Prepubertal gynecomastia (PG) and juvenile macromastia (JM) are rare breast overgrowth phenotypes arising from hormonal or genetic abnormalities. While many cases reflect physiological or endocrine variation, a subset may involve increased peripheral aromatization driven by genomic factors. The molecular basis remains unknown in many idiopathic cases. We evaluated whether copy number variations (CNVs) in CYP19A1 and other estrogen-related genes are associated with PG or JM. We performed a cross-sectional study of 17 patients suspected of aromatase excess syndrome: 10 boys with PG and 7 girls with JM. Clinical and hormonal data at diagnosis and follow-up were reviewed. After excluding numerical and structural chromosomal anomalies, genome-wide oligonucleotide array comparative genomic hybridization (aCGH) was analyzed in Agilent Genomics Workbench (GRCh37/hg19). CNVs were interrogated across estrogen-related genes, including CYP19A1. As comparators, 988 individuals evaluated by aCGH at the same center for unrelated indications and without breast overgrowth served as controls. No pathogenic CNVs were observed in CYP19A1 or the other estrogen-related genes. By contrast, a recurrent 65.2-kilobase (kb) deletion spanning the OR4P4-OR4S2-OR4C6 olfactory receptor cluster at 11q11 occurred in 40.0% (4/10) of PG and 57.1% (4/7) of JM cases, in this cohort, overall, versus 3.4% (34/988) of controls, suggesting a strong association. Estimated risk ratio was 11-fold higher in PG and 16-fold higher in JM. Although estrogen-gene CNVs were not detected, the OR4P4-OR4S2-OR4C6 deletion may represent an under-recognized genomic contributor to idiopathic PG and JM. Prospective studies with tissue-level validation and functional assays are needed to confirm clinical significance and clarify mechanism.

Aromatase excess syndrome (AEXS) is a rare, autosomal dominant disorder, characterized by enhanced aromatization of androgens and estrogen excess. In males it is characterized by pre-/peripubertal gynecomastia, hypogonadotropic hypogonadism, advanced bone age and short adult height. Only a few female patients have been described so far. We report on a family with four members with AEXS and present the long-term effects of aromatase inhibitor use in three of them. Genetic analysis showed a monoallelic 0.3-Mb deletion in 15q21, involving parts of CYP19A1, GLDN and DMXL2 in all four patients with AEXS. The index patient (male, 8 years old) presented with gynecomastia and accelerated growth and bone age. With start of puberty, estradiol levels increased, while testosterone levels remained low. Gynecomastia progressed and a mastectomy was performed twice. Presuming AEXS, a therapy with letrozole was initiated at the age of 19 years. Low-dose letrozole treatment was associated with an increase in testicular volume, increase in virilization and improvement in physical strength and libido. His brother (age 3 years) presented with accelerated growth and bone age. Treatment with letrozole, which was started at the age of 7 years, resulted in achieving an adult height of 179 cm and prevented the appearance of gynecomastia. His sister (age 6 years), who presented with premature thelarche and accelerated growth and bone age, was treated with an estrogen receptor modulator and a GnRH analog followed by letrozole treatment. Menarche occurred at age 13.5 years and adult height was 158 cm. Their father had an early, accelerated growth with an adult height of 171 cm, a delayed puberty and no gynecomastia. In vitro studies provided evidence for involvement of aromatase induction in atypical cells and an increased range of potential mechanisms regulating aromatase activity due to the presence of the mutated allele. In conclusion, we observed a phenotypic variability within family members with AEXS carrying the same CYP19A1 microdeletion. When started early, treatment with letrozole was found to prevent the development of gynecomastia and increase adult height in one patient. In adult life, low-dose letrozole treatment resulted in improved physical strength and libido in the index patient.

Peripheral precocious puberty(PPP),also known as puberty independent from hypothalamic-pituitary axis activation,is stimulated by hormones from other sources, with only partial sexual characteristics development but without mature sexual function. The secondary sexual characteristics development occurs before 7.5 years of age in girls and before 9 years of age in boys. Clinical manifestations are diverse, and PPP has varied etiology including congenital adrenal hyperplasia, McCune-Albright syndrome, ovarian cyst, adrenal tumor, ovarian tumor, testicular tumor, human chorionic gonadotropin producing tumor, familial male precocious puberty, aromatase excess syndrome, and environmental estrogen. Early identification of etiology, accurate differential diagnosis and prenatal gene screening play a significant role in the prevention, diagnosis and treatment of the disease. 外周性性早熟又称非促性腺激素释放激素依赖性性早熟，指非下丘脑-垂体-性腺轴激活，而是由其他来源的激素刺激引起的男孩在9岁前、女孩在7.5岁前出现第二性征发育，但不具备完整的性发育过程，仅有部分性征发育。外周性性早熟临床表现多样，常见的病因包括先天性肾上腺皮质增生症、McCune-Albright综合征、卵巢囊肿、肾上腺肿瘤、卵巢肿瘤、睾丸肿瘤、分泌人绒毛膜促性腺激素肿瘤、家族性男性性早熟、家族性芳香化酶活性增高及环境雌激素等。早期识别病因、精准鉴别诊断、产前基因筛查对该病的预防及诊治具有非常重要的意义。.

Gynecomastia may be due to aromatase excess in several diseases such as obesity and cancer. Aromatase excess syndrome (AEXS) is an autosomal dominant disorder caused by overexpression of CYP19A1. Germinal mutations occurring in AEXS include various genomic rearrangements including duplication, deletion, and inversion identified in the upstream region of CYP19A1. Aromatase overexpression caused by a CYP19A1 somatic mutation has been rarely described. Breast adipose tissue biopsies or surgical specimens were obtained from 19 subjects with gynecomastia. Aromatase quantification was performed by digital PCR and CYP19A1 sequencing by RACE PCR products. We observed localized aromatase overexpression (>10 fold greater than normal) in breast adipose tissue from three prepubertal males with gynecomastia out of the 19 cases. One carried a chromosomal rearrangement between CYP19A1 and DMXL2, consistent with AEXS. In the 2 others, the first exon of CYP19A1 contained 11 different tissue-specific promoter subtypes, specifically I.4 or I.3 normally expressed by adipose tissue, but also the placental I.2 promoter and the more ubiquitous I.7 which is usually expressed in breast cancer, uterine, and endothelial tissues. No differences in clinical or biochemical characteristics were observed between these 3 subjects and 16 others without aromatase overexpression. We describe two cases of aromatase overexpression in breast adipose tissue associated with nonspecific promoter recruitment. Further investigations are necessary to understand the mechanisms involved in aberrant promoter selection.

Estrogens regulate pubertal development and reproductive function in women, spermatogenesis in men, and bone turnover and metabolic conditions in individuals of both sexes. Estradiol, the major estrogen in humans, is synthesized from testosterone by the action of aromatase and exerts its effects though binding to estrogen receptors. Germline loss- and gain-of-function variants in CYP19A1, the gene encoding aromatase, lead to aromatase deficiency and aromatase excess syndrome, respectively. Germline loss-of-function variants in ESR1, the gene encoding estrogen receptor α, are known to cause of estrogen insensitivity/resistance. In addition, rare variants in ESR1 and ESR2 have been implicated in various disease phenotypes. Clinical studies on these rare endocrine disorders provided clues to understand the biological functions of estrogens in the human body. This review introduces the genetic basis, phenotypes, and current management procedures of congenital disorders in estrogen biosynthesis and action.