Klinefelter's syndrome

Klinefelter syndrome, 46/47, XXY, or XXY syndrome is a condition in which human males have an extra X 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. Because of the extra chromosome, individuals with the condition are usually referred to as "XXY Males", or "47, XXY Males".

In humans, Klinefelter syndrome is the most common sex chromosome disorder in males and the second most common condition caused by the presence of extra chromosomes. The condition exists in roughly 1 out of every 500-650 males but many of these people may not show symptoms. Other mammals also have the XXY syndrome, including mice.

Principal effects include hypogonadism and reduced fertility. A variety of other physical and behavioural 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, who in 1942 worked with Fuller Albright at Massachusetts General Hospital in Boston, Massachusetts and first described it in the same year.

Signs and symptoms
Affected males are sometimes infertile, or may have reduced fertility. Advanced reproductive assistance is sometimes possible. Some degree of language learning or reading impairment may be present, and neuropsychological testing often reveals deficits in executive functions, although these deficits can often be successfully ameliorated through early intervention. There may also be delays in motor development which can be addressed through occupational therapy. 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. About 10% of XXY males have gynecomastia noticeable enough that they may choose to have cosmetic 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 (primary) hypogonadism, individuals 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 may 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, male breast cancer, and osteoporosis, risks shared to varying degrees with females. 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.

Diagnosis
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 58% of pregnancies in the United States with a diagnosis of Klinefelter syndrome were terminated.

Cause


The extra X chromosome is retained because of a nondisjunction event during meiosis I (gametogenesis). Nondisjunction occurs when homologous chromosomes, in the 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. 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.

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 syndrome. Dr. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy in her 1981 William Allan Memorial Award address.

Variations
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 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.

Treatment
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.

By 2010 over 100 successful pregnancies have been reported using IVF technology with surgically removed sperm material from men with Klinefelter syndrome.