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's syndrome
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.

Turner's syndrome
This syndrome is characterized by a 45,X genotype in females (in about 50% of cases), with the absence of one X chromosome (and therefore absence of a Barr body). The single X chromosome is of maternal origin in about 70% of cases; therefore there is loss of a sex chromosome due to paternal error. Other possible variations include: Its incidence is about 1:2000 (less common than Klinefelter's) and it is present in about 1.5% of all conceptions.
 * 46,X,i (Xq) in 15% of cases
 * 45,X or 46,XX mosaics in 15% of cases
 * 45,X or 46,X,i (Xq) mosaics in about 5%
 * Other

Patients present with the following features:
 * 1) Short stature (without hormonal stature, average height is 145cm)
 * 2) Ovarian dysgenesis (streak ovary); this is the most common cause of primary amenorrhea
 * 3) Infertility
 * 4) Shield chest with widely-spaced nipples
 * 5) Webbing of the neck postnatally (cystic hygroma in fetal life; seen in ultrasound)
 * 6) Low posterior hairline
 * 7) Average intelligence
 * 8) Renal and cardiovascular abnormalities (e.g. coarctation of the aorta)

There is no actual cure for this syndrome but treatments can be done to alleviate some of its symptoms, e.g. growth hormone, estrogen replacement therapy, and reproductive technologies (to get pregnant as they are infertile).

Triple X syndrome (Superfemale)
This syndrome usually results from errors in maternal meiosis I (90% of cases), and its incidence is about 1:1000. Such patients have non-specific features e.g. average intelligence, normal sexual development. About 70% have serious learning problems. In 47 XXX cells, two of the X chromosomes are inactivated. Variations include:
 * Tetrasomy X syndrome (48 XXXX) with more serious physical and mental retardation
 * Pentasomy (49 XXXXX) with severe developmental retardation

XYY syndrome (Supermale)
It has an incidence of about 1:1000 male live births. It may be caused by paternal non-disjunction at meiosis II (producing a YY sperm) or by a post-zygotic event. Variants of this syndrome include XXYY and XXXYY, which probably also originate from paternal non-disjunction at both meiosis I and II. Patients are usually phenotypically normal and may have the following features:
 * 1) Tall stature
 * 2) Severe acne
 * 3) Average intelligence
 * 4) Antisocial behavior with increased risk of behavioral problems (3% are in prisons & mental hospitals)
 * 5) Can show emotional immaturity and impulsive behavior
 * 6) Normal fertility, without risk of chromosomal aberrations in offspring
 * 7) Normal sexual development

Related articles

 * Turner syndrome
 * Klinefelter syndrome