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Turner syndrome (TS) is a genetic disorder caused by the partial or complete absence of one X chromosome. This is called monosomy and is typically caused by chromosomal nondisjunction. It is a very common abnormality among the sex chromosome disorders, with an incidence of 1 in 2000 liveborn females.
Its typical phenotype includes short stature, primary or secondary amenorrhea (the former being much commoner), ovarian failure due to streak ovaries, webbed neck, cardiac defects, and often hypothyroidism. It is typically treated with growth hormone and estrogen replacement to allow for normal growth in height and development of pubertal characteristics.
About half of living females with TS have only one X chromosome, and this is called pure non-mosaic TS, with a genotype of 45, X. However, partial absence may also cause the same phenotype. It is now established that 99% of pure non-mosaic TS are lost by spontaneous first-trimester abortion. This leads to the conclusion that most living TS individuals have in fact some degree of mosaicism, which is compatible with life and enables them to survive. This may be detected by technologies, such as interphase fluorescent in situ hybridization (FISH) on a large number of cytogenetic samples when a non-mosaic TS genotype is found on karyotyping.
TS with partial absence of one X may be due to any of the following:
Primary amenorrhea is more common with classical TS (45,X) while menstruation may begin with other karyotypes, particularly with mosaic forms. However, secondary amenorrhea soon sets in due to ovarian failure.
Genetic studies have already shown that in normal females with two X chromosomes, one X is always inactivated at random during the development of the embryo. This phenomenon is called lyonization or dosage compensation and is a mechanism to ensure that males and females have the same number of active X-linked genes. On the other hand, it is also known that several genes on the lyonized X chromosome escape total inactivation and are necessary to the female phenotype. It is therefore suspected that TS is due to the absence (in part or whole) of these genes, which are required to be present in double dosage in normal females.
These genes include the SHOX (short statute homeobox) on the pseudo-autosomal region of the X chromosome, which may be responsible for growth stunting and skeletal defects, such as the low-set ears, high arched palate, knock knees and a high carrying angle (abnormal outward angulation of the elbows).
Another phenomenon called genomic imprinting may be responsible for some features of TS. The expression of an imprinted gene depends on which parent it originated from, whether maternal or paternal. Some studies have shown that girls with TS in whom the single X chromosome was from the mother had greater cognitive impairment, and possibly this was due to the abnormal development of the temporal and occipital lobes of the brain. However, others have contradicted this, and this area needs more research.
TS is normally of sporadic occurrence and its incidence is not related to maternal age. It has been found that of the 50% of TS individuals who have the 45,X genotype, three out of four have a single X, which is derived from the mother, as determined by several different methods. In cases of partial retention of the second X chromosome, including ring chromosomes or marker chromosomes, the intact chromosome was usually of maternal origin. This seems to rule out a meiotic error in the maternal ovum, and to suggest that it occurs during the paternal sperm generative process. This kind of error would cause a heavy rate of chromosome loss during mitosis by anaphase lag (if the genotype is 45,X) or by nondisjunction (if mosaicism is present (such as 47,XXX; 46,X, del(Xp); or 46,X,marker (X)).
In contrast, with mosaic X TS or TS with one isochromosome, the possibility of having either maternal or paternal isochromosomes was roughly equal. This means that either an error occurred during gamete formation or after zygote formation and at the first cell division following fertilization.
Partial X deletions may also cause ovarian failure, such as deletion of Xp11 (linked to ovarian failure in 50%) and deletion of Xp21 (more likely to have secondary amenorrhea). Thus the Xp deletion is likely to be the cause of a TS phenotype, especially of short stature. The non-mosaic presence of the pure 46,X,i(Xq) line, with two long Xq arms and no short (Xp) arm is also associated with some TS patients. Gonadal failure is associated with Xq deletion, and the more proximal the deletion the more severe the expression. Thus Xq26-q28 and Xq13.3-q21.1 are now termed POF1 and POF2 (for primary ovarian failure) respectively, due to mutations or rearrangements of chromosomal material that affects ovarian gene expression negatively.