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- Genetic disorder with one or more extra X chromosomes that affects males
- Most common karyotype is 47,XXY.
- Causes cognitive, social, behavioral, and learning difficulties (1)[C]
- Leads to hypergonadotropic hypogonadism: gynecomastia, small firm testicles, decreased facial and pubic hair
- Virtually all men are infertile.
- Diagnosis is often missed during adolescence and adulthood because symptoms are usually subtle.
- Klinefelter syndrome (KS) has been associated with both increased morbidity and mortality.
~1 in 600 males
Etiology and Pathophysiology
- Primary hypergonadotropic hypogonadism
- Unclear whether many aspects of syndrome are caused by hormonal abnormalities or extra X chromosome
- Mutations are spontaneous and patients have no family history.
- Recurrence risk is that of the general population.
- 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 to 16 points.
Weakly associated with advanced maternal age; 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 (>95%)
- Osteopenia/osteoporosis (50%)
- Erectile dysfunction
- Neurodevelopmental sequelae
- Gross motor delay or dysfunction
- Learning disabilities: speech, language, and reading difficulties (most common)
- 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 and diabetes
- Autoimmune diseases (2)[B]
- Addison disease
- Diabetes mellitus type 1
- Multiple sclerosis
- Acquired hypothyroidism
- Rheumatoid arthritis
- Sjögren syndrome
- Systemic lupus erythematosus malignancies (rare)
- Breast cancer (>50 times risk than the general population)
- Extragonadal germ cell tumors, mainly mediastinal (>65 times risk than the general population)