Diagnosis of syndromes due to sex chromosome aberrations

Sex in humans is determined by a pair of chromosomes, X and Y. Female cells contain two X chromosomes, while male cells contain one X and one Y chromosome. The Y chromosome is one of the smallest in the karyotype, and contains only a few genes that are not involved in sex regulation. The X chromosome, on the other hand, is one of the largest in the C group, and contains hundreds of genes, most of which are not involved in sex determination.

Because one of the two X chromosomes in each somatic cell of a woman is genetically inactivated in the early embryonic stages of development (Barr bodies), female and male organisms are balanced in the number of functioning sex-linked genes, since men have one X chromosome and, accordingly, one set of X chromosome genes. In women, regardless of the number of X chromosomes in the genome, one remains active, and the rest are inactivated. The number of Barr bodies is always one less than the number of X chromosomes.

Inactivation of the X chromosome is of great importance for clinical practice. It is this factor that determines that anomalies in the number of X chromosomes are clinically relatively more benign than anomalies in autosomes. A woman with three X chromosomes may have normal mental and physical development, unlike patients with autosome aberrations (Down syndrome, trisomies 13 and 18), who manifest very severe clinical symptoms. Similarly, the absence of one of the autosomes is lethal, while the absence of one of the X chromosomes, although accompanied by the development of a specific syndrome (Shereshevsky-Turner), can be considered a relatively benign condition.

Inactivation of the X chromosome can also explain the heterogeneity of the clinical picture in heterozygotes for X-linked recessive diseases. Women heterozygous for the genes for hemophilia or muscular dystrophy sometimes have a tendency to bleed or muscle weakness, respectively. According to Lyon's hypothesis, inactivation of the X chromosome is a random event, so that in each woman, on average, 50% of the maternal and 50% of the paternal X chromosomes are inactivated. The random process is subject to normal distribution, so in rare cases, almost all maternal or, conversely, almost all paternal X chromosomes can be inactivated. If the normal allele is accidentally inactivated in most cells of a certain tissue of a heterozygous woman, then the symptom of the disease in her will be the same as in a homozygous man.

Turner syndrome (gonadal dysgenesis). The disease is caused by a violation of the divergence of sex chromosomes, resulting in complete or partial monosomy of chromosome X. Typical clinical manifestations are associated with the karyotype 45, X0. Many newborns have pronounced lymphatic edema of the dorsum of the hands and feet, as well as the back of the neck, the latter is almost pathognomonic for Turner syndrome. Older girls and adults are characterized by short stature, pterygoid folds of the neck, barrel-shaped chest, multiple nevi, coarctation of the aorta, amenorrhea, underdevelopment of the mammary glands and external genitalia.

In some cases, a mosaic variant of Shereshevsky-Turner syndrome is detected, i.e. some cells of the body contain a set of chromosomes 45, X0, the other part - 46, XX, or 45, X0/47, XXX. The phenotype in such cases varies from typical for Shereshevsky-Turner syndrome to almost normal, many women are fertile. Karyotyping allows diagnosing the disease.

Sometimes, in patients with Shereshevsky-Turner syndrome, karyotyping reveals that one of the X chromosomes has a normal shape, while the other forms a ring. This variant develops due to the loss of fragments of the short and long arms.

In some patients, one X chromosome is normal and the other is a long-arm isochromosome. The latter is formed by the loss of the short arms followed by the formation of a new chromosome containing only the long arms.

In several families, boys had many features of Shereshevsky-Turner syndrome, but the karyotypes of these children were normal, that is, 46, XY. The phenotype of Shereshevsky-Turner syndrome in boys with a normal karyotype was called Noonan syndrome. This syndrome is characterized by some phenotypic differences from Shereshevsky-Turner syndrome: patients are taller, their sexual development is normal, they are fertile, pulmonary artery stenosis is more often detected than coarctation of the aorta, mental retardation is usually not severe.

All patients with Shereshevsky-Turner syndrome require karyotyping to exclude mosaicism with the presence of a cell line with chromosome Y, i.e. karyotype 46, XY/45, X0. In such cases, intersexuality is detected in some patients. Due to the high risk of developing gonadoblastoma in such patients, they are recommended to undergo prophylactic removal of the gonads in childhood.

Trisomy X syndrome (47, XXX). In women with this syndrome, three X chromosomes are detected during karyotyping, and two Barr bodies can be found in the cells of the cervical epithelium during the study of sex chromatin. Patients are characterized by a slight decrease in intelligence, fertility is often preserved (it is possible to give birth to healthy children with a normal karyotype), in some cases, speech impairment is detected.

In clinical practice, women also experience rarer anomalies of chromosomes X: 48, XXXX and 49, XXXXX. Such patients do not have a specific phenotype, and the risk of mental retardation and congenital malformations increases with an increase in the number of chromosomes X.

Klinefelter syndrome (47,XXY) is a fairly common type of chromosomal abnormality (observed in 1 in 700 newborn boys). Patients are typically tall, have a eunuchoid body type, and have gynecomastia. Puberty occurs at the usual time. Most males have normal intelligence but are infertile (probably all 47,XXY patients are sterile).

Klinefelter syndrome variants with 3, 4, and even 5 X chromosomes are possible (intelligence decreases as their number increases). Some patients have a 46, XX karyotype, in which case a small portion of the Y chromosome is transferred to one of the X chromosomes or an autosome. Translocation is not always detectable by karyotyping; the diagnosis is confirmed using DNA probes specific to the Y chromosome. Mosaicism in Klinefelter syndrome is very rare.

Syndrome 47, XYY. Clinical manifestations of the syndrome are minor, speech disorders are possible. Karyotyping reveals two Y chromosomes in patients.

X-linked mental retardation (fragile X syndrome). There are many X-linked mutant genes that cause mental retardation without congenital malformations (mostly in males). In some of these patients, the X chromosome has a structural feature during karyotyping: the long arm narrows sharply near the end and then widens sharply, as a result of which the end of the long arm is connected to the rest of the chromosome by a thin "stalk". When preparing chromosome preparations, this "stalk" often breaks, so a special cell culturing method must be used to detect it.

Intersexuality. Intersexuality is determined genetically. In case of duality of the external genitalia structure, it is necessary to conduct karyotyping. Using the cytogenetic method, it is possible to identify three main causes of intersexuality.

• Chromosomal abnormalities.
• Masculinization 46, XX (female pseudohermaphroditism).
• Insufficient masculinization 46, XY (male pseudohermaphroditism).

Sex chromosome abnormalities include various forms of mosaicism (with or without the Y chromosome), gonadal dysgenesis syndromes (karyotype 46,XX and 46,XY), and true hermaphroditism (karyotype of lymphocytes is often 46,XX, and in gonadal cells it is mosaic). Duality of genitalia is also possible with trisomies 13 and 18 and abnormalities of other autosomes.

The most common cause of female pseudohermaphroditism is congenital virilizing form of adrenal cortex hyperplasia (adrenogenital syndrome). Adrenogenital syndrome is a group of disorders caused by deficiency of hormone biosynthesis enzymes in the adrenal cortex, inherited autosomal recessively. Exogenous androgens (for example, if the pregnant woman has a tumor that secretes androgens) can also cause fetal masculinization.

The cause of male pseudohermaphroditism may be a deficiency of some enzymes in congenital hyperplasia of the adrenal cortex, which leads to the formation of inactive androgens that are unable to provide a male phenotype in a male fetus. In addition, there is a group of androgen resistance syndromes that arise due to defects in genes (usually X-linked) encoding androgen receptors (for example, testicular feminization syndrome).

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