Klinefelter Syndrome

Snapshot

• A 30-year-old man presents to the physician with his wife with concerns that they have been unable to get pregnant after trying for the past year. The patient’s wife has undergone a female infertility workup with no positive results. On physical examination, the man has scant hair in the axilla and pubic areas, small and firm testes, and the finding seen in the image. Karyotype testing is performed and reveals the presence of an extra X chromosome. 

Overview

Introduction

• Overview
  • Klinefelter syndrome is a sex chromosome disorder that is a common underlying cause of hypogonadism in men
• Epidemiology
  • incidence
    • 1 to 2.5 per 1000 men
      • only 25-50% of Klinefelter syndrome patients are diagnosed during their lifetimes
  • risk factors
    • advanced maternal age
• Pathophysiology
  • pathophysiology
    • male child is born with an extra, inactivated X chromosome 
      • karyotype 47,XXY 
      • nondisjunction during cell division prevents X chromosome from being distributed normally
    • dysgenesis of seminiferous tubules
• results in primary testicular failure with ↓ androgen production

Presentation

• Symptoms
  • infertility
  • signs of androgen deficiency
    • gynecomastia
      • breast development at puberty
    • sexual dysfunction
    • osteoporosis
• Physical exam  
  • female hair distribution
  • gynecomastia
  • long extremities 
  • tall stature
• small, firm testes 

Studies

• Karyotype
  • karyotype 47,XXY provides a definitive diagnosis
  • generally only recommended in prepubertal or pubertal boys, or men with clinical signs of Klinefelter syndrome who are seeking fertility treatment
• Serum hormone levels   
  • ↑ FSH and LH  
  • ↓ testosterone
  • ↑ estradiol 
• due to ↑ expression of aromatase 

Differential

• Double Y males (47,XYY)
  • key distinguishing factor
    • phenotypically normal with intact fertility
• Fragile X syndrome
  • key distinguishing factor
    • enlarged testes
• Marfan syndrome
  • key distinguishing factor
• intact fertility

Treatment

• Medical 
  • androgen (testosterone) replacement therapy
    • indications
      • promote development of normal male secondary sex characteristics
• Lifestyle
  • speech and behavioral therapy
    • indications
• improve speech impairments and psychosocial problems

Complications

• ↑ risk of breast cancer 
  • incidence 
    • up to 50-fold ↑ incidence of male breast cancer compared to the normal population