire body. Bulun (1996) reviewed the clinical features of aromatase deficiency in the then-known 7 affected individuals reported to have P450arom gene defects, including 1 Japanese female infant (Shozu et al., 1991), 1 American adolescent female (Conte et al., 1994), and 2 American adult sibs, 1 female and 1 male (Morishima et al., 1995). The phenotypes of these cases included maternal virilization during the second half of pregnancy; clitoromegaly and posterior labioscrotal fusion in newborn affected females; and absent growth spurt, breast development, primary amenorrhea, virilization and multicystic ovaries in adult affected females. While only 1 affected male had been reported, normal genitalia were noted at birth, normal pubertal development occurred, and adult stature was extremely tall (greater than 3 SD) with osteoporosis, macroorchidism, and infertility (Morishima et al. (1995); Bulun (1996)). In a 29-year-old man with aromatase deficiency, Maffei et al. (2004) reported continuing linear growth, eunuchoid body proportions, diffuse bone pain, and bilateral cryptorchidism. The patient had a complex dysmetabolic syndrome characterized by insulin resistance, diabetes mellitus type 2, acanthosis nigricans, liver steatohepatitis, and signs of precocious atherogenesis. Testosterone treatment at high doses resulted in a severe imbalance in the estradiol-to-testosterone ratio together with insulin resistance and diabetes mellitus type 2. Estrogen treatment resulted in an improvement of acanthosis nigricans, insulin resistance, and liver steatohepatitis, coupled with a better glycemic control and the disappearance of 2 carotid plaques. Testis biopsy showed a pattern of total germ cell depletion that might be due to the concomitant presence of bilateral cryptorchidism. The authors concluded that this case of aromatase deficiency confirmed previous data on bone maturation and mineralization and revealed a high risk for the precocious development of cardiovascular disease in young aromatase-deficient men.
Ito et al. (1993) described compound heterozygosity for 2 mutations in the CYP19A1 gene (107910.0001-107910.0002) in a case of aromatase deficiency suspected on the basis of clinical and biochemical evidence. The patient was an 18-year-old 46,XX female with ... Ito et al. (1993) described compound heterozygosity for 2 mutations in the CYP19A1 gene (107910.0001-107910.0002) in a case of aromatase deficiency suspected on the basis of clinical and biochemical evidence. The patient was an 18-year-old 46,XX female with sexual infantilism, primary amenorrhea, ambiguous external genitalia at birth, and polycystic ovaries. They indicated that this was the first definitive case of an adult with aromatase deficiency to be reported. Harada et al. (1992) demonstrated that the aromatase deficiency (613546) in the case reported by Shozu et al. (1991) was caused by the expression of an abnormal aromatase protein molecule resulting from a genetic defect in the fetus. Specifically, the CYP19A1 gene was found to have an insert of 87 bp, encoding 29 amino acids in-frame with no termination codon. The insert was located at the splice point between exon 6 and intron 6 of the normal gene, and the extra DNA fragment was the first part of intron 6 except that its initial GT was altered to GC. By transient expression in COS-7 cells, the aromatase cDNA of the patient was found to contain a protein with a trace of activity. Harada et al. (1992) suggested that the defect in the placental aromatase gene, a feature of the infant's genotype, might be inherited since the parents were consanguineous in the 'fifth degree.' They showed that the offspring was homozygous for a defect that was present in heterozygous state in both parents (107910.0003). In a brother and sister with aromatase deficiency, Morishima et al. (1995) identified homozygosity for a mutation in the aromatase gene (107910.0004). The parents of these sibs were of Italian descent and were consanguineous. Although very tall with a eunuchoid appearance, the affected male was heterosexual and sexually active. Macroorchidism, with an estimated total testicular volume of 34 ml, was present. Bone age was 14.5 years; only the proximal femoral epiphyses were fused. The ratio of upper segment to lower segment was 0.84. Serum androgen concentrations were all markedly elevated, but serum estrone and estradiol concentrations were undetectable. Serum concentrations of FSH and LH were elevated. Bone mass was reduced at all sites. After treatment with Premarin, linear growth, which had been continuous, ceased and all epiphyses of the hand and wrist were completely fused within 6 months. Serum LH and FSH concentrations decreased to only slightly elevated levels. Estimated testicular volume decreased from 34 to 28 ml. Bone mass increased dramatically at all sites. There were no side effects of the estrogen therapy. There was no change in libido or sexual orientation. Lin et al. (2007) reported 4 patients (46,XX) from 3 kindreds with variable degrees of androgenization and pubertal failure who were homozygous or compound heterozygous for mutations in the CYP19A1 gene. Functional studies revealed low residual aromatase activity in the patients in whom breast development occurred, despite significant androgenization in utero.