Aromatase Excess Syndrome

A number sign (#) is used with this entry because aromatase excess syndrome (AEXS) can be caused by fusion of the aromatase gene (CYP19A1; 107910) with various partners, brought about by translocations and resulting in gain of function of the CYP19A1 gene.

Description

Aromatase excess syndrome is an autosomal dominant disorder characterized by increased extraglandular aromatization of steroids that presents with heterosexual precocity in males and isosexual precocity in females (Tiulpakov et al., 2005).

Clinical Features

Excess estrogen in boys causes gynecomastia, a premature growth spurt, early fusion of epiphyses, and decreased adult height. Hemsell et al. (1977) reported a case of gynecomastia apparently due to excessive peripheral conversion of androgen to estrogen as a result of 50-times-normal aromatase activity. The patient was an adopted boy, aged 11 years 7 months. Effects of excessive estrogen became evident at age 8, the time when plasma androstenedione begins to increase. Extraglandular aromatization, as well as sulfurylation, is extensively involved in C19-steroid metabolism in the fetus, but the activity of the enzymes falls rapidly after birth. In the patient of Hemsell et al. (1977), the fetal situation appeared to persist.

Berkovitz et al. (1985) investigated a black family in which marked gynecomastia with normal male genitalia occurred in 5 men in 3 sibships of 2 generations connected through females. In each, gynecomastia and male sexual differentiation began at an early age (10 to 11 years). The ratio of the concentration of plasma estradiol-17 beta to that of plasma testosterone was elevated in each. In 3 affected sibs, the transfer constant of conversion of androstenedione to estrone (i.e., the fraction of plasma androstenedione that was converted to estrone as measured in the urine) was 10 times the normal. Despite elevated extraglandular aromatase activity, the hypothalamic-pituitary axis responded normally to provocative stimuli. None of the 5 males had children, but 4 were still in their teens; the fifth was 29 years of age. The pattern of inheritance of familial gynecomastia with increased aromatase activity was considered consistent with either X-linked recessive or autosomal dominant, male-limited inheritance.

Autosomal dominant inheritance appeared likely in a family, reported by Leiberman and Zachmann (1992), in which increased steroid aromatization seemed to be responsible for 'familial adrenal feminization.' The father and 2 male and 2 female sibs had gynecomastia, early growth, and short final stature. The 8-year-old propositus had advanced bone age, facial acne, gynecomastia, pubic hair, and prepubertal testicular volume. ACTH-dependent adrenal feminization was confirmed by a transient reduction of breast tissue following dexamethasone or cypropterone acetate treatment. Testolactone, which is an inhibitor of peripheral aromatase activity in vivo, temporarily reduced the breast tissue. This was the first example of male-to-male and male-to-female transmission reported.

Stratakis et al. (1996) described a kindred with clinical and biochemical evidence of the syndrome of increased aromatase activity with gynecomastia and male-to-male transmission. The propositus presented at age 9 years with gynecomastia. His 7-year-old sister had Tanner III breast development and pubic hair, their father had bilateral gynecomastia in early puberty, and the paternal grandmother had massive macromastia. The authors found that a tetranucleotide repeat marker from within the aromatase gene segregated with the disease in all affected family members. Furthermore, rapid amplification of cDNA ends (RACE) showed a novel promoter in the affected but not the unaffected members of the family. In the full report of this family, Stratakis et al. (1998) analyzed CYP19A1 mRNA by PCR of cDNA ends, ribonuclease protection assay, and RT-PCR. Human chorionic gonadotropin testing showed a high rate of conversion of delta-4-androstenedione to estrone and of testosterone to estradiol in the propositus and his father. Treatment of the propositus and his sister was initiated with an aromatase inhibitor (testolactone) and a gonadotropin-releasing hormone analog, which successfully delayed skeletal and pubertal development in both children. Markedly increased aromatase activity was found in the patients' fibroblasts and Epstein-Barr virus-transformed lymphocytes. A new 5-prime splice variant was detected in the patients' CYP19A1 mRNA, identifying another first exon of this gene, which appears to be aberrantly expressed in this family.

Phornphutkul et al. (2001) reported a 7-year-old girl who presented with isosexual precocious puberty secondary to a feminizing adrenal adenoma. The adrenal tumor was found to express CYP19 mRNA. CYP19 activity was approximately 500-fold higher in the tumor than in adjacent normal adrenal tissue. Although histopathologic examination of the tumor was most consistent with a benign adenoma, the CYP19 transcripts present in the tumor corresponded to those associated with malignant as well as benign tumors. The authors concluded that isosexual precocious puberty secondary to a feminizing adrenal tumor can be due to estrogen synthesis from the tumor itself rather than peripheral aromatization.

Shozu et al. (2003) studied skin, fat, and blood samples from a 36-year-old man and his 7-year-old son with severe gynecomastia of prepubertal onset and mild hypogonadotropic hypogonadism and an unrelated 17-year-old boy with severe gynecomastia of prepubertal onset caused by elevated estrogen levels. Aromatase activity and mRNA levels in fat and skin and whole-body aromatization of androstenedione were markedly elevated. Treatment with an aromatase inhibitor decreased serum estrogen levels and normalized gonadotropin and testosterone levels.

Tiulpakov et al. (2005) described a 5-generation Russian family with 16 affected members, which they stated was the largest family with aromatase excess syndrome reported to that time. In both sexes the disorder manifested in early childhood with breast enlargement, growth, and bone age acceleration. In adults there was short stature, gynecomastia in males, and macromastia in females. Fertility was apparently preserved in 2 males. Several female subjects presented with gynecologic disease that could be attributed to estrogen excess (endometrial cancer, leiomyoma, and menstrual irregularities). One female had elevated estrogen levels and persistent menses in the eighth decade of life.

Molecular Genetics

In 3 patients, Shozu et al. (2003) determined that gynecomastia was caused by gain-of-function mutations in the aromatase gene. Heterozygous inversions in 15q21.2-q21.3 caused the coding region of the aromatase gene to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, CGNL1 (607856) in a father and son and TMOD3 (605112) in an unrelated boy, resulting in severe estrogen excess owing to the overexpression of aromatase in many tissues; see 107910.0010 and 107910.0011.

In the large Russian kindred reported by Tiulpakov et al. (2005), aromatase excess syndrome was caused by a rearrangement of chromosome 15q21.2 resulting in a chimeric transcript containing the full coding sequence of CYP19 preceded by exon 1 of the TRPM7 gene, containing the promoter (107910.0013).

Genetic Heterogeneity

Binder et al. (2005) studied a family in which 7 affected males over 3 generations had inherited prepubertal gynecomastia in an autosomal dominant manner. The maternal grandfather and 3 maternal uncles were affected; all had been mastectomized. The mother of the proband had normal age at menarche and no macromastia. Estrone levels of the proband and the other affected boys were elevated, 17-beta-estradiol levels were high normal, and testosterone levels were low. Hormonal analyses of the affected adults, who had all fathered children, revealed pathologically low serum testosterone levels but normal to high normal levels of estradiol and estrone. A repeat polymorphism of the p450 aromatase gene cosegregated with the disease phenotype in the family, making a mutation of the p450 aromatase gene likely. SSCP analysis of alternative untranslated exons and all coding exons of the p450 aromatase gene did not indicate any mutation. In addition, FISH analysis using 4 probes covering the promoter region did not reveal the presence of any major inversion at this locus. The authors concluded that comparison of their data with previous reports indicated that the hormonal, biochemical, and genetic basis of the aromatase excess syndrome is heterogeneous.

History

Disorders of androgen production or function are associated with gynecomastia, e.g., the gynecomastia of Reifenstein syndrome (312300) caused by partial androgen insensitivity from mutations in the androgen receptor gene (AR; 313700). Another cause of familial gynecomastia of prepubertal onset involves the secretion of estrogen by testicular Sertoli-cell tumors associated with the Peutz-Jeghers syndrome (175200).

Male-limited autosomal dominant, autosomal recessive, and X-linked modes of inheritance had been proposed. Wallach and Garcia (1962) reported a family in which 2 brothers, their father, and their paternal uncle had bilateral gynecomastia beginning at puberty. The breasts were tender at the time of enlargement. The patients were well virilized and all endocrine assays yielded normal results. The authors postulated an inherited sensitivity of the breast to the normal hormonal milieu of the male. Some families suggest autosomal recessive inheritance because of involvement of 2 or more brothers with both parents normal but consanguineous. However, because of male limitation the recessive pattern could result by chance of transmission through females for several generations. Berkovitz et al. (1985) described possible X-linked inheritance of increased aromatase activity leading to gynecomastia.