Aromatase Deficiency

A number sign (#) is used with this entry because aromatase deficiency is caused by homozygous or compound heterozygous mutation in the CYP19A1 gene (107910) on chromosome 15q21.

Description

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).

Clinical Features

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.

Biochemical Features

Bulun (1996) reviewed the laboratory findings of aromatase deficiency in the then-known 6 females and 1 male reported to have P450arom gene defects. The findings included (1) extremely low maternal serum estradiol and estriol but very high maternal serum testosterone in pregnant women; (2) high follicle-stimulating hormone (FSH) and undetectable estriol during infancy in affected females; (3) sonographic findings of multicystic ovaries, high FSH and luteinizing hormone (LH) levels in affected females during puberty; and (4) undetectable estradiol but very high FSH and LH levels, unfused epiphyses and osteoporosis, and abnormal semen analysis in the adult affected male (Bulun, 1996).

Clinical Management

This condition of estrogen deficiency, as well as the case of estrogen resistance due to a mutation in the estrogen receptor (133430.0002) reported by Smith et al. (1994), demonstrates that androgens are not solely responsible for the establishment of peak bone mass in males; a man with these 2 genetic disorders showed osteoporosis. Bilezikian et al. (1998) found that treatment for 3 years with conjugated estrogen resulted in restoration of bone mass in the patient reported by Morishima et al. (1995) with aromatase deficiency.

Estrogen replacement therapy reverses the symptoms in both males and females with aromatase deficiency (summary by Jones et al., 2007).

Molecular Genetics

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 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.

Animal Model

Leshin et al. (1981) showed that a similar lesion exists in the henny feathering trait of Sebright Bantam chickens. Further, they concluded that this trait results from a regulatory mutation affecting aromatase activity ( Leshin et al., 1981). George et al. (1990) showed that the henny feathering trait in the Golden Campine chicken is identical to that in the Sebright Bantam; indeed, it may be the same gene, the trait in the Campine having been derived from the Sebright. In the chicken the trait behaves as an incomplete dominant; heterozygotes express half the levels of extraglandular aromatase as do homozygotes on average.

Fisher et al. (1998) generated mice lacking functional aromatase enzyme by targeted disruption of the cyp19 gene. Male and female knockout mice were born with the expected mendelian frequency from F1 parents and grew to adulthood. At 9 weeks of age, female knockout mice displayed underdeveloped external genitalia and uteri. Ovaries contained numerous follicles with abundant granulosa cells and evidence of antrum formation that appeared arrested before ovulation. No corpora lutea were present. Additionally, the stroma were hyperplastic with structures that appeared to be atretic follicles. Development of the mammary glands approximated that of prepubertal females. Male mice of the same age showed essentially normal internal anatomy, but the male accessory sex glands were enlarged because of increased content of secreted material. The testes appeared normal. Male knockout mice were capable of breeding and produced litters of approximately average size. Whereas serum estradiol levels were at the limit of detection, testosterone levels were elevated, as were the levels of follicle-stimulating hormone and luteinizing hormone (see 152780). The phenotype of these animals differed markedly from that of the previously reported estrogen receptor knockout mice in which the estrogen receptor-alpha (ESR1; 133430) was deleted by targeted disruption.

Robertson et al. (1999) investigated spermatogenesis in mice that lack aromatase because of the targeted disruption of the cyp19 gene. Male mice deficient in aromatase were initially fertile but developed progressive infertility, until their ability to sire pups was severely impaired. The mice deficient in aromatase developed disruptions to spermatogenesis between 4.5 months and 1 year, despite no decreases in gonadotropins or androgens. Spermatogenesis primarily was arrested at early spermiogenic stages, as characterized by an increase in apoptosis and the appearance of multinucleated cells, and there was a significant reduction in round and elongated spermatids, but no changes in Sertoli cells or early germ cells. In addition, Leydig cell hyperplasia/hypertrophy was evident, presumably as a consequence of increased circulating luteinizing hormone. The findings indicated that local expression of aromatase is essential for spermatogenesis and provided evidence for a direct action of estrogen on male germ cell development and thus fertility.

Aromatase knockout (ArKO) mice, lacking a functional Cyp19 gene, cannot synthesize endogenous estrogens. Jones et al. (2000) examined the adipose deposits of male and female ArKO mice, observing that these animal progressively accumulated significantly more intraabdominal adipose tissue than their wildtype littermates, reflected in increased adipocyte volume at gonadal and infrarenal sites. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. A striking accumulation of lipid droplets was observed in the livers of ArKO animals. The findings demonstrated an important role for estrogen in the maintenance of lipid homeostasis in both males and females. Along the same lines, Heine et al. (2000) studied male and female Esr1 knockout mice and found that signaling by this receptor is critical in female and male white adipose tissue. Obesity in the males involved a mechanism of reduced energy expenditure rather than increased energy intake.

Bulun (1996) described a possible animal model of aromatase deficiency in spotted hyenas.