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- 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).
~1 in 600 males.
Weakly associated with advanced maternal age; X-chromosome nondisjunction increases with age.Genetics
- 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.
- 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.
- 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)