(→‎Prenatal Diagnosis methods)
==Pathogenesis==
There are two mechanisms by which chromosome distribution can be abnormal and lead to Klinefelter's syndrome. These are anaphase lagging and nondisjunction. The latter of the two is the process which takes place more frequently, when compared to the first.
During anaphase in the cell division, spindle fibers attach to sister chromatids and separate them. However, the abnormal event of anaphase lagging involves spindle fibers missing. Because of this, sister chromatid will not be successfully separate but together will be incorporated into a single daughter nucleus. Thus resulting in a supernumerary chromosome present in a gamete or zygote.
The more common aberrant cell division, nondisjunction takes place during gametogenesis. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content amongst the daughter cell is uneven. Nondisjunction can take place in the first or the second meiotic division. In addition, it can occur in both of the meiotic division, leading to variants of Klinefelter's syndrome with greater number of X chromosomes, such as 48,XXXY and 48,XXXXY. Furthermore, nondisjunction can also take place using postzygotic division. If nondisjunction takes place in the first meiotic division, this means that during the anaphase phase a homologous pair of chromosomes is not separated. The result is, at the end of the first meiosis, one daughter cell having three chromosomes while the other has only one. The daughter cell with one chromosome is not viable. When the daughter cell containing the remaining three chromosomes is followed through meiosis two, its own progeny will include a parental and maternal X chromosome or two copies of the maternal X chromosome.
This more common aberrant cell division takes place during gametogenesis. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. Nondisjunction can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter's syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, nondisjunction can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). Genetics and Cytogenetics of Klinefelter's Syndrome: Karyotype of Klinefelter's Syndrome and Its Variants. In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>
However, if nondisjunction occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase two. As a result, by the end of the second meiosis, one daughter cell contains both sister chromatids of the maternal X chromosome while the other daughter cell does not contain that maternal genetic material. The consequence of nondisjunction is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter's syndrome.
As a result of this genetic mutation, the characteristic shrunken testes and the absence of motile sperm of the Klinefelter syndrome can be observed. These symptoms indicate that the seminiferous tubule and sertoli cells have lost its function. This has many consequences, one of which is the decreased inhibin hormone level. This in turn results in the elevation of gonadotropin level, which is the hallmark of Klinefelter syndrome.
Gonadotropin levels increases as a result of low levels of inhibin because it act as a feedback inhibitor on the pituitary gland. However, the elevated gonadotropin level can only be observed during and after puberty. This is shown in a study with prepubertal boys. One group of subjects have an additional X chromosome while the control group did not. By comparing the two groups a difference in the gonadotropin level was not observed.
<ref>Cynthia M. Smyth, MD; William J. Bremner, MD, PhD Klinefelter Syndrome. Arch Intern Med. 1998;158:1309-1314</ref>