Klinefelter's syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Klinefelter’s syndrome is a condition caused by a chromosome aneuploidy. Affected males have an extra X chromosome. The principal effects are the development of small testicles and reduced fertility. A variety of other physical, behavioral differences, and problems are common. The severity varies and many boys and men with the condition have few detectable symptoms. Because of the extra chromosome, individuals with the condition are usually referred to as “XXY Males”, or “47, XXY Males”.^[1]

In humans, 47,XXY is the most common sex chromosome aneuploidy in males^[2] and the second most common condition caused by the presence of extra chromosomes. Other mammals also have the XXY syndrome, including mice.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The extra X chromosome is retained because of a nondisjunction event during meiosis I (gametogenesis). Nondisjunction occurs when homologous chromosomes, in this case the X and Y sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome. Fertilizing a normal (X) egg produces an XXY offspring. The XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about 1 in 500 live male births.

Another mechanism for retaining the extra X chromosome is through a nondisjunction event during meiosis II in the female. Nondisjunction will occur when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. An XX egg is produced which, when fertilized with a Y sperm, yields XXY offspring.

In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed; this is known as X inactivation. This happens in XXY males as well as normal XX females.^[1] A few genes located in the pseudoautosomal regions, however, have corresponding genes on the Y chromosome and are capable of being expressed.^[2] These triploid genes in XXY males may be responsible for symptoms associated with Klinefelter’s syndrome.

It is currently thought that rare X-linked recessive conditions occur even less frequently in XXY males than in normal XY males. Since these conditions are transmitted by genes on the X chromosome, people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.

The 48, XXYY (male) syndrome occurs 1 in 17,000 births and has traditionally been considered to be a variation of Klinefelter’s syndrome. XXYY is no longer generally considered a variation of KS, although it has not yet been assigned an ICD-9 code.

Males with Klinefelter syndrome may have a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Mosaicism 47,XXY/46,XX with clinical features suggestive of Klinefelter syndrome is very rare. Thus far, only about 10 cases have been described in literature.^[3]

Medical literature shows some individual case studies of Klinefelter’s syndrome coexisting with other disorders, such as pulmonary disease, varicose veins, diabetes mellitus, and rheumatoid arthritis. Possible correlations between Klinefelter’s and these other conditions are not well characterized or understood.

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