GTS5:Klinefelter syndrome
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Primary Author(s)*
Kathleen M. Bone, PhD, Medical College of Wisconsin
WHO Classification of Disease
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| Structure | Disease |
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Related Terminology
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| Acceptable | 47,XXY Syndrome |
| Not Recommended |
Definition/Description of Disease
Klinefelter syndrome (KS) is a genetic condition affecting males and results from the presence of an extra X chromosome (47,XXY). KS can lead to a range of physical, developmental and reproductive issues, including tall stature, reduced muscle mass, gynecomastia, small testes, infertility, azoospermia and learning difficulties.[1] There is a high incidence of symptom variability, and many individuals remain undiagnosed. KS should be suspected in adolescence in males with incomplete or delayed puberty, eunuchoid body habitus (disproportionately long arms and legs), gynecomastia, small and firm testes, low muscle mass, and psychosocial difficulties, and in adults with primary hypogonadism (small testes low testosterone, high FSH/LH), azoospermia, reduced libido or erectile dysfunction, osteoporosis, and mild cognitive or language difficulties.[2][3]
Epidemiology/Prevalence
The incidence of KS is approximately 1 in 500 to 1000 male births.[3][4] However, some studies suggest the prevalence could be as high as 1:600 due to under diagnosis, as many individuals have mild or unnoticed symptoms.[5] Only about 10% of cases are diagnosed before puberty, and many individuals remain undiagnosed. The median age of diagnosis is in the mid-30s.[3] There is a significant association with advanced maternal age: around 50-60% of cases result from maternal non-disjunction during meiosis I, while the remaining cases arise from paternal non-disjunction during meiosis II or postzygotic mitotic errors, which are not associated with parental age.[6]
KS also carriers an increased risk for breast cancer and extragonadal germ cell tumors. Males with KS have a 20-30-fold increased risk of developing breast cancer over the average male population risk of approximately 1 in 726.[7] There is also an increased incidence of mediastinal germ cell tumors (M-GCTs) in KS patients, which can lead to precocious puberty due to human chorionic gonadotropin (hCG)-producing M-GCTs.[8][9] The pathophysiology is unclear, but is thought to be related to genes the extra X chromosome.[10]
Genetic Abnormalities: Germline
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| Gene | Genetic Variant or Variant Type | Molecular Pathogenesis | Inheritance, Penetrance, Expressivity | Notes |
|---|---|---|---|---|
| EXAMPLE: BRCA1 | EXAMPLE: Many | EXAMPLE: Multiple variant types leading to loss of function | EXAMPLE: Autosomal recessive,
~30% penetrant for carriers |
|
| EXAMPLE: Gene X | EXAMPLE: List the specific mutation | |||
Genetic Abnormalities: Somatic
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| Gene | Genetic Variant or Variant Type | Molecular Pathogenesis | Inheritance, Penetrance, Expressivity | Notes |
|---|---|---|---|---|
| EXAMPLE: BRCA1 | EXAMPLE: Biallelic inactivation variants | EXAMPLE: Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene. | ||
| EXAMPLE: BRCA1 | EXAMPLE: Reversion mutation | EXAMPLE: After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism. | ||
Genes and Main Pathways Involved
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| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
Genetic Diagnostic Testing Methods
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Additional Information
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Links
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References
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Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
Prior Author(s):
- ↑ Bearelly, Priyanka; et al. (2019). "Recent advances in managing and understanding Klinefelter syndrome". F1000Research. 8: F1000 Faculty Rev–112. doi:10.12688/f1000research.16747.1. ISSN 2046-1402. PMC 6352920. PMID 30755791.
- ↑ Bojesen, Anders; et al. (2007-04). "Klinefelter syndrome in clinical practice". Nature Clinical Practice. Urology. 4 (4): 192–204. doi:10.1038/ncpuro0775. ISSN 1743-4289. PMID 17415352. Check date values in:
|date=(help) - ↑ 3.0 3.1 3.2 Groth, Kristian A.; et al. (2013-01). "Clinical review: Klinefelter syndrome--a clinical update". The Journal of Clinical Endocrinology and Metabolism. 98 (1): 20–30. doi:10.1210/jc.2012-2382. ISSN 1945-7197. PMID 23118429. Check date values in:
|date=(help) - ↑ Berglund, Agnethe; et al. (2020-06). "The epidemiology of sex chromosome abnormalities". American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 184 (2): 202–215. doi:10.1002/ajmg.c.31805. ISSN 1552-4876. PMID 32506765 Check
|pmid=value (help). Check date values in:|date=(help) - ↑ Bojesen, Anders; et al. (2003-02). "Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study". The Journal of Clinical Endocrinology and Metabolism. 88 (2): 622–626. doi:10.1210/jc.2002-021491. ISSN 0021-972X. PMID 12574191. Check date values in:
|date=(help) - ↑ Thomas, N. S.; et al. (2003). "Aberrant recombination and the origin of Klinefelter syndrome". Human Reproduction Update. 9 (4): 309–317. doi:10.1093/humupd/dmg028. ISSN 1355-4786. PMID 12926525.
- ↑ Swerdlow, Anthony J.; et al. (2005-08-17). "Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study". Journal of the National Cancer Institute. 97 (16): 1204–1210. doi:10.1093/jnci/dji240. ISSN 1460-2105. PMID 16106025.
- ↑ Hasle, H.; et al. (1992-10). "Mediastinal germ cell tumour associated with Klinefelter syndrome. A report of case and review of the literature". European Journal of Pediatrics. 151 (10): 735–739. doi:10.1007/BF01959079. ISSN 0340-6199. PMID 1425792. Check date values in:
|date=(help) - ↑ Völkl, Thomas M. K.; et al. (2006-03-01). "Klinefelter syndrome and mediastinal germ cell tumors". American Journal of Medical Genetics. Part A. 140 (5): 471–481. doi:10.1002/ajmg.a.31103. ISSN 1552-4825. PMID 16470792.
- ↑ Rapley, E. A.; et al. (2000-02). "Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours". Nature Genetics. 24 (2): 197–200. doi:10.1038/72877. ISSN 1061-4036. PMID 10655070. Check date values in:
|date=(help)