What are the genetic causes of gynecomastia?

Genetic Causes of Gynecomastia

Klinefelter syndrome is the most significant genetic cause of gynecomastia, with a relative risk of 24.7 compared to the general population. 1

Primary Genetic Factors

• Klinefelter syndrome (47,XXY karyotype) significantly increases the risk of gynecomastia due to hypogonadism and altered estrogen-to-androgen ratio 1
• BRCA2 mutation carriers have a significantly higher risk of both male breast cancer and gynecomastia 1
• Family history of male breast disorders increases the risk of gynecomastia, suggesting other potential genetic components 1

Pathophysiological Mechanisms

• Genetic conditions primarily cause gynecomastia through hormonal imbalance between estrogens and androgens, resulting in increased estrogen action relative to androgen action at the breast tissue level 2
• Genetic disorders may affect:
  • Estrogen production (increased)
  • Androgen production (decreased)
  • Hormone receptor sensitivity
  • Peripheral conversion of androgens to estrogens 1, 3

Specific Genetic Conditions Associated with Gynecomastia

• Klinefelter syndrome:

  • Most common chromosomal abnormality causing gynecomastia
  • Characterized by at least one extra X chromosome (47,XXY)
  • Results in testicular dysgenesis, androgen deficiency, and relative estrogen excess 1
  • Typically presents with small, firm testes, tall stature, and gynecomastia 4

• BRCA2 mutations:

  • Associated with increased risk of both gynecomastia and male breast cancer
  • Requires careful monitoring due to the elevated malignancy risk 1

• Other genetic conditions that may present with gynecomastia:

  • Androgen insensitivity syndromes (partial forms)
  • Aromatase excess syndromes
  • Genetic forms of hypogonadism 4

Clinical Evaluation of Potential Genetic Causes

• Assess for family history of breast disorders, as this may indicate genetic predisposition 1
• Consider genetic testing for Klinefelter syndrome in males with:
  • Persistent unexplained gynecomastia
  • Small, firm testes
  • Infertility
  • Tall stature with eunuchoid proportions 4
• Evaluate for BRCA2 mutations in males with:
  • Family history of male or female breast cancer
  • Personal or family history of other BRCA2-associated cancers 1

Management Considerations for Genetic Gynecomastia

• Endocrinology referral is recommended for patients with suspected genetic causes of gynecomastia 5
• Hormone replacement therapy may be beneficial in cases of hypogonadism, such as Klinefelter syndrome 4
• For established gynecomastia from genetic causes that is persistent and bothersome:
  • Medical therapy has limited efficacy in long-standing cases 2
  • Surgical correction (combining liposuction and mammary adenectomy) often provides the best results 3

Common Pitfalls to Avoid

• Failing to distinguish between true gynecomastia and pseudogynecomastia, especially in obese patients 1
• Overlooking the possibility of male breast cancer, particularly in BRCA2 mutation carriers 1
• Unnecessary imaging in clear cases of gynecomastia, which can lead to additional unnecessary benign biopsies 1, 5
• Neglecting to consider genetic causes in persistent, unexplained cases of gynecomastia 4