Cytogenetic abnormalities X.2.2.1 Aneuploidy

Aneuploidy describes cells which have a loss or gain of chromosomal material, resulting in an unbalanced genetic complement. This can occur in all cells or can be mosaic for example, an individual may have predominantly normal cells with a subset of aneuploid cells. Aneuploidy can involve whole chromosomes (trisom y/ monosomy) or segments of chromosomes (partial monosomy/ trisomy.

It is common for constitutional aneuploidy to have a lethal effect. Only trisomy for chromosomes 13, 18, 21 and X are viable. Individuals with trisomy 13 and 18 commonly die in early childhood and do not reach reproductive age. The ovaries from infants with trisomy 13 and 18 were studied at autopsy by Cunniff et a l (1991). He found a complete absence of primary oocytes, which means that even if affected individuals were to reach reproductive age they would be infertile. Female trisomy 21 patients can be fertile although their mental retardation may stop them from reproducing. Autosomal monosomy is incompatible with life.

X chromosome monosomy is compatible with life and is not associated with mental retardation. This is presumably due to X chromosome inactivation. In normal 46,XX females one of the X chromosomes in every cell is randomly inactivated on the 12 th day of embryonic life (Lyon, 1961). The inactivated chromosome carries some essential genes which are not inactivated. Additionally, the chromosome is reactivated during fetal gametogenesis. This may explain why females with 47,XXX are viable, generally show no evidence of mental retardation and can be fertile. Whereas the majority of fetuses exhibiting monosomy for chromosome X (Turner syndrome) are spontaneously aborted. There have been many cases of constitutional 45,X women reported in the literature, who are characteristically infertile.

1.2.2.1.1, Turner syndrome (45,X) I.2.2.I.I.2. History

Turner first described this syndrome in 1938. It is characterised by a distinct phenotype i.e. sexual infantilism, short stature, shield like chest, cubitus valgus (abnormal angle of elbow) and webbed neck.

In 1954 Polani et a l used the skin biopsy sexing technique of Moore et a l (1953) to show that Turner syndrome women are sex chromatin negative. He also collected evidence from nuclear sexing and colour blindness inheritance to suggest Turner women have a 45,X constitution. Additionally, this study suggested that the presence of a Y chromosome denotes males rather than the absence of an X chromosome. This was confirmed cytogenetically by Ford in 1959.

Turner syndrome characteristics can also be caused by structural rearrangements involving the X chromosome. An individual with an isochromosome Xq will have the full Turner phenotype, whereas rearrangements throughout the X chromosome show a range of severity. Broad chromosomal locations of putative genes have been suggested following investigations of individuals with rearrangements of the X chromosome (Therman and Susman 1990, Therman et a l 1990, Ogata and Matsuo

1995).

Due to the loss of the X chromosome there is an increased risk of Turner syndrome patients being affected by X linked recessive disease. For example there has been a case of Duchenne Muscular Dystrophy reported in a 45,X woman (Baiget et a l

1.2.2.1.3, Mechanism of loss

The precise mechanism behind the loss of the chromosome is not known. It was originally thought that meiotic non disjunction was the primary cause, however some studies have indicated this is not the case (Warburton e ta l 1980, Singh e ta l 1980)

Warburton et a l (1980) suggested a correlation between 45,X and young maternal age. Studies on trisomies, which have long been believed to be due to meiotic non disjunction, have shown correlation with an increase in age. Additionally, Sanger et a l (1977) discovered that in 11% of the 45,X individuals studied it was the paternal sex chromosomes that were lost, suggesting that there is little maternal causation. From this Chandley (1981) proposed that the loss of an X chromosome is most likely to occur shortly after sperm entry into the egg. However, meiotic loss or loss during early cleavage cannot be ruled out.

If 45,X was due to a mitotic non-disjunction error then additional 47,XXX and possibly 46,XX cell lines would be present. Although these cell lines are seen in some individuals exhibiting mosaicism, it is not seen in classic 45,X patients. Due to this, Singh e ta l (1980) and Hassold(1986) concluded that mitotic non disjunction could not be the principle cause. However, it is now thought that extra cell lines may be present in the fetus for prenatal survival (Held e ta l 1992).

1.2.2.1.4. Prenatal survival

The high in utero lethality of the 45,X constitution results in only 1% of 45,X conceptions being bom. This has led some authors (Hassold et a l 1985, Hook and Warburton, 1983) to suggest that live bom Tumer individuals must be mosaics and that additional cell lines have a fetoprotective effect in essential organs. This hypothesis was corroborated by Held et a l in 1992 using cytogenetic and molecular data.

Held et a l. proposed that more than one tissue should be investigated to find more accurate figures for the proportion of 45,X individuals exhibiting mosaicism. After analysing both lymphocyte and fibroblast cultures in 87 patients, 58 (66.7%) were found to be mosaic, 11 (12.6%) were due to constitutional structural aberrations and only 18 (20.7%) were due to constitutional 45,X. Held et a l also found small marker chromosomes in certain organs that after molecular analysis were shown to be of Y chromosome origin.

It was proposed that these markers may allow normal development of organs or convey an advantage in escaping spontaneous abortion. When the markers were looked for in passaged cultures they found that there was selection against the markers or cells carrying the markers.

Mice can be used as an experimental model for Turner syndrome. The normal karyotype of a mouse is 40,XX or XY. 39,X fetuses do not exhibit the same in utero

lethality as human 45,X fetuses and are not quite as developmentally delayed as humans. They do have a reduced number of oocytes and consequently increased infertility.

Studies by Boué et a l in (1974) suggested that the loss of 99% of human 45,X conceptuses may be due to a reproductive strategy towards the end of the first trimester. In humans, placental steroids become essential towards the end of the first trimester, whereas in 39,X mice it is still the maternal ovarian steroids which are important. Perhaps normal cell lines may be essential in ensuring the production of steroids by the placenta. Burgoyne et a l (1983) used the hypothesis of Boué et a l to explain why 39,X mice are not as developmentally delayed as human 45,X fetuses through gestation. In essence they suggest that the physiological shock of the near­ failure of pregnancy causes the more severe human phenotype to develop.