Olfactory Receptor Gene Deletions: A Novel Genetic Findings in Idiopathic Prepubertal Gynecomastia and Juvenile Macromastia

Introduction 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. Methods 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. Results 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 were 11-fold higher in PG and 16-fold higher in JM. Conclusion 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.