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