Description

• Abnormal body regional proportion, decreased trunk-to-leg ratio, eunuchoid body habitus
• Clinical features of hypergonadotropic hypogonadism: Gynecomastia, small firm testicles, decreased facial and pubic hair
• Presents in males who have ≥1 additional X chromosome(s); most common karyotype is 47,XXY.
• Virtually all men are infertile.
• Diagnosis is usually made during adolescence and adulthood; may remain undiagnosed because symptoms are usually subtle.
• Klinefelter syndrome has been associated with both increased morbidity and mortality believed to be related to genetic, hormonal, behavioral, and socioeconomic factors (1).

Epidemiology

Prevalence
~1 in 600 males.

Risk Factors

Weakly associated with advanced maternal age; X-chromosome nondisjunction increases with age.

• The most common sex chromosome abnormality
• 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) have been identified, but are much less common.
• Severity of phenotype is directly correlated with extra number of X-chromosomes, suggesting an effect related to gene dosage:
  • Each extra X is associated with a decrease in IQ of ≥15–16 points.

Pathophysiology

• Primary hypergonadotropic hypogonadism
• Unclear whether many aspects of syndrome are caused by hormonal abnormalities or extra X chromosome

Etiology

Mutations are spontaneous and patients have no family history. Recurrence risk is that of the general population.
Pregnancy Considerations

• Prenatal diagnosis is possible by karyotyping cells obtained from amniocentesis.
• Diagnosis made via amniocentesis is usually incidental.

Commonly Associated Conditions

• Clinical manifestations of hypogonadism:
  • Infertility (>99%)
  • Azoospermia (>95%)
  • Osteopenia/Osteoporosis (50%)
  • Erectile dysfunction

• Neurodevelopmental sequelae:
  • Low IQ
  • Gross motor delay or dysfunction
  • Learning disabilities: Speech, language, and reading difficulties
  • Autism spectrum behavior
  • ADHD, attention deficits
  • Emotional and behavior problem

• Cardiovascular and metabolic disorders:
  • Thromboembolic disease
  • Mitral valve prolapse and aortic valve disease
  • Metabolic syndrome (46%) and diabetes (10–39%)
• Autoimmune diseases (uncommon):
  • Rheumatoid arthritis
  • Chronic thyroiditis
• Malignancies (rare):
  • Breast cancer (>50× risk than the general population)
  • Extragonadal germ cell tumors, mainly mediastinal (>65× risk than the general population)