Klinefelter Syndrome



  • Most common congenital anomaly causing primary hypogonadism
  • Additional X chromosome in males, with most common karyotype 47,XXY (80–90%)
  • Causes cognitive, social, behavioral, and learning difficulties (1)[C]
  • Leads to hypergonadotropic hypogonadism: gynecomastia, small firm testes, decreased facial and pubic hair
  • Virtually all men are infertile due to hyalinization and fibrosis of the testes.
  • Up to two-thirds of cases are undiagnosed due to subtle findings.
  • Klinefelter syndrome (KS) has been associated with both increased morbidity and mortality, with average reduction in lifespan of approximately 2.1 years.



  • Approximately 1 in 500 to 1,000 males
  • Seen in 3–4% of infertile males and >10% of azoospermic males

Etiology and Pathophysiology

  • Primary hypergonadotropic hypogonadism
  • Unclear whether many aspects of the syndrome are caused by hormonal abnormalities or extra X chromosome
  • Mutations are spontaneous, and patients have no family history.


  • The classic form of KS (47,XXY) occurs following meiotic nondisjunction of the sex chromosomes during gametogenesis.
    • 40% during spermatogenesis
    • 60% during oogenesis
  • Mosaic forms of KS (46,XY/47,XXY) are thought to result from chromosomal mitotic nondisjunction within the zygote and occur in 10% of individuals with KS.
  • Other chromosome variants of KS (48,XXYY; 48,XXXY) are infrequently seen.
  • Severity of phenotype is directly correlated with additional numbers of X chromosomes.
    • Each extra X is associated with a decrease in IQ of 15 to 16 points.
  • Length of CAG polymorphism of the androgen receptor gene affects KS phenotype.
    • Increased CAG repeat length decreases the translational activity of the androgen receptor.

Risk Factors

Advanced maternal age >40 years (4-fold increased risk) as X-chromosome nondisjunction increases with age.

Pregnancy Considerations
Prenatal diagnosis is incidental by karyotyping cells obtained from amniocentesis or chorionic villus sampling.

Commonly Associated Conditions

  • Clinical manifestations of hypogonadism
    • Infertility (>99%)
    • Azoospermia (>90%), oligozoospermia
    • Osteopenia/osteoporosis (>40%), fracture risk
    • Erectile dysfunction
    • Decreased virilization
  • Neurodevelopmental sequelae
    • Learning disabilities: speech, language, and reading difficulties (most common)
    • Gross motor delay or dysfunction
    • Autism spectrum behavior
    • ADHD, attention deficits
    • Emotional and behavior problems
    • Psychosocial abnormalities, lack of insight
  • Cardiovascular and metabolic disorders
    • Metabolic syndrome (5-fold risk), obesity, and diabetes due to insulin resistance
    • Thromboembolic disease (HR 6.63 for DVT and 3.60 for PE)
    • Mitral valve prolapse and aortic valve disease
  • Pulmonary disease
    • Chronic bronchitis
    • Bronchiectasis
    • Emphysema
  • Autoimmune disease (2)[B]
    • Addison disease
    • Type 1 diabetes mellitus
    • Multiple sclerosis
    • Hashimoto hypothyroidism
    • Rheumatoid arthritis
    • Sjögren syndrome
    • Systemic lupus erythematosus
  • Malignancies (rare)
    • Breast cancer (>30 times risk than the general population, diagnosed usually in the 7th decade)
    • Extragonadal germ cell tumors, mainly mediastinal (>30 to 40 times risk)
    • Non-Hodgkin lymphoma
    • Lower risk of prostate cancer compared to 46,XY

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