Understanding Klinefelter Syndrome: Genetics and Symptoms

In 1942 Doctor Harry Klinefelter wrote a paper about some men who he found had strange symptoms. These symptoms included very little facial/body hair, small testes, and an inability to produce sperm. Seventeen years later in 1959 the extra X chromosome that is characteristic of the condition was discovered. Klinefelter Syndrome is a condition that affects male chromosomes. Humans in general have about 46 chromosomes in total. Out of these 46, only two will determine if a person will be male or female. The sex chromosomes in women typically present as XX, while the sex chromosomes in males present as XY. With Klinefelter syndrome, also known as (47, XXY) and XXY Syndrome only males are able to affected with this chromosomal condition where they end up with an extra X chromosome on almost all of their cells.
GENETICS OF THE DISEASE
Klinefelter Syndrome, as previously stated, is a chromosomal condition process begins during meiosis. Before meiosis has finished chromosomes pair up with their corresponding half and they exchange pieces of genetic material, however something may go wrong during the process and sister chromatids might not separate completely. During normal embryonic development one of the two X chromosomes from the mother are made inactive. In some 15%

of cases the second X chromosome somehow escapes deactivation and can end up being expressed in the male phenotype. There is great phenotypic variation in Klinefelter syndrome due to several reasons: the deactivation of an X-chromosome didn't happen or happened incorrectly, the extra X chromosome is donated from one of the parents, or CAG repeats on in the Androgen Receptor gene. While some studies have suggested that maybe genes inherited from one of the parents have resulted in an unfavorable (re: ugly) phenotype this has yet to be proven. The incorrect deactivation of an X chromosome has been documented in women who become mothers later in life but this has not yet been linked to (47, XXY) in clinical experiments.

The androgen receptor gene is found on X chromosomes at the level of q-11 and q-12.

It is composed of eight exons, segments of DNA that contain the information for coding both proteins and peptides. The first exon of the AR gene has a polymorphic sequence of CAG repeats - CAG being the combination of nucleotide bases that occur in this exon- that varies in number from ten to thirty-five repeats in a normal X chromosome. In one study of 77 recently diagnosed men that the average CAG repeat was 23 times on the first exon. In the same study a longer CAG repeat number was associated with patient height – the longer the repeat the taller the patient- lower bone density and gynecomastia.

VARIATIONS ON A

THEME
Klinefelter syndrome usually presents itself as 47 chromosomes instead of the regular 46 chromosomes. However there are a few variations of KS in which the patient may have more than just two X chromosomes. In (48, XXXY) the person with this condition has three X chromosomes instead of two. These people experience more severe developmental problems then those with (47, XXY). A second variant is known as (49, XXXXY) and the person has 4 X chromosomes. Like with 48, XXXY the person with this chromosomal condition can experience severe developmental problems and deformities in different body systems. The last and most mild variation of KS is known as (46, XY) Mosaic. With this variation not all of the affected persons cells carry the extra X chromosome so they may experience any developmental issues to a lesser degree depending on which cells were affected.