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. It is characterized by a karyotype of two or more X chromosomes (47, XXY is present in 82% of all cases). It is one of the most common causes of male hypogonadism, reduced spermatogenesis, and male infertility. Histologic examination of the testis in these patients reveals some or all of the testicular tubules to be completely atrophied and replaced by pink, hyalinized tissue.

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.