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
Book
Category
Family
Type
Subtype(s)

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. 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.

The majority of patients (~80%-90%) with KS are 47,XXY by chromosome analysis, with the remainder being 48,XXXY, 48,XXYY, 49,XXXXY, or mosaic with a normal cell line. While the majority of mosaic KS patients have a normal male cell line, individuals with a normal female karyotype have also been described. Mosaic individuals typically present with a more variability clinical phenotype, and are often diagnosed due to infertility. Individuals with a normal female cell line may have ambiguous genitalia and the presence of ovotestes.

G-banded chromosome analysis of a PHA-stimulated peripheral blood specimen from a patient with Klinefelter Syndrome and a 47,XXY karyotype; Courtesy of Wisconsin Diagnostics Laboratories

Epidemiology/Prevalence

The incidence of KS is approximately 1 in 500 to 1000 male births. 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. Only about 10% of cases are diagnosed before puberty, and many individuals remain undiagnosed. The median age of diagnosis is in the mid-30s. 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.

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. 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. The pathophysiology is unclear, but is thought to be related to genes on the extra X chromosome.

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):