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Klinefelter's syndrome, 47, XXY, or XXY syndrome is a condition in which males have an extra X sex chromosome. While females have an XX chromosomal makeup, and males an XY, affected individuals have at least two X chromosomes and at least one Y chromosome. Klinefelter's syndrome is the most common sex chromosome disorder and the second most common condition caused by the presence of extra chromosomes. The condition exists in roughly 1 out of every 1,000 males. One in every 500 males have an extra X chromosome but do not have the syndrome.
The principal effects are development of small testicles and reduced fertility. A variety of other physical and behavioral differences and problems are common, though severity varies and many boys and men with the condition have few detectable symptoms. The syndrome was named after Dr. Harry Klinefelter, an endocrinologist at Massachusetts General Hospital in Boston, Massachusetts, who first described it in 1942. Because of the extra chromosome, individuals with the condition are usually referred to as "XXY Males", or "47, XXY Males".
Affected males are almost always effectively infertile, although advanced reproductive assistance is sometimes possible. Some degree of language learning impairment may be present, and neuropsychological testing often reveals deficits in executive functions. In adults, possible characteristics vary widely and include little to no signs of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue). Gynecomastia is present to some extent in about a third of affected individuals, a slightly higher percentage than in the XY population, but only about 10% of XXY males' gynecomastia is noticeable enough to require surgery.
The term hypogonadism in XXY symptoms is often misinterpreted to mean "small testicles" or "small penis". In fact, it means decreased testicular hormone/endocrine function. Because of this hypogonadism, patients will often have a low serum testosterone level but high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. Despite this misunderstanding of the term, however, it is true that XXY men often also have microorchidism (i.e. small testicles).
The more severe end of the spectrum of symptom expression is also associated with an increased risk of germ cell tumors, breast cancer, and osteoporosis, risks shared to varying degrees with females. Additionally, 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, but possible correlations between Klinefelter's and these other conditions are not well characterized or understood.
In contrast to these potentially increased risks, it is currently thought that rare X-linked recessive conditions 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.
There are many variances within the XXY population, just as in the most common 46,XY population. While it is possible to characterise 47,XXY males with certain body types, that in itself should not be the method of identification as to whether or not someone has 47,XXY. The only reliable method of identification is karyotype testing.
A karyotype is used to confirm the diagnosis. In this procedure, a small blood sample is drawn. White blood cells are then separated from the sample, mixed with tissue culture medium, incubated, and checked for chromosomal abnormalities, such as an extra X chromosome.
Diagnosis can also be made prenatally via chorionic villus sampling or amniocentesis, tests in which fetal tissue is extracted and the fetal DNA is examined for genetic abnormalities. A 2002 literature review of elective abortion rates found that approximately 50% of pregnancies in the United States with a diagnosis of Klinefelter's syndrome were terminated.
The extra X chromosome is retained because of a nondisjunction event during meiosis (sex cell division). 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.
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. 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. These triploid genes in XXY males may be responsible for symptoms associated with Klinefelter's syndrome.
The first published report of a man with a 47,XXY karyotype was by Patricia A. Jacobs and Dr. J.A. Strong at Western General Hospital in Edinburgh, Scotland in 1959. This karyotype was found in a 24-year-old man who had signs of Klinefelter's syndrome. Dr. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy in her 1981 William Allan Memorial Award address.
The genetic variation is irreversible. Testosterone treatment is an option for some individuals who desire a more masculine appearance and identity. Often individuals that have noticeable breast tissue or hypogonadism experience depression and/or social anxiety because they are outside of social norms. This is academically referred to as psychosocial morbidity. 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.
The 48, XXYY (male) syndrome occurs in 1 in 18,000–40,000 births and has traditionally been considered to be a variation of Klinefelter's syndrome. XXYY tetrasomy is no longer generally considered a variation of KS, although it has not yet been assigned an ICD-10 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.