Disorders of the Sex Chromosomes

Disorders of the sex chromosome (like disorders of the autosomes) can be either numerical or structural, and can be present in all cells or in a mosaic form. Clinical indications that should raise suspicions of a sex chromosome abnormality are:
 * Delay in onset of puberty
 * Primary or secondary amenorrhea
 * Infertility
 * Ambiguous genitalia

These disorders are considered very common with incidence of about 1:400-500. Phenotypes associated with sex chromosome disorders are less severe than autosomal defects and this is mainly due to X chromosome inactivation, as well as the fact that Y chromosomes have a low gene content. X chromosome inactivation is the the process by which most genes on one of the two X chromosomes in females are silenced epigenetically and randomly, and so fail to produce any product. In somatic cells in normal females (but not in normal males), one X chromosome is inactivated early in development, thus equalizing the expression of X-linked genes in the 2 sexes. Thus females are mosaic with respect to X-linked gene expression.

Klinefelter syndrome (XXY)
This syndrome was the first sex chromosome abnormality to be reported (in 1942) and has an incidence of about 1:850. Patients have 3 sex chromosomes rather than the normal XX or XY. Patients present with the following features:
 * 1) Appear physically normal until puberty
 * 2) Eunuchoid body shape
 * 3) Tall and thin stature with relatively long limbs
 * 4) Testicular atrophy
 * 5) Infertility (azoospermia)
 * 6) Gynecomastia
 * 7) Female hair distribution
 * 8) Average intelligence
 * 9) May have mild learning difficulties – 2/3rds have dyslexia
 * 10) Increased incidence of leg ulcers, osteoporosis, breast carcinoma in adults

This disorder is caused by an additional X chromosome which results from:
 * 1) Errors in paternal meiosis I (50% of cases)
 * 2) Errors in maternal meiosis I (33%) – associated with advanced maternal age
 * 3) Errors in meiosis II or a postzygotic mitotic error leading to mosaicism
 * 4) There are also mosaic karyotypes in 15% of patients; the most common mosaic karyotypes are 46XY/47XXY

Variations are also possible i.e. 48XXYY, 48XXXY, 49XXXXY. Every additional X chromosome in such patients causes a more abnormal phenotype, including more defective sexual development and more severe mental impairment.

There is a possibility of treatment and disappearance of some physical features with testosterone from puberty onwards.