Klinefelter syndrome

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Klinefelter syndrome
Synonyms XXY syndrome, Klinefelter’s syndrome, Klinefelter-Reifenstein-Albright syndrome
Human chromosomesXXY01.png
47,XXY karyotype
Specialty Medical genetics
Symptoms Often few[1]
Usual onset At birth
Duration Long term
Causes Two or more X chromosomes in males[2]
Risk factors Older mother[3]
Diagnostic method Genetic testing (karyotype)[4]
Treatment Physical therapy, speech and language therapy, counselling[5]
Prognosis Nearly normal life expectancy[6]
Frequency 1:500 to 1:1,000 males[3][7]

Klinefelter syndrome (KS) also known as 47,XXY or XXY, is the set of symptoms that result from two or more X chromosomes in males.[2] The primary features are sterility and small testicles.[2][8] Often symptoms may be subtle and many people do not realize they are affected.[1] Sometimes symptoms are more prominent and may include weaker muscles, greater height, poor coordination, less body hair, breast growth, and less interest in sex.[1] Often it is only at puberty that these symptoms are noticed.[4] Intelligence is usually normal; however, reading difficulties and problems with speech are more common.[1] Symptoms are typically more severe if three or more X chromosomes are present.[1]

Klinefelter syndrome usually occurs randomly.[3] An older mother may have a slightly increased risk of a child with Klinefelter syndrome.[3] The condition is not typically inherited from one’s parents.[3] The underlying mechanisms involves at least one extra X chromosome in addition to a Y chromosome such that there is a total of 47 or more chromosomes rather than the usual 46.[9] KS is diagnosed by the genetic test known as a karyotype.[4]

While there is no cure, a number of treatments may help.[6] Physical therapy, speech and language therapy, counselling, and adjustments of teaching methods may be useful.[5] Testosterone replacement may be used in those who have significantly lower levels.[5] Enlarged breasts may be removed by surgery.[5] About half of affected males have a chance of fathering children with the help of assisted reproductive technology, but this is expensive and not risk free.[5] Males appear to have a higher risk of breast cancer than typical but still lower than that of females.[10] The condition has a nearly normal life expectancy.[6]

Klinefelter syndrome is one of the most common chromosomal disorders, occurring in 1:500 to 1:1,000 live male births.[3][7] It is named after Harry Klinefelter who identified the condition in the 1940s.[11] In 1956 identification of the extra X chromosome was first noticed.[12] Mice can also have the XXY syndrome, making them a useful research model.[13]

File:Klinefelter syndrome.webm

Video explanation

Signs and symptoms[edit]

A person with typical untreated (surgery/hormones) Klinefelter 46,XY/47,XXY mosaic, diagnosed at age 19. Scar from biopsy may be visible on left nipple.

While it is possible to characterise XXY males based on physical characteristics, substantial variation in physical and developmental traits mean the only reliable method of positive or negative identification is karyotype testing.[citation needed]


As babies and children, XXY males may have weaker muscles and reduced strength. As they grow older, they tend to become taller than average. They may have less muscle control and coordination than other boys of their age.[14]

During puberty, the physical traits of the syndrome become more evident; because these boys do not produce as much testosterone as other boys, they have a less muscular body, less facial and body hair, and broader hips. As teens, XXY males may develop breast tissue[15] and also have weaker bones, and a lower energy level than other males.[14]

By adulthood, XXY males look similar to males without the condition, although they are often taller. In adults, possible characteristics vary widely and include little to no sign of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue).[16] Gynecomastia is present to some extent in about a third of affected individuals, a slightly higher percentage than in the XY population. About 10% of XXY males have gynecomastia noticeable enough that they may choose to have cosmetic surgery.[17]

Affected males are often infertile, or may have reduced fertility. Advanced reproductive assistance is sometimes possible.[18]

The term hypogonadism in XXY symptoms is often misinterpreted to mean “small testicles” when it means decreased testicular hormone/endocrine function. Because of this (primary) hypogonadism, individuals will often have a low serum testosterone level but high serum follicle-stimulating hormone(FSH) and luteinizing hormone (LH) levels.[19] Despite this misunderstanding of the term, however, it is true that XXY men may also have microorchidism(i.e., small testicles).[19]

The testicle size of affected males are usually less than 2 cm in length (and always shorter than 3.5 cm[20]), 1 cm in width and 4 ml in volume.[21]

XXY males are also more likely than other men to have certain health problems that typically affect females, such as autoimmune disorders, breast cancer, venous thromboembolic disease, and osteoporosis.[14][22] In contrast to these potentially increased risks, it is currently thought that rare X-linked recessiveconditions occur less frequently in XXY males than in normal XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.[citation needed]

Cognitive and developmental[edit]

Some degree of language learning or reading impairment may be present,[23] and neuropsychological testing often reveals deficits in executive functions, although these deficits can often be overcome through early intervention.[24] There may also be delays in motor development which can be addressed through occupational therapy and physical therapy.[25] XXY males may sit up, crawl, and walk later than other infants; they may also struggle in school, both academically and with sports.[14]


Birth of a cell with karyotype XXY due to a non-disjunction event of one X chromosome from a Y chromosome during meiosis I in the male.

Birth of a cell with karyotype XXY due to a non-disjunction event of one X chromosome during meiosis II in the female.

The extra chromosome is retained because of a nondisjunction event during paternal or maternal meiosis I (gametogenesis). Nondisjunction occurs when homologous chromosomes, in this case the X and Y or two X sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome or an egg with two X chromosomes. Fertilizing a normal (X) egg with this sperm produces an XXY offspring (Klinefelter). Fertilizing a double X egg with a normal sperm also produces an XXY offspring (Klinefelter).[26]

Another mechanism for retaining the extra chromosome is through a nondisjunction event during meiosis II in the egg. Nondisjunction will occur when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. (meiosis) An XX egg is produced which, when fertilized with a Y sperm, yields XXY offspring. This XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about 1 in 500 live male births.[14] See also Triple X syndrome.

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.[27] However, in XXY males, a few genes located in the pseudoautosomal regions of their X chromosomes, have corresponding genes on their Y chromosome and are capable of being expressed.[28]


48,XXYY and 48,XXXY occur in 1 in 18,000–50,000 male births. The incidence of 49,XXXXY is 1 in 85,000 to 100,000 male births.[29] These variations are extremely rare. Additional chromosomal material can contribute to cardiac, neurological, orthopedic and other anomalies.

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.[30]

Analogous XXY syndromes are known to occur in cats—specifically, the presence of calico or tortoiseshell markings in male cats is an indicator of the relevant abnormal karyotype. As such, male cats with calico or tortoiseshell markings are a model organism for Klinefelter syndrome, because a color gene involved in cat tabby coloration is on the X chromosome.[31]


Percentages of Klinefelter’s diagnosis divided by age groups, with most diagnoses occurring in adulthood.[32]

About 10% of Klinefelter cases are found by prenatal diagnosis.[33] The first clinical features may appear in early childhood or, more frequently, during puberty, such as lack of secondary sexual characteristics and aspermatogenesis.[34] Despite the presence of small testes, only a quarter of the affected males are recognized as having Klinefelter syndrome at puberty.[35][36] Another quarter receive their diagnosis in late adulthood. About 64% of affected individuals are never recognized.[37] Often the diagnosis is made incidentally as a result of examinations and medical visits for reasons not linked to the condition.[38]

The standard diagnostic method is the analysis of the chromosomes’ karyotype on lymphocytes. In the past, the observation of the Barr body was common practice as well.[36] To confirm mosaicism, it is also possible to analyze the karyotype using dermal fibroblasts or testicular tissue.[39]

Other methods may be: research of high serum levels of gonadotropins (follicle-stimulating hormone and luteinizing hormone), presence of azoospermia, determination of the sex chromatin,[40] and prenatally via chorionic villus sampling or amniocentesis. A 2002 literature review of elective abortion rates found that approximately 58% of pregnancies in the United States with a diagnosis of Klinefelter syndrome were terminated.[41]

Differential diagnosis[edit]

The symptoms of Klinefelter syndrome are often variable; therefore, a karyotype analysis should be ordered when small testes, infertility, gynecomastia, long legs/arms, developmental delay, speech/language deficits, learning disabilities/academic issues and/or behavioral issues are present in an individual.[9] The differential diagnosis for the Klinefelter syndrome can include the following conditions: fragile X syndrome, Kallmann syndrome and Marfan syndrome. The cause of hypogonadism can be attributed to many other different medical conditions.

There have been some reports of individuals with Klinefelter syndrome who also have other chromosome abnormalities, such as Down syndrome.[42]


The genetic variation is irreversible, however, individuals who want to look more masculine can take testosterone.[43] Treating adolescents with implants of controlled release testosterone has shown good results when appropriately monitored.[44] Hormone therapy is also useful in preventing the onset of osteoporosis.

Often individuals that have noticeable breast tissue or hypogonadism experience depression and/or social anxiety because they are outside of social norms. An academic term for this is psychosocialmorbidity.[45] At least one study indicates that planned and timed support should be provided for young men with Klinefelter syndrome to ameliorate current poor psychosocial outcomes.[45] The surgical removal of the breasts may be considered for both the psychological reasons and to reduce the risk of breast cancer.[46]

The use of behavioral therapy can mitigate any language disorders, difficulties at school and socialization. An approach by occupational therapy is useful in children, especially those who have dyspraxia.[47]

Infertility treatment[edit]

By 2010 over 100 successful pregnancies have been reported using IVF technology with surgically removed sperm material from males with Klinefelter syndrome.[48]Microdissection testicular sperm extraction in adult men with Klinefelter syndrome reported success rates of up to 45%.[49]


Children with XXY differ little from other children. Although they can face problems during adolescence, often emotional and behavioral, and difficulties at school, most of them can achieve full independence from their families in adulthood. Most can lead a normal, healthy life.[citation needed]

The results of a study carried out on 87 Australian adults with the syndrome shows that those who have had a diagnosis and appropriate treatment from a very young age had a significant benefit with respect to those who had been diagnosed in adulthood.[50]

There is research suggesting Klinefelter syndrome substantially decreases life expectancy among affected individuals, though the evidence is not definitive.[51] A 1985 publication identified a greater mortality mainly due to diseases of the aortic valve, development of tumors and possible subarachnoid hemorrhages, reducing life expectancy by about 5 years.[52] Later studies have reduced this estimated reduction to an average of 2.1 years.[53] These results are still questioned data, are not absolute, and will need further testing.[51]


This syndrome, evenly spread in all ethnic groups, has a prevalence of 1-2 subjects per every 1000 males in the general population.[35][54][55][56] 3.1% of infertile males have Klinefelter syndrome. The syndrome is also the main cause of male hypogonadism.[57]

According to 2008 meta-analysis, the prevalence of the syndrome has increased over the past decades; however, this does not appear to be related to increased age of the mother at conception, as no increase was observed in the rates of other trisomies of sex chromosomes (XXX and XYY).[58] The National Institutes of Health; however, state that older mothers might have a slightly increased risk.[3]


The syndrome was named after Harry Klinefelter, who, in 1942, worked with Fuller Albright and E. C. Reifenstein at Massachusetts General Hospital in Boston, Massachusetts, and first described it in the same year.[16][34] The account given by Klinefelter came to be known as Klinefelter syndrome as his name appeared first on the published paper, and seminiferous tubule dysgenesis was no longer used. Considering the names of all three researchers, it is sometimes also called Klinefelter-Reifenstein-Albright syndrome.[59]

The first published report of a man with a 47,XXY karyotype was by Patricia Jacobs and John Strong at Western General Hospital in Edinburgh, Scotland in 1959.[60] This karyotype was found in a 24-year-old man who had signs of Klinefelter syndrome. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy in her 1981 William Allan Memorial Award address.[61]