Diagnosis of syndromes caused by aberrations of sex chromosomes

The sex of a person is determined by a pair of chromosomes - X and Y. In women cells, there are two X chromosomes, in men's cells there is one chromosome X and one Y. The chromosome Y is one of the smallest in a karyotype, only a few genes that are not related to it regulation of sex. Chromosome X, in contrast, is one of the largest in group C, contains hundreds of genes, most of which have nothing to do with sex determination.

Due to the fact that one of the two X chromosomes in each somatic cell of a woman is genetically inactivated in the early embryonic stages of development (Barra's body), female and male organisms are balanced by the number of functioning genes linked to the sex, since in men there is one chromosome X and, respectively , one set of genes for chromosome X. In women, regardless of the number of chromosomes X in the genome, one remains active, and the others are inactivated. The number of Barr bulls is always one less than the number of chromosomes X.

Inactivation of chromosome X is important for clinical practice. It is this factor that determines the anomalies in the number of X chromosomes that are clinically relatively more benign than the anomalies of the autosomes. In a woman with three chromosomes X, mental and physical development can be normal, in contrast to patients with autosomal aberrations (Down's syndrome, trisomy 13 and 18), manifesting 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 as a relatively benign condition.

Inactivation of chromosome X can also explain the heterogeneity of the clinical picture in heterozygotes for X-linked recessive diseases. In women heterozygous for the genes of hemophilia or muscular dystrophy, sometimes a tendency to bleeding or muscle weakness, respectively. According to the hypothesis of Lyon, the inactivation of chromosome X is a random event, therefore 50% of maternal and 50% of paternal X chromosomes are on average inactivated by each woman. The random process obeys the normal distribution, therefore in rare cases virtually all maternal, or, on the contrary, almost all paternal chromosome X. If a normal allele is inadvertently inactivated in most cells of a certain tissue of a heterozygous woman, then the symptom of the disease will be the same as for a homozygous man.

Syndrome Shereshevsky-Turner (gonadal dysgenesis). At the heart of the development of the disease is the violation of the discrepancy between sex chromosomes, as a result of which there is complete or partial monosomy over the chromosome X. Typical clinical manifestations are associated with karyotype 45, X0. Many newborns are marked by a marked lymphatic edema of the dorsal surface of the hands and feet, as well as the posterior surface of the neck, the latter almost pathognomonic for the Shereshevsky-Turner syndrome. For girls of older age and adults, low growth, pterygium of the neck, barrel chest, multiple nevuses, coarctation of the aorta, amenorrhea, underdevelopment of the mammary glands and external genital organs are characteristic.

In a number of cases, a mosaic version of the Shereshevsky-Turner syndrome is revealed, that is, some of the cells in 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 the typical for the Shereshevsky-Turner syndrome to almost normal, many women are fertile. Karyotyping allows you to diagnose a disease.

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

In some patients, one of the X chromosomes is normal, and the second is represented by an isochromosome along the long arm. The latter is formed as a result of the loss of short arms with the subsequent formation of a new chromosome containing only long shoulders.

In several families, the boys had many signs of Shereshevsky-Turner syndrome, but the karyotypes of these children were normal, that is, 46, XY. The phenotype of the Shereshevsky-Turner syndrome in boys with a normal karyotype was called the Noonan syndrome. This syndrome is characterized by some phenotypic differences from the Shereshevsky-Turner syndrome: patients have higher growth, 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 heavy.

All patients with Shereshevsky-Turner syndrome need a karyotyping to exclude mosaicism with the presence of a cell line with the Y chromosome, that is karyotype 46, XY / 45, X0. In such cases, part of the patients are exposed to intersexuality. Because of the high risk of developing gonadoblastoma in such patients, they are shown prophylactic removal of gonads in childhood.

The syndrome of trisomy X (47, XXX). In women with this syndrome, three chromosomes X are detected during karyotyping, and in the cervical epithelial cells, two Barra's bodies can be found in the study of sexual chromatin. For patients characterized by a slight decrease in intelligence, fertility is often preserved (possibly the birth of healthy children with normal karyotypes), in some cases, a speech disorder is detected.

In clinical practice, women also observe more rare chromosome anomalies X: 48, XXXX and 49, XXXXX. There is no specific phenotype in such patients, and the risk of mental retardation and congenital malformations increases with an increase in the number of chromosomes X.

Klinefelter's syndrome (47, ХХY) refers to fairly widespread types of chromosomal abnormalities (observed in 1 of 700 newborn boys). Typical for patients are high growth, echinodal physique, gynecomastia. Sexual maturation occurs at the usual time. Most men have normal intelligence, but are infertile (probably all patients 47, XXY are sterile).

Possible variants of Klinefelter syndrome with 3, 4 and even 5 chromosomes X (the intellect decreases as their number increases). In some patients, karyotype 46, XX, in such cases, there is a transfer of a small part of the Y chromosome to one of the X chromosomes or an autosome. Translocation is not always possible to detect during karyotyping, the diagnosis is confirmed with DNA probes specific for Y chromosome. Mosaicism for Kleinfelter syndrome is very rarely observed.

Syndrome 47, XYY. Clinical manifestations of the syndrome are minor, speech disorders are possible. In the case of karyotyping, two chromosomes of Y are detected in patients.

X-linked mental retardation (syndrome of brittle chromosome X). There are many X-linked mutant genes that cause mental retardation without congenital malformations (predominantly in men). In some of these patients, when the chromosome is carotyped, X has a structural feature: the long arm near the end sharply narrows, and then also sharply expands, as a result, the end of the long arm is connected to the rest of the chromosome by a thin "stem". When preparing chromosome preparations this "stalk" often breaks, so for its detection it is necessary to use a special method of cell cultivation.

Intersexuality. Intersexuality is genetically determined. When the structure of the external genitalia is dual, it is necessary to carry out 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).

The anomalies of the sex chromosomes include various forms of mosaicism (with or without participation of the Y chromosome), gonadal dysgenesis syndromes (karyotype 46, XX and 46, XY) and true hermaphrodism (karyotype of lymphocytes is often 46, XX, and in gonad cells is mosaic). The duality of the genitals is also possible with trisomy 13 and 18 and the anomalies of other autosomes.

The most common cause of female pseudohermaphroditism is the congenital virilizing form of hyperplasia of the adrenal cortex (adrenogenital syndrome). Adrenogenital syndrome is a group of disorders caused by insufficiency of enzymes of biosynthesis of hormones in the adrenal cortex inherited by autosomal recessive. The cause of masculinization of the fetus can also be exogenous androgens (for example, in the presence of a pregnant tumor that secretes androgens).

The cause of male pseudohermaphroditism may be the insufficiency of certain enzymes in congenital hyperplasia of the adrenal cortex, which leads to the formation of inactive androgens unable to provide a male phenotype in a male fetus. In addition, there is a group of syndromes of androgen resistance, arising from gene defects (often X-linked) that encode the androgen receptors (eg, testicular feminization syndrome).

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