Description

• 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.

Epidemiology

Prevalence

• 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.

Genetics

• 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