ESPE Abstracts

Background: Aromatase excess syndrome (AEXS) (OMIM 139300) is a rare condition characterized with gynecomastia in boys and macromastia in girls. Estrogen excess in boys can lead to prepubertal and pubertal gynecomastia, bone age progression and short adult stature. While most of girls are usually asymptomatic, there are few reported female patients with excessive breast growth, early puberty, menstrual irregularities, and short adult stature. Male and female children with AEXS have shown heterozygous structural mutations in CYP19A1, leading to increased activity of aromatase enzyme and consequently excessive estrogen production.

Aim: Investigation of Copy Number Variations (CNVs) in CYP19A1 and other pathway related genes in patients with prepubertal gynecomastia and macromastia.

Subjects and Methods: Patients who were followed with AEXS diagnosis (6 male patients with prepubertal gynecomastia and 7 female patients with macromastia). Clinical and hormonal findings of the patients at diagnosis and follow-up were reviewed retrospectively. Oligonucleotide array comparative genomic hybridization (a-CGH) was performed (Agilent Technologies, Inc., Santa Clara, CA, USA) according to manufacturer protocol. Data were analyzed with the use of Agilent Genomics Workbench, with data aligned to the Human Genome release 19 (hg19). Predicted pathogenic CNVs is searched and group of genes 8CYP19A1, TNFAIP8L3, AP4E1, GLDN, DMXL2, TMOD3, SEMA6D, SCG3, CGNL1, ESR1, and PTEN) are specifically investigated.

Results: The median age of patients at presentation was 13 (min-max: 12–22.1) years in female patients and 8.9 (6.3–12.7) years in male patients. Three males had gynecomastia and two males had macromastia history in their families. Four females had a history of macromastia in the family. Median BMI SDS was 1.6 (0.6–3.6) in female and 1.6 (0.2–2.4) in male patients. Median bone age was 15 (13–18) years in females and 11.5 (5–14) years in males. Median estradiol (E2) level was 96.8 (25.8–357) pg/ml in females and 19.5 (11.4–64.3) pg/ml in males. Median E1 level of males was 22 (10.8–30) pg/ml. No mutation was detected by a-CGH technique neither in CYP19A1 nor investigated genes. But, interestingly, we detected a 65.172 kb deletion in olfactory receptor gene cluster OR4P4, OR4S2, OR4C6 (CHR 11q11.1) in four females and in 2 males (46.2%). Whereas, in our a-CGH cohort we detected the same type of deletion in 34 out of 988 cases (3.4%).

Conclusion: No association CYP19A1 CNVs revealed in our cohort. Increased frequency of olfactory genes region deletion in our cohort requires further attention if obesity associated genes may play role in development of gynecomastia and macromastia.