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Klinefelter Syndrome

Klinefelter Syndrome is a topic covered in the 5-Minute Clinical Consult.

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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.

Risk Factors

Weakly associated with advanced maternal age; 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 (>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)

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Stephens, Mark B., et al., editors. "Klinefelter Syndrome." 5-Minute Clinical Consult, 27th ed., Wolters Kluwer, 2019. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116971/all/Klinefelter_Syndrome.
Klinefelter Syndrome. In: Stephens MB, Golding J, Baldor RA, et al, eds. 5-Minute Clinical Consult. 27th ed. Wolters Kluwer; 2019. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116971/all/Klinefelter_Syndrome. Accessed April 21, 2019.
Klinefelter Syndrome. (2019). In Stephens, M. B., Golding, J., Baldor, R. A., & Domino, F. J. (Eds.), 5-Minute Clinical Consult. Available from https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116971/all/Klinefelter_Syndrome
Klinefelter Syndrome [Internet]. In: Stephens MB, Golding J, Baldor RA, Domino FJ, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2019. [cited 2019 April 21]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116971/all/Klinefelter_Syndrome.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Klinefelter Syndrome ID - 116971 ED - Stephens,Mark B, ED - Golding,Jeremy, ED - Baldor,Robert A, ED - Domino,Frank J, BT - 5-Minute Clinical Consult, Updating UR - https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116971/all/Klinefelter_Syndrome PB - Wolters Kluwer ET - 27 DB - Medicine Central DP - Unbound Medicine ER -