Chromosomal diseases. Autosomal trisomy

GENERAL ISSUES

Chromosomal diseases are a large group of hereditary diseases with multiple congenital malformations. They are based on chromosomal or genomic mutations. These two different types of mutations are collectively called “chromosomal abnormalities” for short.

Nosological identification of at least three chromosomal diseases as clinical syndromes of congenital developmental disorders was made before their chromosomal nature was established.

The most common disease, trisomy 21, was clinically described in 1866 by the English pediatrician L. Down and was called “Down syndrome.” Subsequently, the cause of the syndrome was repeatedly subjected to genetic analysis. Suggestions have been made about a dominant mutation, a congenital infection, or a chromosomal nature.

The first clinical description of X-chromosome monosomy syndrome as a separate form of the disease was made by the Russian clinician N.A. Shereshevsky in 1925, and in 1938 G. Turner also described this syndrome. Based on the names of these scientists, monosomy on the X chromosome is called Shereshevsky-Turner syndrome. In foreign literature, the name “Turner syndrome” is mainly used, although no one disputes the merit of N.A. Shereshevsky.

Anomalies in the sex chromosome system in men (trisomy XXY) were first described as a clinical syndrome by G. Klinefelter in 1942.

The listed diseases became the object of the first clinical cytogenetic studies conducted in 1959. Deciphering the etiology of Down, Shereshevsky-Turner and Klinefelter syndromes opened a new chapter in medicine - chromosomal diseases.

In the 60s of the XX century. Thanks to the widespread deployment of cytogenetic studies in the clinic, clinical cytogenetics was fully established as a specialty. The role of chro-

* Corrected and supplemented with the participation of Dr. Biol. Sciences I.N. Lebedeva.

mosomal and genomic mutations in human pathology, the chromosomal etiology of many syndromes has been deciphered birth defects development, the frequency of chromosomal diseases among newborns and spontaneous abortions was determined.

Along with the study of chromosomal diseases as congenital conditions, intensive cytogenetic research began in oncology, especially in leukemia. The role of chromosomal changes in tumor growth turned out to be very significant.

As cytogenetic methods, especially differential staining and molecular cytogenetics, have improved, new opportunities have opened up for the detection of previously undescribed chromosomal syndromes and the establishment of a relationship between karyotype and phenotype for small changes in chromosomes.

As a result of intensive study of human chromosomes and chromosomal diseases over the course of 45-50 years, the doctrine of chromosomal pathology, which has great importance V modern medicine. This area of ​​medicine includes not only chromosomal diseases, but also pathology of the prenatal period (spontaneous abortions, miscarriages), as well as somatic pathology (leukemia, radiation sickness). The number of described types of chromosomal abnormalities is approaching 1000, of which several hundred forms have a clinically defined picture and are called syndromes. Diagnosis of chromosomal abnormalities is necessary in the practice of doctors of various specialties (geneticist, obstetrician-gynecologist, pediatrician, neurologist, endocrinologist, etc.). All multidisciplinary modern hospitals (more than 1000 beds) in developed countries have cytogenetic laboratories.

The clinical importance of chromosomal pathology can be judged by the frequency of abnormalities presented in Table. 5.1 and 5.2.

Table 5.1. Approximate frequency of newborns with chromosomal abnormalities

Table 5.2. Birth outcomes per 10,000 pregnancies

As can be seen from the tables, cytogenetic syndromes make up a large share of reproductive losses (50% among spontaneous abortions in the first trimester), congenital malformations and mental retardation. In general, chromosomal abnormalities occur in 0.7-0.8% of live-born children, and in women who give birth after 35 years, the likelihood of having a child with a chromosomal pathology increases to 2%.

ETIOLOGY AND CLASSIFICATION

The etiological factors of chromosomal pathology are all types of chromosomal mutations and some genomic mutations. Although genomic mutations in the animal and plant world are diverse, only 3 types of genomic mutations are found in humans: tetraploidy, triploidy and aneuploidy. Of all the variants of aneuploidy, only trisomy on autosomes, polysomy on sex chromosomes (tri-, tetra- and pentasomy) are found, and among monosomies, only monosomy X is found.

As for chromosomal mutations, all types of them have been found in humans (deletions, duplications, inversions, translocations). From a clinical and cytogenetic point of view deletion in one of the homologous chromosomes means a lack of a region or partial monosomy for this region, and duplication- excess or partial trisomy. Modern methods of molecular cytogenetics make it possible to detect small deletions at the gene level.

Reciprocal(mutual) translocation without loss of sections of the chromosomes involved in it is called balanced. Like inversion, it does not lead to pathological manifestations in the carrier. However

as a result complex mechanisms crossing over and reduction in the number of chromosomes during the formation of gametes in carriers of balanced translocations and inversions can form unbalanced gametes those. gametes with partial disomy or partial nullisomy (normally, each gamete is monosomic).

A translocation between two acrocentric chromosomes with loss of their short arms results in the formation of one meta or submetacentric chromosome instead of two acrocentric ones. Such translocations are called Robertsonian. Formally, their carriers have monosomy on the short arms of two acrocentric chromosomes. However, such carriers are healthy, because the loss of the short arms of two acrocentric chromosomes is compensated by the work of the same genes in the remaining 8 acrocentric chromosomes. Carriers of Robertsonian translocations can produce 6 types of gametes (Fig. 5.1), but nullisomal gametes should lead to monosomy of autosomes in the zygote, and such zygotes do not develop.

Rice. 5.1. Types of gametes in carriers of Robertsonian translocation 21/14: 1 - monosomy 14 and 21 (normal); 2 - monosomy 14 and 21 with Robertsonian translocation; 3 - disomy 14 and monosomy 21; 4 - disomy 21, monosomy 14; 5 - nullisomy 21; 6 - nullisomia 14

The clinical picture of simple and translocation forms of trisomy on acrocentric chromosomes is the same.

In the case of terminal deletions in both arms of the chromosome, ring chromosome. An individual who has inherited a ring chromosome from one of the parents will have partial monosomy at the two terminal regions of the chromosome.

Rice. 5.2. Isochromosomes X along the long and short arms

Sometimes the chromosome break passes through the centromere. Each arm separated after replication has two sister chromatids connected by the remaining part of the centromere. Sister chromatids of the same arm become arms of the same chro-

mosomes (Fig. 5.2). From the next mitosis, this chromosome begins to replicate and be transmitted from cell to cell as an independent unit along with the rest of the set of chromosomes. Such chromosomes are called isochromosomes. They have the same set of genes on their shoulders. Whatever the mechanism of isochromosome formation (it has not yet been fully elucidated), their presence causes chromosomal pathology, because it is both partial monosomy (for the missing arm) and partial trisomy (for the present arm).

The classification of chromosomal pathology is based on 3 principles that make it possible to accurately characterize the form of chromosomal pathology and its variants in the subject.

The first principle is characteristic of a chromosomal or genomic mutation(triploidy, simple trisomy on chromosome 21, partial monosomy, etc.) taking into account a specific chromosome. This principle can be called etiological.

The clinical picture of chromosomal pathology is determined by the type of genomic or chromosomal mutation, on the one hand, and

individual chromosome - on the other. The nosological division of chromosomal pathology is based, therefore, on the etiological and pathogenetic principle: for each form of chromosomal pathology, it is established which structure is involved in the pathological process (chromosome, segment) and what the genetic disorder consists of (lack or excess of chromosomal material). Differentiation of chromosomal pathology based on the clinical picture is not significant, since different chromosomal abnormalities are characterized by a large commonality of developmental disorders.

Second principle - determination of the type of cells in which the mutation occurred(in gametes or zygote). Gametic mutations lead to complete forms of chromosomal diseases. In such individuals, all cells carry a chromosomal abnormality inherited from the gamete.

If a chromosomal abnormality occurs in the zygote or in the early stages of cleavage (such mutations are called somatic, as opposed to gametic), then an organism develops with cells of different chromosomal constitutions (two types or more). These forms of chromosomal diseases are called mosaic.

For the appearance of mosaic forms, the clinical picture of which coincides with the full forms, at least 10% of cells with an abnormal set are needed.

Third principle - identifying the generation in which the mutation occurred: it arose anew in the gametes of healthy parents (sporadic cases) or the parents already had such an anomaly (inherited, or familial, forms).

ABOUT inherited chromosomal diseases they say when the mutation is present in the cells of the parent, including the gonads. These may also be cases of trisomy. For example, individuals with Down syndrome and triplo-X syndrome produce normal and disomic gametes. This origin of disomic gametes is a consequence of secondary nondisjunction, i.e. Chromosome nondisjunction in an individual with trisomy. Most inherited cases of chromosomal diseases are associated with Robertsonian translocations, balanced reciprocal translocations between two (rarely more) chromosomes and inversions in healthy parents. Clinically significant chromosomal abnormalities in these cases arose due to complex chromosome rearrangements during meiosis (conjugation, crossing over).

Thus, for accurate diagnosis chromosomal disease must be determined:

Type of mutation;

The chromosome involved in the process;

Shape (full or mosaic);

Occurrence in a pedigree is a sporadic or inherited case.

Such a diagnosis is possible only with a cytogenetic examination of the patient, and sometimes of his parents and siblings.

EFFECTS OF CHROMOSOMAL ANOMALIES IN ONTOGENESIS

Chromosomal abnormalities cause a disruption of the overall genetic balance, the coordination in the work of genes and the systemic regulation that developed during the evolution of each species. It is not surprising that the pathological effects of chromosomal and genomic mutations manifest themselves at all stages of ontogenesis and, possibly, even at the level of gametes, affecting their formation (especially in men).

Humans are characterized by a high frequency of reproductive losses in the early stages of post-implantation development due to chromosomal and genomic mutations. Detailed information about cytogenetics embryonic development person can be found in the book by V.S. Baranova and T.V. Kuznetsova (see recommended literature) or in the article by I.N. Lebedev “Cytogenetics of human embryonic development: historical aspects and modern concept” on CD.

The study of the primary effects of chromosomal abnormalities began in the early 1960s shortly after the discovery of chromosomal diseases and continues to this day. The main effects of chromosomal abnormalities are manifested in two related variants: mortality and congenital malformations.

Mortality

There is convincing evidence that the pathological effects of chromosomal abnormalities begin to manifest themselves already from the zygote stage, being one of the main factors in intrauterine death, which is quite high in humans.

It is difficult to fully identify the quantitative contribution of chromosomal abnormalities to the death of zygotes and blastocysts (the first 2 weeks after fertilization), since during this period pregnancy is not yet diagnosed either clinically or laboratory. However, some information about the diversity of chromosomal disorders at the most early stages embryo development can be obtained from the results of preimplantation genetic diagnosis of chromosomal diseases carried out as part of artificial insemination procedures. Using molecular cytogenetic methods analysis shown that the frequency of numerical chromosome abnormalities in preimplantation embryos varies between 60-85% depending on the groups of patients examined, their age, indications for diagnosis, as well as the number of analyzed chromosomes during fluorescent hybridization in situ(FISH) on interphase nuclei of individual blastomeres. Up to 60% of embryos at the 8-cell morula stage have a mosaic chromosomal constitution, and from 8 to 17% of embryos, according to comparative genomic hybridization (CGH), have a chaotic karyotype: different blastomeres within such embryos carry different variants of numerical chromosomal abnormalities. Among chromosomal abnormalities in preimplantation embryos, trisomy, monosomy and even nullisomy of autosomes were identified, all possible options violations of the number of sex chromosomes, as well as cases of tri- and tetraploidy.

Such a high level of karyotype anomalies and their diversity certainly negatively affect the success of the preimplantation stages of ontogenesis, disrupting key morphogenetic processes. About 65% of embryos with chromosomal abnormalities stop their development already at the stage of morula compaction.

Such cases of early developmental arrest can be explained by the fact that disruption of the genomic balance due to the development of some specific form of chromosomal abnormality leads to discoordination of switching on and off of genes at the corresponding stage of development (temporal factor) or in the corresponding place of the blastocyst (spatial factor). This is quite understandable: since approximately 1000 genes localized on all chromosomes are involved in developmental processes in the early stages, chromosomal anomaly

malia disrupts the interaction of genes and inactivates some specific developmental processes (intercellular interactions, cell differentiation, etc.).

Numerous cytogenetic studies of material from spontaneous abortions, miscarriages and stillbirths make it possible to objectively judge the effects of different types of chromosomal abnormalities in the prenatal period of individual development. The lethal or dysmorphogenetic effect of chromosomal abnormalities is detected at all stages of intrauterine ontogenesis (implantation, embryogenesis, organogenesis, fetal growth and development). The total contribution of chromosomal abnormalities to intrauterine death (after implantation) in humans is 45%. Moreover, the earlier the pregnancy is terminated, the more likely it is that this is due to abnormalities in the development of the embryo caused by a chromosomal imbalance. In 2-4 week old abortions (embryo and its membranes), chromosomal abnormalities are detected in 60-70% of cases. In the first trimester of gestation, chromosomal abnormalities occur in 50% of abortions. In second trimester miscarriages, such anomalies are found in 25-30% of cases, and in fetuses that died after the 20th week of gestation - in 7% of cases.

Among perinatally dead fetuses, the frequency of chromosomal abnormalities is 6%.

The most severe forms of chromosomal imbalance occur in early abortions. These are polyploidies (25%), complete autosomal trisomies (50%). Trisomies for some autosomes (1; 5; 6; 11; 19) are extremely rare even in eliminated embryos and fetuses, which indicates the great morphogenetic significance of the genes in these autosomes. These anomalies interrupt development in the preimplantation period or disrupt gametogenesis.

The high morphogenetic significance of autosomes is even more pronounced in complete autosomal monosomies. The latter are rarely detected even in the material of early spontaneous abortions due to the lethal effect of such an imbalance.

Congenital malformations

If a chromosomal abnormality does not have a lethal effect in the early stages of development, then its consequences manifest themselves in the form of congenital malformations. Almost all chromosomal abnormalities (except balanced ones) lead to birth defects

development, combinations of which are known as nosological forms of chromosomal diseases and syndromes (Down syndrome, Wolf-Hirschhorn syndrome, cat cry, etc.).

The effects caused by uniparental disomes can be found in more detail on the CD in the article by S.A. Nazarenko “Hereditary diseases determined by uniparental disomes and their molecular diagnostics.”

Effects of chromosomal abnormalities in somatic cells

The role of chromosomal and genomic mutations is not limited to their influence on the development of pathological processes in the early periods of ontogenesis (misconception, spontaneous abortion, stillbirth, chromosomal disease). Their effects can be seen throughout life.

Chromosomal abnormalities that arise in somatic cells in the postnatal period can cause various consequences: remain neutral for the cell, cause cell death, activate cell division, change function. Chromosomal abnormalities occur in somatic cells constantly with a low frequency (about 2%). Normally, such cells are eliminated immune systems oh, if they act alien. However, in some cases (activation of oncogenes during translocations, deletions), chromosomal abnormalities become the cause of malignant growth. For example, a translocation between chromosomes 9 and 22 causes myeloid leukemia. Irradiation and chemical mutagens induce chromosomal aberrations. Such cells die, which, along with the action of other factors, contributes to the development of radiation sickness, aplasia bone marrow. There is experimental evidence of the accumulation of cells with chromosomal aberrations during aging.

PATHOGENESIS

Despite the well-studied clinical picture and cytogenetics of chromosomal diseases, their pathogenesis, even in general outline still unclear. A general scheme for the development of complex pathological processes caused by chromosomal abnormalities and leading to the appearance of complex phenotypes of chromosomal diseases has not been developed. The key link in the development of chromosomal disease in any

form not identified. Some authors suggest that this link is an imbalance of the genotype or a violation of the general gene balance. However, such a definition does not provide anything constructive. An imbalance of the genotype is a condition, not a link in pathogenesis; it must be realized through some specific biochemical or cellular mechanisms into the phenotype (clinical picture) of the disease.

Systematization of data on the mechanisms of disorders in chromosomal diseases shows that for any trisomies and partial monosomies, 3 types of genetic effects can be distinguished: specific, semispecific and nonspecific.

Specific the effects should be associated with a change in the number of structural genes encoding protein synthesis (with trisomy their number increases, with monosomy it decreases). Numerous attempts to find specific biochemical effects have confirmed this position only for a few genes or their products. Often, with numerical chromosomal disorders, there is no strictly proportional change in the level of gene expression, which is explained by the imbalance of complex regulatory processes in the cell. Thus, studies of patients with Down syndrome made it possible to identify 3 groups of genes located on chromosome 21, depending on changes in the level of their activity during trisomy. The first group included genes whose expression level significantly exceeds the level of activity in disomic cells. It is assumed that it is these genes that determine the formation of the main clinical signs of Down syndrome, which are recorded in almost all patients. The second group consisted of genes whose expression level partially overlaps with the expression level in a normal karyotype. These genes are believed to determine the formation of variable signs of the syndrome, which are not observed in all patients. Finally, the third group included genes whose expression levels in disomic and trisomic cells were practically the same. Apparently, these genes are least likely to be involved in the formation of clinical signs of Down syndrome. It should be noted that only 60% of genes located on chromosome 21 and expressed in lymphocytes and 69% of genes expressed in fibroblasts belonged to the first two groups. Some examples of such genes are given in table. 5.3.

Table 5.3. Dose-dependent genes that determine the formation of clinical signs of Down syndrome in trisomy 21

End of table 5.3

Biochemical study of the phenotype of chromosomal diseases has not yet led to an understanding of the pathogenesis of congenital disorders of morphogenesis arising as a result of chromosomal abnormalities in the broad sense of the word. It is still difficult to associate the discovered biochemical abnormalities with the phenotypic characteristics of diseases at the organ and system levels. A change in the number of alleles of a gene does not always cause a proportional change in the production of the corresponding protein. With a chromosomal disease, the activity of other enzymes or the number of proteins whose genes are localized on chromosomes not involved in the imbalance always changes significantly. In no case was a marker protein detected for chromosomal diseases.

Semi-specific effects in chromosomal diseases may be caused by a change in the number of genes that are normally presented in the form of numerous copies. These genes include genes for rRNA and tRNA, histone and ribosomal proteins, contractile proteins actin and tubulin. These proteins normally control key stages of cell metabolism, cell division processes, and intercellular interactions. What are the phenotypic effects of this imbalance?

groups of genes, how their deficiency or excess is compensated is still unknown.

Nonspecific effects chromosomal abnormalities are associated with changes in heterochromatin in the cell. The important role of heterochromatin in cell division, cell growth and other biological functions is beyond doubt. Thus, nonspecific and partially semispecific effects bring us closer to the cellular mechanisms of pathogenesis, which certainly play a crucial role in congenital malformations.

A large amount of factual material allows for a comparison of the clinical phenotype of the disease with cytogenetic changes (phenocaryotypic correlations).

What is common to all forms of chromosomal diseases is the multiplicity of lesions. These are craniofacial dysmorphia, congenital malformations of internal and external organs, slow intrauterine and postnatal growth and development, mental retardation, dysfunction of the nervous, endocrine and immune systems. For each form of chromosomal diseases, 30-80 different abnormalities are observed, partially overlapping (coinciding) in different syndromes. Only a small number of chromosomal diseases manifest themselves as a strictly defined combination of developmental abnormalities, which is used in clinical and pathological-anatomical diagnostics.

The pathogenesis of chromosomal diseases develops in the early prenatal period and continues in the postnatal period. Multiple congenital malformations, as the main phenotypic manifestation of chromosomal diseases, are formed in early embryogenesis, therefore, by the period of postnatal ontogenesis, all the main malformations are already present (except for malformations of the genital organs). Early and multiple damage to body systems explains some of the common clinical picture of different chromosomal diseases.

Phenotypic manifestation of chromosomal abnormalities, i.e. the formation of the clinical picture depends on the following main factors:

The individuality of the chromosome or its region involved in the abnormality (a specific set of genes);

Type of anomaly (trisomy, monosomy; complete, partial);

The size of the missing (with deletion) or excess (with partial trisomy) material;

The degree of mosaic of the body in terms of aberrant cells;

The genotype of the organism;

Environmental conditions (intrauterine or postnatal).

The degree of deviations in the development of the organism depends on the qualitative and quantitative characteristics of the inherited chromosomal abnormality. When studying clinical data in humans, the relatively low biological value of heterochromatic regions of chromosomes, proven in other species, is fully confirmed. Complete trisomies in live births are observed only for autosomes rich in heterochromatin (8; 9; 13; 18; 21). This also explains polysomy (before pentasomy) on sex chromosomes, in which the Y chromosome has few genes, and additional X chromosomes are heterochromatic.

Clinical comparison of complete and mosaic forms of the disease shows that mosaic forms are, on average, milder. This appears to be due to the presence of normal cells that partially compensate for the genetic imbalance. In the individual prognosis, there is no direct connection between the severity of the disease and the ratio of abnormal and normal clones.

As we study pheno- and karyotypic correlations with different extents of chromosomal mutation, it turns out that the most specific manifestations for a particular syndrome are due to deviations in the content of relatively small chromosome segments. An imbalance in a significant amount of chromosomal material makes the clinical picture more nonspecific. Thus, specific clinical symptoms of Down syndrome appear with trisomy on the segment of the long arm of chromosome 21q22.1. For the development of “cry the cat” syndrome with deletions of the short arm of autosome 5, the most important middle part segment (5р15). The characteristic features of Edwards syndrome are associated with trisomy on chromosome segment 18q11.

Each chromosomal disease is characterized by clinical polymorphism, determined by the genotype of the organism and environmental conditions. Variations in the manifestations of pathology can be very wide: from a lethal effect to minor developmental deviations. Thus, 60-70% of cases of trisomy 21 end in death in the prenatal period, in 30% of cases children are born with Down syndrome, which has various clinical manifestations. Monosomy on the X chromosome among newborns (Shereshevsky-syndrome)

Turner) is 10% of all embryos monosomic on the X chromosome (the rest die), and if we take into account the pre-implantation death of X0 zygotes, then live births with Shereshevsky-Turner syndrome make up only 1%.

Despite the insufficient understanding of the patterns of pathogenesis of chromosomal diseases in general, some links in the general chain of events in the development of individual forms are already known and their number is constantly increasing.

CLINICAL AND CYTOGENETIC CHARACTERISTICS OF THE MOST COMMON CHROMOSOMAL DISEASES

Down syndrome

Down syndrome, trisomy 21, is the most studied chromosomal disorder. The incidence of Down syndrome among newborns is 1:700-1:800, and does not have any temporal, ethnic or geographic differences when the parents are the same age. The frequency of births of children with Down syndrome depends on the age of the mother and, to a lesser extent, on the age of the father (Fig. 5.3).

With age, the likelihood of having children with Down syndrome increases significantly. So, in women aged 45 years it is about 3%. A high incidence of children with Down syndrome (about 2%) is observed in women who give birth early (before 18 years of age). Therefore, for population comparisons of the frequency of births of children with Down syndrome, it is necessary to take into account the distribution of women giving birth by age (the proportion of women giving birth after 30-35 years, in the total number of women giving birth). This distribution sometimes changes within 2-3 years for the same population (for example, with a sharp change in the economic situation in the country). The increase in the incidence of Down syndrome with increasing maternal age is known, but the majority of children with Down syndrome are still born to mothers under 30 years of age. This is due to the higher number of pregnancies in this age group compared to older women.

Rice. 5.3. Dependence of the birth rate of children with Down syndrome on the age of the mother

The literature describes the “bundling” of births of children with Down syndrome at certain periods of time in some countries (cities, provinces). These cases can be explained more by stochastic fluctuations in the spontaneous level of chromosome nondisjunction than by the influence of putative etiological factors (viral infection, low doses of radiation, chlorophos).

Cytogenetic variants of Down syndrome are varied. However, the majority (up to 95%) are cases of complete trisomy 21 due to chromosome nondisjunction in meiosis. The contribution of maternal nondisjunction to these gametic forms of the disease is 85-90%, and paternal nondisjunction is only 10-15%. Moreover, approximately 75% of disorders occur in the first division of meiosis in the mother and only 25% in the second. About 2% of children with Down syndrome have mosaic forms of trisomy 21 (47,+21/46). Approximately 3-4% of patients have a translocation form of trisomy similar to Robertsonian translocations between acrocentrics (D/21 and G/21). About 1/4 of translocation forms are inherited from carrier parents, while 3/4 of translocations arise de novo. The main types of chromosomal abnormalities found in Down syndrome are presented in table. 5.4.

Table 5.4. Main types of chromosomal abnormalities in Down syndrome

The ratio of boys to girls with Down syndrome is 1:1.

Clinical symptoms Down syndrome is diverse: these are congenital malformations, and disorders of postnatal development of the nervous system, and secondary immunodeficiency, etc. Children with Down syndrome are born at term, but with moderate prenatal hypoplasia (8-10% below average). Many symptoms of Down syndrome are noticeable at birth and become more pronounced later on. A qualified pediatrician makes the correct diagnosis of Down syndrome in the maternity hospital in at least 90% of cases. Craniofacial dysmorphias include a Mongoloid eye shape (for this reason, Down syndrome has long been called Mongoloidism), brachycephaly, a round flattened face, a flat dorsum of the nose, epicanthus, a large (usually protruding) tongue, and deformed ears (Fig. 5.4). Muscle hypoto-

Rice. 5.4.Children of different ages with characteristic features of Down syndrome (brachycephaly, round face, macroglossia and open mouth, epicanthus, hypertelorism, wide bridge of the nose, carp mouth, strabismus)

nia is combined with joint laxity (Fig. 5.5). Often there are congenital heart defects, clinodactyly, typical changes in dermatoglyphics (four-finger, or “monkey”, fold in the palm (Fig. 5.6), two skin folds instead of three on the little finger, high position of the triradius, etc.). Gastrointestinal defects are rare.

Rice. 5.5.Severe hypotension in a patient with Down syndrome

Rice. 5.6.Palms of an adult man with Down syndrome (increased wrinkling, four-fingered or “monkey” fold on the left hand)

The diagnosis of Down syndrome is made based on a combination of several symptoms. The following 10 signs are most important for making a diagnosis, the presence of 4-5 of them reliably indicates Down syndrome:

Flattening of the facial profile (90%);

Absence of sucking reflex (85%);

Muscular hypotonia (80%);

Mongoloid section of the palpebral fissures (80%);

Excess skin on the neck (80%);

Loose joints (80%);

Dysplastic pelvis (70%);

Dysplastic (deformed) ears (60%);

Clinodactyly of the little finger (60%);

Four-finger fold (transverse line) of the palm (45%).

The dynamics of the child’s physical and mental development are of great importance for diagnosis - with Down syndrome it is delayed. The height of adult patients is 20 cm below average. Mental retardation can reach the level of imbecility without special methods training. Children with Down syndrome are affectionate, attentive, obedient, and patient when learning. IQ (IQ) in different children it can range from 25 to 75.

The reaction of children with Down syndrome to environmental influences is often pathological due to weak cellular and humoral immunity, decreased DNA repair, insufficient production of digestive enzymes, and limited compensatory capabilities of all systems. For this reason, children with Down syndrome often suffer from pneumonia and have severe childhood infections. They are underweight and have severe hypovitaminosis.

Congenital defects internal organs, reduced adaptability of children with Down syndrome often leads to death in the first 5 years. The consequence of altered immunity and insufficiency of repair systems (for damaged DNA) are leukemias, which often occur in patients with Down syndrome.

Differential diagnosis is carried out with congenital hypothyroidism, other forms of chromosomal abnormalities. A cytogenetic examination of children is indicated not only for suspected Down syndrome, but also for a clinically established diagnosis, since the cytogenetic characteristics of the patient are necessary to predict the health of future children of parents and their relatives.

Ethical issues in Down syndrome are multifaceted. Despite the increased risk of having a child with Down syndrome and other chromosomal syndromes, the doctor should avoid direct recommendations

guidelines to limit childbearing in older women age group, since the risk by age remains quite low, especially taking into account the possibilities of prenatal diagnosis.

Parents are often dissatisfied with the way the doctor informs them about the diagnosis of Down syndrome in their child. Down syndrome can usually be diagnosed based on phenotypic characteristics immediately after delivery. A doctor who tries to refuse to make a diagnosis before examining the karyotype may lose the respect of the child's relatives. It is important to inform parents as soon as possible after the baby is born, at least about your suspicions, but you should not completely inform the baby's parents about the diagnosis. You need to provide enough information in response to immediate questions and maintain contact with parents until a more detailed discussion is possible. Immediate information should include an explanation of the etiology of the syndrome to avoid mutual accusations between the spouses and a description of the tests and procedures necessary to fully evaluate the health of the child.

A full discussion of the diagnosis should take place as soon as the mother has more or less recovered from the stress of delivery, usually on the 1st day after birth. By this time, mothers have many questions that need to be answered accurately and definitely. It is important to make every effort to have both parents present at this meeting. The child becomes the subject of direct discussion. During this period, it is too early to burden parents with all the information about the disease, since new and complex concepts require time to comprehend.

Don't try to make predictions. It is futile to try to accurately predict the future of any child. Ancient myths like: “At least he will always love and enjoy music” are unforgivable. It is necessary to present a picture painted in broad strokes, and note that the abilities of each child develop individually.

85% of children with Down syndrome born in Russia (in Moscow - 30%) are left by their parents in the care of the state. Parents (and often pediatricians) do not know that with proper training, such children can become full-fledged members of the family.

Therapeutic care for children with Down syndrome is multifaceted and nonspecific. Congenital heart defects are eliminated promptly.

General strengthening treatment is constantly carried out. Nutrition should be complete. Attentive care for a sick child and protection from harmful environmental factors (colds, infections) are necessary. Great successes in preserving the lives of children with Down syndrome and their development are provided by special teaching methods, strengthening physical health from early childhood, and some forms of drug therapy aimed at improving the functions of the central nervous system. Many patients with trisomy 21 are now able to lead an independent life, master simple professions, and start families. Average duration The lifespan of such patients in industrialized countries is 50-60 years.

Patau syndrome (trisomy 13)

Patau syndrome was identified as an independent nosological form in 1960 as a result of a cytogenetic examination of children with congenital malformations. The frequency of Patau syndrome among newborns is 1: 5000-7000. There are cytogenetic variants of this syndrome. Simple complete trisomy 13 as a consequence of chromosome nondisjunction in meiosis in one of the parents (mainly the mother) occurs in 80-85% of patients. The remaining cases are mainly due to the transfer of an additional chromosome (more precisely, its long arm) in Robertsonian translocations of type D/13 and G/13. Other cytogenetic variants have been discovered (mosaicism, isochromosome, non-Robertsonian translocations), but they are extremely rare. The clinical and pathological-anatomical picture of simple trisomic forms and translocation forms does not differ.

The sex ratio for Patau syndrome is close to 1: 1. Children with Patau syndrome are born with true prenatal hypoplasia (25-30% below average), which cannot be explained by slight prematurity (average gestational age 38.3 weeks). A characteristic complication of pregnancy when carrying a fetus with Patau syndrome is polyhydramnios: it occurs in almost 50% of cases. Patau syndrome is accompanied by multiple congenital malformations of the brain and face (Fig. 5.7). This is a pathogenetically unified group of early (and, therefore, severe) disorders of the formation of the brain, eyeballs, bones of the brain and facial parts of the skull. The skull circumference is usually reduced, and trigonocephaly is also common. The forehead is sloping, low; the palpebral fissures are narrow, the bridge of the nose is sunken, the ears are low and deformed

Rice. 5.7. Newborns with Patau syndrome (trigonocephaly (b); bilateral cleft lip and palate (b); narrow palpebral fissures (b); low-lying (b) and deformed (a) ears; microgenia (a); flexor position of the hands)

modified. A typical sign of Patau syndrome is clefts. upper lip and palate (usually bilateral). Defects of several internal organs are always found in different combinations: defects of the septum of the heart, incomplete intestinal rotation, kidney cysts, anomalies of the internal genital organs, defects of the pancreas. As a rule, polydactyly (usually bilateral and on the hands) and flexor position of the hands are observed. The frequency of different symptoms in children with Patau syndrome by system is as follows: face and cerebral part of the skull - 96.5%, musculoskeletal system- 92.6%, central nervous system - 83.3%, eyeball - 77.1%, cardiovascular system - 79.4%, digestive organs - 50.6%, urinary system - 60.6%, genital organs - 73, 2%.

Clinical diagnosis of Patau syndrome is based on a combination of characteristic developmental defects. If Patau syndrome is suspected, an ultrasound of all internal organs is indicated.

Due to severe congenital malformations, most children with Patau syndrome die in the first weeks or months of life (95% die before 1 year of age). However, some patients live for several years. Moreover, in developed countries there is a tendency to increase the life expectancy of patients with Patau syndrome to 5 years (about 15% of patients) and even up to 10 years (2-3% of patients).

Other syndromes of congenital malformations (Meckel and Mohr syndromes, Opitz trigonocephaly) have certain characteristics that coincide with Patau syndrome. The decisive factor in diagnosis is the study of chromosomes. Cytogenetic research is indicated in all cases, including in deceased children. An accurate cytogenetic diagnosis is necessary to predict the health of future children in the family.

Therapeutic care for children with Patau syndrome is nonspecific: operations for congenital malformations (for health reasons), restorative treatment, careful care, prevention of colds and infectious diseases. Children with Patau syndrome are almost always profound idiots.

Edwards syndrome (trisomy 18)

In almost all cases, Edwards syndrome is caused by a simple trisomic form (a gametic mutation in one of the parents). There are also mosaic forms (non-divergence in the early stages of crushing). Translocation forms are extremely rare, and, as a rule, these are partial rather than complete trisomies. There are no clinical differences between cytogenetically different forms of trisomy.

The incidence of Edwards syndrome among newborns is 1:5000-1:7000. The ratio of boys to girls is 1: 3. The reasons for the predominance of girls among patients are still unclear.

With Edwards syndrome, there is a pronounced delay in prenatal development with a normal duration of pregnancy (delivery at term). In Fig. 5.8-5.11 show defects in Edwards syndrome. These are multiple congenital malformations of the facial part of the skull, heart, skeletal system, and genitals. The skull is dolichocephalic in shape; the lower jaw and mouth opening are small; palpebral fissures are narrow and short; the ears are deformed and low-set. Other external signs include a flexor position of the hands, an abnormal foot (the heel protrudes, the arch sags), the first toe is shorter than the second toe. Spinal

Rice. 5.8. Newborn with Edwards syndrome (protruding occiput, microgenia, flexor position of the hand)

Rice. 5.9. The position of the fingers characteristic of Edwards syndrome (child's age is 2 months)

Rice. 5.10. Rocker foot (heel protrudes, arch sags)

Rice. 5.11. Hypogenitalism in a boy (cryptorchidism, hypospadias)

hernia and cleft lip are rare (5% of Edwards syndrome cases).

The diverse symptoms of Edwards syndrome in each patient are only partially manifested: face and brain part of the skull - 100%, musculoskeletal system - 98.1%, central nervous system - 20.4%, eyes - 13.61%, cardiovascular system - 90 .8%, digestive organs - 54.9%, urinary system - 56.9%, genital organs - 43.5%.

As can be seen from the presented data, the most significant changes in the diagnosis of Edwards syndrome are changes in the skull and face, the musculoskeletal system, and malformations of the cardiovascular system.

Children with Edwards syndrome die in early age(90% up to 1 year) from complications caused by congenital malformations (asphyxia, pneumonia, intestinal obstruction, cardiovascular failure). Clinical and even pathological-anatomical differential diagnosis of Edwards syndrome is complex, therefore, cytogenetic research is indicated in all cases. The indications for it are the same as for trisomy 13 (see above).

Trisomy 8

The clinical picture of trisomy 8 syndrome was first described by different authors in 1962 and 1963. in children with mental retardation, absence of the patella and other congenital malformations. Cytogenetically, mosaicism was determined on a chromosome from group C or D, since there was no individual identification of chromosomes at that time. Full trisomy 8 is usually fatal. It is often found in prenatally dead embryos and fetuses. Among newborns, trisomy 8 occurs with a frequency of no more than 1: 5000, boys predominate (the ratio of boys to girls is 5: 2). Most of the described cases (about 90%) refer to mosaic forms. The conclusion about complete trisomy in 10% of patients was based on the study of one tissue, which in a strict sense is not enough to exclude mosaicism.

Trisomy 8 is the result of a new mutation (chromosomal nondisjunction) in the early stages of blastula, with the exception of rare cases of a new mutation during gametogenesis.

There were no differences in the clinical picture of complete and mosaic forms. The severity of the clinical picture varies widely.

Rice. 5.12. Trisomy 8 (mosaicism) (inverted lower lip, epicanthus, abnormal pinna)

Rice. 5.13. 10-year-old boy with trisomy 8 (intellectual disability, large protruding ears with a simplified pattern)

Rice. 5.14. Contractures of the interphalangeal joints with trisomy 8

The reasons for such variations are unknown. No correlation was found between disease severity and the proportion of trisomic cells.

Babies with trisomy 8 are born full-term. The age of parents is not distinguished from the general sample.

The disease is most characterized by deviations in the structure of the face, defects of the musculoskeletal system and the urinary system (Fig. 5.12-5.14). These are a protruding forehead (72%), strabismus, epicanthus, deep-set eyes, hypertelorism of the eyes and nipples, high palate (sometimes cleft), thick lips, inverted lower lip (80.4%), large ears with thick lobes, joint contractures (in 74%), camptodactyly, patellar aplasia (in 60.7%), deep grooves between the interdigital pads (in 85.5%), four-digit fold, anomalies of the anus. Ultrasound reveals spinal anomalies (additional vertebrae, incomplete closure of the spinal canal), anomalies in the shape and position of the ribs, or additional ribs.

The number of symptoms in newborns ranges from 5 to 15 or more.

With trisomy 8, the prognosis for physical, mental development and life is unfavorable, although patients aged 17 years have been described. Over time, patients develop mental retardation, hydrocephalus, inguinal hernia, new contractures, aplasia of the corpus callosum, kyphosis, scoliosis, hip joint abnormalities, narrow pelvis, narrow shoulders.

There are no specific treatment methods. Surgical interventions are carried out according to vital indications.

Polysomy on sex chromosomes

This is a large group of chromosomal diseases, represented by various combinations of additional X or Y chromosomes, and in cases of mosaicism, combinations of different clones. The overall frequency of polysomy on X- or Y-chromosomes among newborns is 1.5: 1000-2: 1000. These are mainly polysomies XXX, XXY and XYY. Mosaic forms make up approximately 25%. Table 5.5 shows the types of polysomy by sex chromosomes.

Table 5.5. Types of polysomies on sex chromosomes in humans

Generalized data on the frequency of children with sex chromosome abnormalities are presented in Table. 5.6.

Table 5.6. Approximate frequency of children with sex chromosome abnormalities

Triplo-X syndrome (47,XXX)

Among newborn girls, the frequency of the syndrome is 1: 1000. Women with the XXX karyotype in the complete or mosaic version have generally normal physical and mental development, are usually detected by chance during examination. This is explained by the fact that in cells two X chromosomes are heterochromatinized (two sex chromatin bodies), and only one functions, like in a normal woman. As a rule, a woman with an XXX karyotype does not have abnormalities in sexual development and has normal fertility, although the risk of chromosomal abnormalities in offspring and spontaneous abortions is increased.

Intellectual development is normal or at the lower limit of normal. Only some women with triplo-X have reproductive dysfunction (secondary amenorrhea, dysmenorrhea, early menopause, etc.). Anomalies in the development of the external genitalia (signs of dysembryogenesis) are detected only with a thorough examination, are mildly expressed and do not serve as a reason to consult a doctor.

Variants of X-polysomy syndrome without a Y chromosome with more than 3 X chromosomes are rare. With an increase in the number of additional X chromosomes, deviations from the norm increase. In women with tetra- and pentasomy, abnormalities in mental development, craniofacial dysmorphia, abnormalities of the teeth, skeleton and genital organs have been described. However, women even with tetrasomy on the X chromosome have offspring. True, such women have an increased risk of giving birth to a girl with triplo-X or a boy with Klinefelter syndrome, because triploid oogonia form monosomic and disomic cells.

Klinefelter syndrome

Includes cases of sex chromosome polysomy in which there are at least two X chromosomes and at least one Y chromosome. The most common and typical clinical syndrome is Klinefelter syndrome with a set of 47,XXY. This syndrome (in complete and mosaic versions) occurs with a frequency of 1: 500-750 newborn boys. Polysomy variants with a large number of X and Y chromosomes (see Table 5.6) are rare. Clinically, they also refer to Klinefelter syndrome.

The presence of the Y chromosome determines the formation of the male sex. Before puberty, boys develop almost normally, with only a slight lag in mental development. Genetic imbalance due to the extra X chromosome manifests itself clinically during puberty in the form of testicular underdevelopment and secondary male sexual characteristics.

Patients are tall, have a female body type, gynecomastia, and weak facial, axillary, and pubic hair (Fig. 5.15). The testicles are reduced, histologically, degeneration of the germinal epithelium and hyalinosis of the spermatic cords are detected. Patients are infertile (azoospermia, oligospermia).

Disomy syndrome

on the Y chromosome (47,XYY)

Occurs with a frequency of 1:1000 newborn boys. Most men with this set of chromosomes differ slightly from those with a normal chromosome set in physical and mental development. They are slightly above average in height, mentally developed, and not dysmorphic. There are no noticeable deviations in sexual development, hormonal status, or fertility in the majority of XYY individuals. There is no increased risk of having chromosomally abnormal children in XYY individuals. Almost half of the boys 47, XYY require additional pedagogical assistance due to delayed speech development, difficulties in reading and pronunciation. The intelligence quotient (IQ) is on average 10-15 points lower. Behavioral characteristics include attention deficit, hyperactivity and impulsivity, but without pronounced aggression or psychopathological behavior. In the 1960-70s it was stated that the proportion of XYY men was increased in prisons and psychiatric hospitals, especially among tall ones. Currently, these assumptions are considered incorrect. However, it is impossible

Rice. 5.15. Klinefelter's syndrome. Tall height, gynecomastia, female pattern pubic hair

predicting the developmental outcome in individual cases makes the identification of the XYY fetus one of the most difficult tasks in genetic counseling in prenatal diagnosis.

Shereshevsky-Turner syndrome (45,Х)

This the only form monosomy in live births. At least 90% of conceptions with karyotype 45.X are aborted spontaneously. Monosomy X accounts for 15-20% of all abnormal karyotypes of abortus.

The frequency of Shereshevsky-Turner syndrome is 1: 2000-5000 newborn girls. The cytogenetics of the syndrome is diverse. Along with true monosomy, other forms of chromosomal abnormalities on sex chromosomes are found in all cells (45,X). These are deletions of the short or long arm of the X chromosome, isochromosomes, ring chromosomes, as well as various variants of mosaicism. Only 50-60% of patients with Shereshevsky-Turner syndrome have simple complete monosomy (45,X). The only X chromosome in 80-85% of cases is of maternal origin and only in 15-20% of paternal origins.

In other cases, the syndrome is caused by a variety of mosaicism (in general 30-40%) and more rare variants of deletions, isochromosomes, and ring chromosomes.

Hypogonadism, underdevelopment of the genital organs and secondary sexual characteristics;

Congenital malformations;

Short stature.

On the part of the reproductive system, absence of gonads (gonadal agenesis), uterine hypoplasia and fallopian tubes, primary amenorrhea, scanty pubic and axillary hair, underdevelopment of the mammary glands, estrogen deficiency, excess pituitary gonadotropins. Children with Shereshevsky-Turner syndrome often (up to 25% of cases) have various congenital heart and kidney defects.

The appearance of patients is quite unique (although not always). Newborns and infants have a short neck with excess skin and pterygoid folds, lymphedema of the feet (Fig. 5.16), legs, hands and forearms. At school and especially in adolescence, growth retardation is detected, in

Rice. 5.16. Lymphatic edema of the foot in a newborn with Shereshevsky-Turner syndrome. Small convex nails

Rice. 5.17. A girl with Shereshevsky-Turner syndrome (cervical pterygoid folds, widely spaced and underdeveloped nipples of the mammary glands)

development of secondary sexual characteristics (Fig. 5.17). In adults, skeletal disorders, craniofacial dysmorphia, valgus deviation of the knee and elbow joints, shortening of the metacarpal and metatarsal bones, osteoporosis, barrel-shaped chest, low hair growth on the neck, anti-Mongoloid incision of the palpebral fissures, ptosis, epicanthus, retrogenia, low location of the ears. The height of adult patients is 20-30 cm below average. The severity of clinical (phenotypic) manifestations depends on many still unknown factors, including the type of chromosomal pathology (monosomy, deletion, isochromosome). Mosaic forms of the disease, as a rule, have weaker manifestations depending on the 46XX:45X clone ratio.

Table 5.7 presents data on the frequency of the main symptoms in Shereshevsky-Turner syndrome.

Table 5.7. Clinical symptoms of Shereshevsky-Turner syndrome and their occurrence

Treatment of patients with Shereshevsky-Turner syndrome is complex:

Reconstructive surgery (congenital malformations of internal organs);

Plastic surgery (removal of pterygoid folds, etc.);

Hormonal treatment(estrogens, growth hormone);

Psychotherapy.

Timely use of all treatment methods, including the use of genetically engineered growth hormone, gives patients the opportunity to achieve acceptable height and lead a full life.

Partial aneuploidy syndromes

This large group of syndromes is caused by chromosomal mutations. Whatever type of chromosomal mutation was initially (inversion, translocation, duplication, deletion), the occurrence of clinical chromosomal syndrome is determined by either an excess (partial trisomy) or a deficiency (partial monosomy) of genetic material or simultaneously both effects of different altered sections of the chromosomal set. To date, about 1000 different variants of chromosomal mutations, inherited from parents or arising in early embryogenesis, have been discovered. However, clinical forms of chromosomal syndromes are considered only those rearrangements (there are about 100) for which

Several probands have been described with a coincidence in the nature of cytogenetic changes and the clinical picture (correlation of karyotype and phenotype).

Partial aneuploidies arise mainly as a result of inaccurate crossing over of chromosomes with inversions or translocations. Only in a small number of cases is it possible that deletions may initially occur in a gamete or in a cell in the early stages of cleavage.

Partial aneuploidies, like complete ones, cause sharp deviations in development, therefore they belong to the group of chromosomal diseases. Most forms of partial trisomies and monosomies do not repeat the clinical picture of complete aneuploidies. They are independent nosological forms. Only in a small number of patients the clinical phenotype of partial aneuploidies coincides with that of complete forms (Shereshevsky-Turner syndrome, Edwards syndrome, Down syndrome). In these cases, we are talking about partial aneuploidy in the so-called chromosome regions critical for the development of the syndrome.

There is no dependence of the severity of the clinical picture of chromosomal syndrome on the form of partial aneuploidy or on the individual chromosome. The size of the chromosome region involved in the rearrangement may be important, but cases of this kind (smaller or longer length) should be considered as different syndromes. General patterns It is difficult to identify correlations between the clinical picture and the nature of chromosomal mutations, because many forms of partial aneuploidy are eliminated in the embryonic period.

The phenotypic manifestations of any autosomal deletion syndrome consist of two groups of abnormalities: nonspecific findings common to many different forms of partial autosomal aneuploidies (prenatal development delay, microcephaly, hypertelorism, epicanthus, apparently low-set ears, micrognathia, clinodactyly, etc.); combinations of findings typical for this syndrome. The most appropriate explanation for the causes of nonspecific findings (most of which are not clinically significant) is the nonspecific effects of the autosomal imbalance itself rather than the results of deletions or duplications of specific loci.

Chromosomal syndromes caused by partial aneuploidies share the common properties of all chromosomal diseases:

congenital disorders of morphogenesis (congenital malformations, dysmorphia), violation of postnatal ontogenesis, severity of the clinical picture, shortened life expectancy.

Cry of the cat syndrome

This is a partial monosomy on the short arm of chromosome 5 (5p-). Monosomy 5p syndrome was the first described syndrome caused by a chromosomal mutation (deletion). This discovery was made by J. Lejeune in 1963.

Children with this chromosomal abnormality have an unusual cry, reminiscent of a demanding cat meow or cry. For this reason, the syndrome was called "cry the cat" syndrome. The frequency of the syndrome is quite high for deletion syndromes - 1: 45,000. Several hundred patients have been described, so the cytogenetics and clinical picture of this syndrome have been well studied.

Cytogenetically, in most cases, a deletion is detected with a loss of 1/3 to 1/2 of the length of the short arm of chromosome 5. The loss of the entire short arm or, conversely, a small section is rare. For the development of the clinical picture of 5p syndrome, it is not the size of the lost area that matters, but the specific fragment of the chromosome. Only a small region in the short arm of chromosome 5 (5p15.1-15.2) is responsible for the development of the full syndrome. In addition to a simple deletion, other cytogenetic variants have been found in this syndrome: ring chromosome 5 (naturally, with a deletion of the corresponding section of the short arm); mosaicism by deletion; reciprocal translocation of the short arm of chromosome 5 (with loss of a critical region) with another chromosome.

The clinical picture of 5p-syndrome varies quite greatly in individual patients according to the combination of congenital malformations of organs. The most characteristic sign - “cat cry” - is caused by changes in the larynx (narrowing, softness of cartilage, reduction of the epiglottis, unusual folding of the mucous membrane). Almost all patients have certain changes in the brain part of the skull and face: moon-shaped face, microcephaly, hypertelorism, microgenia, epicanthus, anti-Mongoloid eye shape, high palate, flat dorsum of the nose (Fig. 5.18, 5.19). The ears are deformed and located low. In addition, congenital heart defects and some

Rice. 5.18. A child with pronounced signs of the “cry of the cat” syndrome (microcephaly, moon-shaped face, epicanthus, hypertelorism, wide flat nasal bridge, low-set ears)

Rice. 5.19. A child with mild signs of “cry the cat” syndrome

other internal organs, changes in the musculoskeletal system (syndactyly of the feet, clinodactyly of the fifth finger, clubfoot). Muscle hypotonia and sometimes diastasis of the rectus abdominis muscles are detected.

Expressiveness individual signs and the clinical picture as a whole changes with age. Thus, “cat cry”, muscle hypotonia, moon-shaped face disappear almost completely with age, and microcephaly is revealed more clearly, psychomotor underdevelopment and strabismus become more noticeable. The life expectancy of patients with 5p syndrome depends on the severity of congenital defects of internal organs (especially the heart), the severity of the clinical picture as a whole, the level of medical care and everyday life. Most patients die in the first years, about 10% of patients reach 10 years of age. There are isolated descriptions of patients aged 50 years and older.

In all cases, patients and their parents are shown a cytogenetic examination, because one of the parents may have a reciprocal balanced translocation, which, when passing through the meiosis stage, can cause a deletion of the region

5р15.1-15.2.

Wolf-Hirschhorn syndrome (partial monosomy 4p-)

It is caused by a deletion of a segment of the short arm of chromosome 4. Clinically, Wolf-Hirschhorn syndrome is manifested by numerous congenital defects followed by a sharp delay in physical and psychomotor development. Already in utero fetal hypoplasia is noted. The average body weight of children at birth from full-term pregnancy is about 2000 g, i.e. prenatal hypoplasia is more pronounced than with other partial monosomies. Children with Wolf-Hirschhorn syndrome have the following signs (symptoms): microcephaly, beaked nose, hypertelorism, epicanthus, abnormal auricles (often with preauricular folds), cleft lip and palate, abnormalities of the eyeballs, antimongoloid eye shape, small

Rice. 5.20. Children with Wolf-Hirschhorn syndrome (microcephaly, hypertelorism, epicanthus, abnormal pinnae, strabismus, microgenia, ptosis)

cue mouth, hypospadias, cryptorchidism, sacral fossa, foot deformity, etc. (Fig. 5.20). Along with malformations of external organs, more than 50% of children have malformations of internal organs (heart, kidneys, gastrointestinal tract).

The vitality of children is sharply reduced, most die before the age of 1 year. Only 1 patient aged 25 years is described.

The cytogenetics of the syndrome is quite characteristic, like many deletion syndromes. In approximately 80% of cases, the proband has a deletion of part of the short arm of chromosome 4, while the parents have normal karyotypes. The remaining cases are caused by translocation combinations or ring chromosomes, but there is always a loss of the 4p16 fragment.

A cytogenetic examination of the patient and his parents is indicated to clarify the diagnosis and prognosis of the health of future children, since parents may have balanced translocations. The frequency of births of children with Wolf-Hirschhorn syndrome is low (1: 100,000).

Partial trisomy syndrome on the short arm of chromosome 9 (9p+)

This is the most common form of partial trisomy (about 200 reports of such patients have been published).

The clinical picture is diverse and includes intrauterine and postnatal developmental disorders: growth retardation, mental retardation, microbrachycephaly, antimongoloid eye shape, enophthalmos (deep-set eyes), hypertelorism, rounded tip of the nose, drooping corners of the mouth, low-set protruding auricles with a flattened pattern, hypoplasia (sometimes dysplasia) of the nails (Fig. 5.21). Congenital heart defects were found in 25% of patients.

Other congenital anomalies common to all chromosomal diseases are less common: epicanthus, strabismus, micrognathia, high arched palate, sacral sinus, syndactyly.

Patients with 9p+ syndrome are born at term. Prenatal hypoplasia is moderately expressed (average body weight of newborns is 2900-3000 g). The life prognosis is relatively favorable. Patients live to old and advanced age.

The cytogenetics of 9p+ syndrome is diverse. Most cases are the result of unbalanced translocations (familial or sporadic). Simple duplications, isochromosomes 9p, have also been described.

Rice. 5.21. Trisomy 9p+ syndrome (hypertelorism, ptosis, epicanthus, bulbous nose, short filter, large, low-set ears, thick lips, short neck): a - 3-year-old child; b - woman 21 years old

The clinical manifestations of the syndrome are the same for different cytogenetic variants, which is understandable, since in all cases there is a triple set of genes for part of the short arm of chromosome 9.

Syndromes caused by microstructural aberrations of chromosomes

This group includes syndromes caused by minor, up to 5 million bp, deletions or duplications of strictly defined sections of chromosomes. Accordingly, they are called microdeletion and microduplication syndromes. Many of these syndromes were initially described as dominant diseases (point mutations), but later, with the help of modern high-resolution cytogenetic methods (especially molecular cytogenetics), the true etiology of these diseases was established. Using CGH on microarrays, it became possible to detect deletions and duplications of chromosomes extending up to one gene with adjacent regions, which made it possible not only to significantly expand the list of microdeletion and microduplication syndromes, but also to get closer to

understanding genophenotypic correlations in patients with microstructural chromosome aberrations.

It is through the example of deciphering the mechanisms of development of these syndromes that one can see the mutual penetration of cytogenetic methods into genetic analysis, and molecular genetic methods into clinical cytogenetics. This makes it possible to decipher the nature of previously unclear hereditary diseases, as well as to clarify functional dependencies between genes. It is obvious that the development of microdeletion and microduplication syndromes is based on changes in gene dosage in the chromosome region affected by the rearrangement. However, it has not yet been established what exactly forms the basis for the formation of most of these syndromes - the absence of a specific structural gene or a more extended area containing several genes. Diseases that arise as a result of microdeletions of a chromosome region containing several gene loci are proposed to be called adjacent gene syndromes. To form the clinical picture of this group of diseases, the absence of the product of several genes affected by microdeletion is fundamentally important. By their nature, adjacent gene syndromes are on the border between Mendelian monogenic diseases and chromosomal diseases (Fig. 5.22).

Rice. 5.22. The size of genomic rearrangements in various types of genetic diseases. (According to Stankiewicz P., Lupski J.R. Genome architecture, rearrangements and genomic disorders // Trends in Genetics. - 2002. - V. 18 (2). - P. 74-82.)

A typical example of such a disease is Prader-Willi syndrome, which occurs as a result of a microdeletion of 4 million bp. in the q11-q13 region on chromosome 15 of paternal origin. Microdeletion in Prader-Willi syndrome affects 12 imprinted genes (SNRPN, NDN, MAGEL2 and a number of others), which are normally expressed only from the paternal chromosome.

It also remains unclear how the state of the locus on the homologous chromosome affects the clinical manifestation of microdeletion syndromes. Apparently, the nature of the clinical manifestations of different syndromes is different. The pathological process in some of them unfolds through the inactivation of tumor suppressors (retinoblastoma, Wilms tumor), the clinic of other syndromes is caused not only by deletions as such, but also by the phenomena of chromosomal imprinting and uniparental disomies (Prader-Willi, Angelman, Beckwith-Wiedemann syndromes). The clinical and cytogenetic characteristics of microdeletion syndromes are constantly being refined. Table 5.8 provides examples of some syndromes caused by microdeletions or microduplications of small fragments of chromosomes.

Table 5.8. General information about syndromes caused by microdeletions or microduplications of chromosomal regions

Continuation of Table 5.8

End of table 5.8

Most microdeletion/microduplication syndromes are rare (1:50,000-100,000 births). Their clinical picture is usually clear. The diagnosis can be made by a combination of symptoms. However, due to the prognosis of the health of future children in the family, including relatives

Rice. 5.23. Langer-Gideon syndrome. Multiple exostoses

Rice. 5.24. Boy with Prader-Willi syndrome

Rice. 5.25. Girl with Angelman syndrome

Rice. 5.26. Child with DiGeorge syndrome

parents of the proband, it is necessary to conduct a high-resolution cytogenetic study of the proband and his parents.

Rice. 5.27. Transverse notches on the earlobe are a typical symptom of Beckwith-Wiedemann syndrome (indicated by an arrow)

The clinical manifestations of the syndromes vary greatly due to the different extent of deletion or duplication, as well as due to the parental origin of the microreorganization - whether it is inherited from the father or from the mother. In the latter case, we are talking about imprinting at the chromosomal level. This phenomenon was discovered during a cytogenetic study of two clinically different syndromes (Prader-Willi and Angelman). In both cases, microdeletion is observed in chromosome 15 (section q11-q13). Only molecular cytogenetic methods have established the true nature of the syndromes (see Table 5.8). The q11-q13 region on chromosome 15 gives such a pronounced effect

imprinting that syndromes can be caused by uniparental disomies (Fig. 5.28) or mutations with an imprinting effect.

As can be seen in Fig. 5.28, disomy on maternal chromosome 15 causes Prader-Willi syndrome (because the q11-q13 region of the paternal chromosome is missing). The same effect is achieved by a deletion of the same region or a mutation in the paternal chromosome with a normal (bi-parental) karyotype. The exact opposite situation is observed with Angelman syndrome.

More detailed information about genome architecture and hereditary diseases caused by microorganisms structural disorders chromosomes, can be found in the article of the same name by S.A. Nazarenko on CD.

Rice. 5.28. Three classes of mutations in Prader-Willi syndrome (PWS) and Angelman (SA): M - mother; O - father; URD - uniparental disomy

FACTORS OF INCREASED RISK OF BIRTH OF CHILDREN WITH CHROMOSOMAL DISEASES

In recent decades, many researchers have turned to the causes of chromosomal diseases. There was no doubt that the formation of chromosomal abnormalities (both chromosomal and genomic mutations) occurs spontaneously. The results of experimental genetics were extrapolated and induced mutagenesis in humans was assumed (ionizing radiation, chemical mutagens, viruses). However, the actual reasons for the occurrence of chromosomal and genomic mutations in germ cells or in the early stages of embryo development have not yet been deciphered.

Many hypotheses of chromosome nondisjunction were tested (seasonality, race-ethnicity, maternal and paternal age, delayed fertilization, birth order, family accumulation, drug treatment mothers, bad habits, non-hormonal and hormonal contraception, fluridins, viral diseases in women). In most cases, these hypotheses were not confirmed, but a genetic predisposition to the disease cannot be excluded. Although most cases of chromosome nondisjunction in humans are sporadic, it can be assumed that it is genetically determined to a certain extent. This is evidenced by the following facts:

Offspring with trisomy appear repeatedly in the same women with a frequency of at least 1%;

Relatives of a proband with trisomy 21 or other aneuploidies have a slightly increased risk of having a child with aneuploidy;

Parental consanguinity may increase the risk of trisomy in the offspring;

The frequency of conceptions with double aneuploidy may be higher than predicted by the frequency of individual aneuploidies.

Biological factors that increase the risk of chromosome nondisjunction include maternal age, although the mechanisms of this phenomenon are unclear (Table 5.9, Fig. 5.29). As can be seen from table. 5.9, the risk of having a child with a chromosomal disease caused by aneuploidy gradually increases with maternal age, but especially sharply after 35 years. In women over 45 years of age, every 5th pregnancy ends in the birth of a child with a chromosomal disease. The age dependence is most clearly manifested for triso-

Rice. 5.29. Dependence of the frequency of chromosomal abnormalities on the age of the mother: 1 - spontaneous abortions in registered pregnancies; 2 - overall frequency of chromosomal abnormalities in the second trimester; 3 - Down syndrome in the second trimester; 4 - Down syndrome among live births

mii 21 (Down's disease). For sex chromosome aneuploidies, the age of the parents either does not matter at all or its role is very insignificant.

Table 5.9. Dependence of the frequency of births of children with chromosomal diseases on the age of the mother

In Fig. Figure 5.29 shows that the frequency of spontaneous abortions also increases with age, which by the age of 45 increases by 3 times or more. This situation can be explained by the fact that spontaneous abortions are largely caused (up to 40-45%) by chromosomal abnormalities, the frequency of which is age dependent.

Factors of increased risk of aneuploidy in children from karyotypically normal parents were discussed above. Essentially, of the numerous putative factors, only two are important for pregnancy planning, or rather, they are strict indications for prenatal diagnosis. This is the birth of a child with autosomal aneuploidy and the mother’s age over 35 years.

Cytogenetic research in married couples allows us to identify karyotypic risk factors: aneuploidy (mainly in mosaic form), Robertsonian translocations, balanced reciprocal translocations, ring chromosomes, inversions. The increased risk depends on the type of anomaly (from 1 to 100%): for example, if one of the parents has homologous chromosomes involved in the Robertsonian translocation (13/13, 14/14, 15/15, 21/21, 22/22), then The carrier of such rearrangements cannot have healthy offspring. Pregnancies will end either in spontaneous abortions (in all cases of translocations 14/14, 15/15, 22/22 and partially in translocations).

locations 13/13, 21/21), or the birth of children with Patau syndrome (13/13) or Down syndrome (21/21).

To calculate the risk of having a child with a chromosomal disease in the case of an abnormal karyotype in the parents, empirical risk tables were compiled. Now there is almost no need for them. Prenatal cytogenetic diagnostic methods have made it possible to move from risk assessment to establishing a diagnosis in the embryo or fetus.

KEY WORDS AND CONCEPTS

Isochromosomes

Imprinting at the chromosomal level Isodisomy

History of the discovery of chromosomal diseases

Classification of chromosomal diseases

Ring chromosomes

Correlation of pheno- and karyotype

Microdeletion syndromes

General clinical features of chromosomal diseases

Uniparental disomies

Pathogenesis of chromosomal diseases

Indications for cytogenetic diagnostics

Robertsonian translocations

Balanced reciprocal translocations

Types of chromosomal and genomic mutations

Risk factors for chromosomal diseases

Chromosomal abnormalities and spontaneous abortions

Partial monosomies

Partial trisomies

Frequency of chromosomal diseases

Effects of chromosomal abnormalities

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Ginter E.K. Medical genetics. - M.: Medicine, 2003. -

445 pp.

Kozlova S.I., Demikova N.S. Hereditary syndromes and medical genetic counseling: atlas-reference book. - 3rd ed., add. and processed - M.: T-vo scientific publications KMK; Author's Academy, 2007. - 448 pp.: 236 ill.

Nazarenko S.A. Chromosome variability and human development. - Tomsk: Tomsk State University Publishing House, 1993. -

200 s.

Prokofieva-Belgovskaya A.A. Fundamentals of human cytogenetics. - M.: Medicine, 1969. - 544 p.

Puzyrev V.P., Stepanov V.A. Pathological anatomy of the human genome. - Novosibirsk: Nauka, 1997. - 223 p.

Smirnov V.G. Cytogenetics. - M.: Higher School, 1991. - 247 p.

The article is based on the work of Prof. Bue.

Stopping the development of the embryo subsequently leads to the expulsion of the fertilized egg, which manifests itself in the form of spontaneous miscarriage. However, in many cases, development stops at very early stages and the very fact of conception remains unknown to the woman. In a large percentage of cases, such miscarriages are associated with chromosomal abnormalities in the embryo.

Spontaneous miscarriages

Spontaneous miscarriages, defined as “spontaneous termination of pregnancy between the time of conception and the period of viability of the fetus,” are in many cases very difficult to diagnose: a large number of miscarriages occur at very early stages: there is no delay in menstruation, or this delay is so small that it itself the woman does not suspect she is pregnant.

Clinical data

Expulsion of the ovum may occur suddenly or may be preceded by clinical symptoms. More often risk of miscarriage manifested by bloody discharge and pain in the lower abdomen, turning into contractions. This is followed by the expulsion of the fertilized egg and the disappearance of signs of pregnancy.

Clinical examination may reveal a discrepancy between the estimated gestational age and the size of the uterus. Hormone levels in the blood and urine may be sharply reduced, indicating a lack of fetal viability. Ultrasound examination allows you to clarify the diagnosis, revealing either the absence of an embryo (“empty ovum”), or developmental delay and absence of heartbeat

The clinical manifestations of spontaneous miscarriage vary significantly. In some cases, a miscarriage goes unnoticed, in others it is accompanied by bleeding and may require curettage of the uterine cavity. The chronology of symptoms may indirectly indicate the cause of spontaneous miscarriage: bloody issues from the early stages of pregnancy, cessation of uterine growth, disappearance of signs of pregnancy, a “silent” period for 4-5 weeks, and then expulsion of the fertilized egg most often indicate chromosomal abnormalities of the embryo, and the correspondence of the period of development of the embryo with the period of miscarriage speaks in favor of maternal causes of miscarriage pregnancy.

Anatomical data

Analysis of material from spontaneous miscarriages, the collection of which began at the beginning of the twentieth century at the Carnegie Institution, revealed a huge percentage of developmental anomalies among early abortions

In 1943, Hertig and Sheldon published the results of a pathological study of material from 1000 early miscarriages. Maternal reasons they excluded miscarriage in 617 cases. Current evidence indicates that macerated embryos in apparently normal membranes may also be associated with chromosomal abnormalities, which totaled about 3/4 of all cases in this study.

Morphological study of 1000 abortions (after Hertig and Sheldon, 1943)
Gross pathological disorders of the ovum: fertilized egg without an embryo or with an undifferentiated embryo	489
Local abnormalities of embryos	32
Abnormalities of the placenta	96	617
Fertilized egg without gross anomalies
with macerated germs	146
		763
with non-macerated embryos	74
Uterine abnormalities	64
Other violations	99

Further studies by Mikamo and Miller and Poland made it possible to clarify the relationship between the timing of miscarriage and the incidence of fetal developmental disorders. It turned out that the shorter the miscarriage period, the higher the frequency of anomalies. In the materials of miscarriages that occurred before the 5th week after conception, macroscopic morphological anomalies of the fetal egg are found in 90% of cases, with a miscarriage period of 5 to 7 weeks after conception - in 60%, with a period of more than 7 weeks after conception - in less than 15-20%.

The importance of stopping the development of the embryo in early spontaneous miscarriages was shown primarily by the fundamental research of Arthur Hertig, who in 1959 published the results of a study of human embryos up to 17 days after conception. It was the fruit of his 25 years of work.

In 210 women under 40 years of age undergoing hysterectomy (removal of the uterus), the date of surgery was compared with the date of ovulation (possible conception). After the operation, the uteri were subjected to the most thorough histological examination to identify a possible short-term pregnancy. Of the 210 women, only 107 were retained in the study due to the detection of signs of ovulation and the absence of gross disorders of the tubes and ovaries that would prevent pregnancy. Thirty-four gestational sacs were found, of which 21 gestational sacs were apparently normal, and 13 (38%) had obvious signs of abnormalities, which, according to Hertig, would necessarily lead to miscarriage either at the implantation stage or shortly after implantation. Since at that time it was not possible to conduct genetic research on fertilized eggs, the causes of developmental disorders of the embryos remained unknown.

When examining women with confirmed fertility (all patients had several children), it was found that one out of three fertilized eggs had anomalies and was miscarried before signs of pregnancy appeared.

Epidemiological and demographic data

The unclear clinical symptoms of early spontaneous miscarriages lead to the fact that a fairly large percentage of short-term miscarriages go unnoticed by women.

In clinically confirmed pregnancies, approximately 15% of all pregnancies end in miscarriage. Most spontaneous miscarriages (about 80%) occur in the first trimester of pregnancy. However, if we take into account the fact that miscarriages often occur 4-6 weeks after pregnancy stops, we can say that more than 90% of all spontaneous miscarriages are associated with the first trimester.

Special demographic studies have made it possible to clarify the frequency of intrauterine mortality. So, French and Birman in 1953 - 1956. recorded all pregnancies among women on the island of Kanai and showed that out of 1000 pregnancies diagnosed after 5 weeks, 237 did not result in the birth of a viable child.

Analysis of the results of several studies allowed Leridon to compile a table of intrauterine mortality, which also includes fertilization failures (sexual intercourse at the optimal time - within 24 hours after ovulation).

Complete table of intrauterine mortality (per 1000 eggs exposed to the risk of fertilization) (after Leridon, 1973)
Weeks after conception	Arrest of development followed by expulsion	Percentage of ongoing pregnancies
	16*	100
0	15	84
1	27	69
2	5,0	42
6	2,9	37
10	1,7	34,1
14	0,5	32,4
18	0,3	31,9
22	0,1	31,6
26	0,1	31,5
30	0,1	31,4
34	0,1	31,3
38	0,2	31,2
* - failure to conceive

All these data indicate a huge frequency of spontaneous miscarriages and the important role of developmental disorders of the ovum in this pathology.

These data reflect the general frequency of developmental disorders, without highlighting specific exo- and endogenous factors (immunological, infectious, physical, chemical, etc.) among them.

It is important to note that, regardless of the cause of the damaging effects, when studying the material of miscarriages, a very high frequency is found genetic disorders(chromosomal aberrations (best studied today) and gene mutations) and developmental anomalies, such as neural tube defects.

Chromosomal abnormalities responsible for stopping the development of pregnancy

Cytogenetic studies of miscarriage material made it possible to clarify the nature and frequency of certain chromosomal abnormalities.

Overall frequency

When evaluating the results of large series of analyses, the following should be kept in mind. The results of studies of this kind can be significantly influenced by the following factors: the method of collecting material, the relative frequency of earlier and later miscarriages, the proportion of induced abortion material in the study, which often cannot be accurately estimated, the success of culturing abortus cell cultures and chromosomal analysis of the material, subtle methods processing of macerated material.

The general estimate of the frequency of chromosomal aberrations in miscarriage is about 60%, and in the first trimester of pregnancy - from 80 to 90%. As will be shown below, analysis based on the stages of embryo development allows us to draw much more accurate conclusions.

Relative frequency

Almost all large studies of chromosomal aberrations in miscarriage material have yielded strikingly similar results regarding the nature of the abnormalities. Quantitative anomalies make up 95% of all aberrations and are distributed as follows:

Quantitative chromosomal abnormalities

Various types of quantitative chromosomal aberrations can result from:

• meiotic division failures: we are talking about cases of “non-disjunction” (non-separation) of paired chromosomes, which leads to the appearance of either trisomy or monosomy. Non-division can occur during either the first or second meiotic division and can involve both eggs and sperm.
• failures that occur during fertilization:: cases of fertilization of an egg by two sperm (dispermia), resulting in a triploid embryo.
• failures that occur during the first mitotic divisions: Complete tetraploidy occurs when the first division results in chromosome duplication but non-division of the cytoplasm. Mosaics occur in the event of similar failures at the stage of subsequent divisions.

Monosomy

Monosomy X (45,X) is one of the most common anomalies in material from spontaneous miscarriages. At birth it corresponds to Shereshevsky-Turner syndrome, and at birth it is less common than other quantitative sex chromosome abnormalities. This striking difference between the relatively high incidence of extra X chromosomes in newborns and the relatively rare detection of monosomy X in newborns indicates the high lethality of monosomy X in the fetus. In addition, noteworthy is the very high frequency of mosaics in patients with Shereshevsky-Turner syndrome. In the material of miscarriages, on the contrary, mosaics with monosomy X are extremely rare. Research data has shown that only less than 1% of all monosomy X cases reach the due date. Autosomal monosomies in miscarriage materials are quite rare. This is in sharp contrast to the high incidence of corresponding trisomies.

Trisomy

In the material from miscarriages, trisomies represent more than half of all quantitative chromosomal aberrations. It is noteworthy that in cases of monosomy, the missing chromosome is usually the X chromosome, and in cases of redundant chromosomes, the additional chromosome most often turns out to be an autosome.

Accurate identification of the additional chromosome has become possible thanks to the G-banding method. Research has shown that all autosomes can participate in non-disjunction (see table). It is noteworthy that the three chromosomes most often found in trisomies in newborns (15th, 18th and 21st) are most often found in lethal trisomies in embryos. Variations in the relative frequencies of various trisomies in embryos largely reflect the time frame at which the death of embryos occurs, since the more lethal the combination of chromosomes is, the earlier the arrest of development occurs, the less often such an aberration will be detected in the materials of miscarriages (the shorter the period of arrest development, the more difficult it is to detect such an embryo).

An extra chromosome in lethal trisomies in the embryo (data from 7 studies: Boué (France), Carr (Canada), Creasy (Great Britain), Dill (Canada), Kaji (Switzerland), Takahara (Japan), Terkelsen (Denmark))
Additional autosome		Number of observations
A	1
	2	15
	3	5
B	4	7
	5
C	6	1
	7	19
	8	17
	9	15
	10	11
	11	1
	12	3
D	13	15
	14	36
	15	35
E	16	128
	17	1
	18	24
F	19	1
	20	5
G	21	38
	22	47

Triploidy

Extremely rare in stillbirths, triploidies are the fifth most common chromosomal abnormality in miscarriage specimens. Depending on the ratio of sex chromosomes, there can be 3 variants of triploidy: 69XYY (the rarest), 69, XXX and 69, XXY (the most common). Analysis of sex chromatin shows that with configuration 69, XXX, most often only one clump of chromatin is detected, and with configuration 69, XXY, most often no sex chromatin is detected.

The figure below illustrates the various mechanisms leading to the development of triploidy (diandry, digyny, dispermy). Using special methods (chromosomal markers, histocompatibility antigens), it was possible to establish the relative role of each of these mechanisms in the development of triploidy in the embryo. It turned out that in 50 cases of observations, triploidy was a consequence of digyny in 11 cases (22%), diandry or dispermia - in 20 cases (40%), dispermia - in 18 cases (36%).

Tetraploidy

Tetraploidy occurs in approximately 5% of cases of quantitative chromosomal aberrations. The most common tetraploidies are 92, XXXX. Such cells always contain 2 clumps of sex chromatin. In cells with tetraploidy 92, XXYY, sex chromatin is never visible, but 2 fluorescent Y chromosomes are detected in them.

Double aberrations

The high frequency of chromosomal abnormalities in the miscarriage material explains the high frequency of combined abnormalities in the same embryo. In contrast, combined anomalies are extremely rare in newborns. Typically, in such cases, combinations of sex chromosome abnormalities and autosomal abnormalities are observed.

Due to the higher frequency of autosomal trisomies in the material of miscarriages, with combined chromosomal abnormalities in abortions, double autosomal trisomies most often occur. It is difficult to say whether such trisomies are associated with a double “non-disjunction” in the same gamete, or with the meeting of two abnormal gametes.

The frequency of combinations of different trisomies in the same zygote is random, which suggests that the appearance of double trisomies is independent of each other.

The combination of two mechanisms leading to the appearance of double anomalies helps explain the appearance of other karyotype anomalies that occur during miscarriages. “Non-disjunction” during the formation of one of the gametes in combination with the mechanisms of polyploidy formation explains the appearance of zygotes with 68 or 70 chromosomes. Failure of the first mitotic division in such a zygote with trisomy can lead to karyotypes such as 94,XXXX,16+,16+.

Structural chromosomal abnormalities

According to classical studies, the frequency of structural chromosomal aberrations in miscarriage material is 4-5%. However, many studies were done before the widespread use of G-banding. Modern research indicates a higher frequency of structural chromosomal abnormalities in abortions. The most different types structural abnormalities. In about half of the cases these anomalies are inherited from parents, in about half of the cases they arise de novo.

The influence of chromosomal abnormalities on the development of the zygote

Chromosomal abnormalities of the zygote usually appear in the first weeks of development. Determining the specific manifestations of each anomaly is associated with a number of difficulties.

In many cases, establishing the gestational age when analyzing material from miscarriages is extremely difficult. Typically, the period of conception is considered to be the 14th day of the cycle, but women with miscarriage often experience cycle delays. In addition, it can be very difficult to establish the date of “death” of the fertilized egg, since a lot of time can pass from the moment of death to the miscarriage. In the case of triploidy, this period can be 10-15 weeks. Application hormonal drugs may lengthen this time even further.

Taking into account these reservations, we can say that the shorter the gestational age at the time of death of the fertilized egg, the higher the frequency of chromosomal aberrations. According to research by Creasy and Lauritsen, with miscarriages before 15 weeks of pregnancy, the frequency of chromosomal aberrations is about 50%, with a period of 18 - 21 weeks - about 15%, with a period of more than 21 weeks - about 5-8%, which approximately corresponds to the frequency of chromosomal aberrations in studies of perinatal mortality.

Phenotypic manifestations of some lethal chromosomal aberrations

Monosomy X usually stop developing by 6 weeks after conception. In two thirds of cases, the fetal bladder measuring 5-8 cm does not contain an embryo, but there is a cord-like formation with elements of embryonic tissue, remnants of the yolk sac, the placenta contains subamniotic thrombi. In one third of cases, the placenta has the same changes, but a morphologically unchanged embryo is found that died at the age of 40-45 days after conception.

With tetraploidy development stops by 2-3 weeks after conception; morphologically, this anomaly is characterized by an “empty amniotic sac”.

For trisomies Various types of developmental abnormalities are observed, depending on which chromosome is the extra one. However, in the overwhelming majority of cases, development stops at very early stages, and no elements of the embryo are detected. This classic case"empty fertilized egg" (anembryonia).

Trisomy 16, a very common anomaly, is characterized by the presence of a small fetal egg with a diameter of about 2.5 cm, in the chorionic cavity there is a small amniotic sac of about 5 mm in diameter and an embryonic rudiment measuring 1-2 mm. Most often, development stops at the embryonic disc stage.

With some trisomies, for example, with trisomies 13 and 14, it is possible for the embryo to develop before about 6 weeks. The embryos are characterized by a cyclocephalic head shape with defects in the closure of the maxillary colliculi. Placentas are hypoplastic.

Fetuses with trisomy 21 (Down syndrome in newborns) do not always have developmental anomalies, and if they do, they are minor and cannot cause their death. Placentas in such cases are poor in cells and appear to have stopped developing at an early stage. The death of the embryo in such cases appears to be a consequence of placental insufficiency.

Skids. A comparative analysis of cytogenetic and morphological data allows us to distinguish two types of moles: classic hydatidiform moles and embryonic triploid moles.

Miscarriages with triploidy have a clear morphological picture. This is expressed in a combination of complete or (more often) partial cystic degeneration of the placenta and amniotic sac with an embryo, the size of which (the embryo) is very small compared to the relatively large amniotic sac. Histological examination shows not hypertrophy, but hypotrophy of the vesicularly changed trophoblast, forming microcysts as a result of numerous invaginations.

Against, classic mole does not affect either the amniotic sac or the embryo. The vesicles reveal excessive formation of syncytiotrophoblast with pronounced vascularization. Cytogenetically, most classic hydatidiform moles have a karyotype of 46.XX. The studies carried out made it possible to establish the chromosomal abnormalities involved in the formation of hydatidiform mole. The 2 X chromosomes in a classic hydatidiform mole have been shown to be identical and of paternal origin. The most likely mechanism for the development of hydatidiform mole is true androgenesis, which occurs as a result of fertilization of an egg by a diploid sperm resulting from a failure of the second meiotic division and subsequent complete exclusion of the chromosomal material of the egg. From the point of view of pathogenesis, such chromosomal disorders are close to disorders in triploidy.

Estimating the frequency of chromosomal abnormalities at the time of conception

You can try to calculate the number of zygotes with chromosomal abnormalities at conception, based on the frequency of chromosomal abnormalities found in miscarriage material. However, first of all, it should be noted that the striking similarity of the results of studies of miscarriage material conducted in different parts of the world suggests that chromosomal abnormalities at the time of conception are a very characteristic phenomenon in human reproduction. In addition, it can be stated that the least common anomalies (for example, trisomy A, B and F) are associated with arrest of development at very early stages.

Analysis of the relative frequency of various anomalies that occur during chromosome nondisjunction during meiosis allows us to draw the following important conclusions:

1. The only monosomy found in the miscarriage material is monosomy X (15% of all aberrations). On the contrary, autosomal monosomies are practically not found in the material of miscarriages, although theoretically there should be as many of them as autosomal trisomies.

2. In the group of autosomal trisomies, the frequency of trisomies of different chromosomes varies significantly. Studies using the G-banding method have shown that all chromosomes can be involved in trisomy, but some trisomies are much more common, for example, trisomy 16 occurs in 15% of all trisomies.

From these observations we can conclude that, most likely, the frequency of nondisjunction of different chromosomes is approximately the same, and the different frequency of anomalies in the miscarriage material is due to the fact that individual chromosomal aberrations lead to arrest of development at very early stages and are therefore difficult to detect.

These considerations allow us to approximately calculate the actual frequency of chromosomal abnormalities at the time of conception. Calculations made by Bouet showed that every second conception produces a zygote with chromosomal aberrations.

These figures reflect the average frequency of chromosomal aberrations during conception in the population. However, these figures can vary significantly between different married couples. For some couples, the risk of developing chromosomal aberrations at the time of conception is significantly higher than the average risk in the population. In such married couples, short-term miscarriage occurs much more often than in other married couples.

These calculations are confirmed by other studies conducted using other methods:

1. Classical research by Hertig
2. Determination of the level of chorionic hormone (CH) in the blood of women after 10 days of conception. Often this test turns out to be positive, although menstruation comes on time or with a slight delay, and the woman does not subjectively notice the onset of pregnancy (“biochemical pregnancy”)
3. Chromosomal analysis of material obtained during induced abortions showed that during abortions at a period of 6-9 weeks (4-7 weeks after conception) the frequency of chromosomal aberrations is approximately 8%, and during induced abortions at a period of 5 weeks (3 weeks after conception ) this frequency increases to 25%.
4. Chromosome nondisjunction has been shown to be very common during spermatogenesis. So Pearson et al. found that the probability of nondisjunction during spermatogenesis for the 1st chromosome is 3.5%, for the 9th chromosome - 5%, for the Y chromosome - 2%. If other chromosomes have a probability of nondisjunction of approximately the same order, then only 40% of all sperm have a normal chromosome set.

Experimental models and comparative pathology

Frequency of developmental arrest

Although differences in the type of placentation and number of fetuses make it difficult to compare the risk of failure to develop a pregnancy in domestic animals and in humans, certain analogies can be traced. In domestic animals, the percentage of lethal conceptions ranges between 20 and 60%.

Studies of lethal mutations in primates have yielded figures comparable to those in humans. Of 23 blastocysts isolated from preconception macaques, 10 had gross morphological abnormalities.

Frequency of chromosomal abnormalities

Only experimental studies make it possible to carry out chromosomal analysis of zygotes at different stages of development and estimate the frequency of chromosomal aberrations. Ford's classic studies found chromosomal aberrations in 2% of mouse embryos between 8 and 11 days after conception. Further studies showed that this is too advanced a stage of embryo development, and that the frequency of chromosomal aberrations is much higher (see below).

Impact of chromosomal aberrations on development

A major contribution to elucidating the scale of the problem was made by the research of Alfred Gropp from Lübeck and Charles Ford from Oxford, carried out on the so-called “tobacco mice” ( Mus poschiavinus). Crossing such mice with normal mice produces a wide range of triploidies and monosomies, making it possible to evaluate the impact of both types of aberrations on development.

Professor Gropp's data (1973) are given in the table.

Distribution of euploid and aneuploid embryos in hybrid mice
Stage of development	Day	Karyotype			Total
		Monosomy	Euploidy	Trisomy
Before implantation	4	55	74	45	174
After implantation	7	3	81	44	128
	9—15	3	239	94	336
	19		56	2	58
Live mice			58		58

These studies made it possible to confirm the hypothesis about the equal probability of the occurrence of monosomies and trisomies during conception: autosomal monosomies occur with the same frequency as trisomies, but zygotes with autosomal monosomies die before implantation and are not detected in the material of miscarriages.

In trisomies, the death of embryos occurs at later stages, but not a single embryo in autosomal trisomies in mice survives to birth.

Research by Gropp's group has shown that, depending on the type of trisomy, embryos die at different dates: with trisomy 8, 11, 15, 17 - before the 12th day after conception, with trisomy 19 - closer to the due date.

Pathogenesis of developmental arrest due to chromosomal abnormalities

A study of the material from miscarriages shows that in many cases of chromosomal aberrations, embryogenesis is sharply disrupted, so that the elements of the embryo are not detected at all (“empty fertilized eggs”, anembryony) (cessation of development before 2-3 weeks after conception). In other cases, it is possible to detect elements of the embryo, often unformed (development stops up to 3-4 weeks after conception). In the presence of chromosomal aberrations, embryogenesis is often either impossible or severely disrupted from the earliest stages of development. The manifestations of such disorders are expressed to a much greater extent in the case of autosomal monosomies, when the development of the zygote stops in the first days after conception, but in the case of trisomy of chromosomes, which are of key importance for embryogenesis, development also stops in the first days after conception. For example, trisomy 17 is found only in zygotes that have stopped developing at the earliest stages. In addition, many chromosomal abnormalities are generally associated with a reduced ability to divide cells, as studies of cultures of such cells show in vitro.

In other cases, development can continue up to 5-6-7 weeks after conception, in rare cases - longer. As Philip's research has shown, in such cases, the death of the fetus is explained not by a violation of embryonic development (detected defects in themselves cannot be the cause of the death of the embryo), but by a violation of the formation and functioning of the placenta (the stage of fetal development is ahead of the stage of placenta formation.

Studies of placental cell cultures with various chromosomal abnormalities have shown that in most cases, placental cell division occurs much more slowly than with a normal karyotype. This largely explains why newborns with chromosomal abnormalities usually have low birth weight and reduced placental weight.

It can be assumed that many developmental disorders due to chromosomal aberrations are associated precisely with a reduced ability of cells to divide. In this case, a sharp dissynchronization of the processes of embryo development, placental development and induction of cell differentiation and migration occurs.

Insufficient and delayed formation of the placenta can lead to malnutrition and hypoxia of the embryo, as well as to a decrease in hormonal production of the placenta, which can be an additional reason for the development of miscarriages.

Studies of cell lines for trisomies 13, 18 and 21 in newborns have shown that cells divide more slowly than with a normal karyotype, which is manifested in a decrease in cell density in most organs.

The mystery is why, with the only autosomal trisomy compatible with life (trisomy 21, Down syndrome), in some cases there is a delay in the development of the embryo in the early stages and spontaneous miscarriage, and in others there is unimpaired development of pregnancy and the birth of a viable child. A comparison of cell cultures of material from miscarriages and full-term newborns with trisomy 21 showed that differences in the ability of cells to divide in the first and second cases differ sharply, which may explain the different fate of such zygotes.

Causes of quantitative chromosomal aberrations

Studying the causes of chromosomal aberrations is extremely difficult, primarily due to the high frequency, one might say, the universality of this phenomenon. It is very difficult to correctly collect a control group of pregnant women; disorders of spermatogenesis and oogenesis are very difficult to study. Despite this, some etiological factors for increasing the risk of chromosomal aberrations have been identified.

Factors directly related to parents

The influence of maternal age on the likelihood of having a child with trisomy 21 suggests a possible influence of maternal age on the likelihood of lethal chromosomal aberrations in the embryo. The table below shows the relationship between maternal age and the karyotype of miscarriage material.

Average age of mother at chromosomal aberrations of abortions
Karyotype	Number of observations	Average age
Normal	509	27,5
Monosomy X	134	27,6
Triploidy	167	27,4
Tetraploidy	53	26,8
Autosomal trisomies	448	31,3
Trisomy D	92	32,5
Trisomy E	157	29,6
Trisomy G	78	33,2

As the table shows, there was no association between maternal age and spontaneous miscarriages associated with monosomy X, triploidy, or tetraploidy. An increase in the average maternal age was noted for autosomal trisomies in general, but different figures were obtained for different groups of chromosomes. However, the total number of observations in groups is not enough to confidently judge any patterns.

Maternal age is more associated with increased risk miscarriages with trisomies of acrocentric chromosomes of groups D (13, 14, 15) and G (21, 22), which also coincides with the statistics of chromosomal aberrations in stillbirths.

For some cases of trisomy (16, 21), the origin of the extra chromosome has been determined. It turned out that maternal age is associated with an increased risk of trisomy only in the case of maternal origin of the extra chromosome. Paternal age was not found to be associated with an increased risk of trisomy.

In light of animal studies, there have been suggestions of a possible connection between gamete aging and delayed fertilization and the risk of chromosomal aberrations. Gamete aging refers to the aging of sperm in the female reproductive tract, the aging of the egg either as a result of overmaturity inside the follicle or as a result of a delay in the release of the egg from the follicle, or as a result of tubal overmaturity (delayed fertilization in the tube). Most likely, similar laws operate in humans, but reliable evidence of this has not yet been obtained.

Environmental factors

The likelihood of chromosomal aberrations at conception has been shown to increase in women exposed to ionizing radiation. A connection is assumed between the risk of chromosomal aberrations and the action of other factors, in particular chemical ones.

Conclusion

1. Not every pregnancy can be maintained for a short period. In a large percentage of cases, miscarriages are caused by chromosomal abnormalities in the fetus, and it is impossible to give birth to a live child. Hormonal treatment can delay the miscarriage, but cannot help the fetus survive.

2. Increased instability of the genome of spouses is one of the causative factors of infertility and miscarriage. Cytogenetic examination with analysis for chromosomal aberrations helps to identify such married couples. In some cases of increased genomic instability, specific antimutagenic therapy may help increase the likelihood of conception healthy child. In other cases, donor insemination or the use of a donor egg is recommended.

3. In case of miscarriage caused by chromosomal factors, the woman’s body can “remember” the unfavorable immunological response to the fertilized egg (immunological imprinting). In such cases, a rejection reaction may also develop for embryos conceived after donor insemination or using a donor egg. In such cases, a special immunological examination is recommended.

(trisomy 18, or trisomy 19) is a rare genetic disease in which either part of the human chromosome 18 or an entire pair of chromosomes is duplicated. People with such a defect usually have low birth weight, low intelligence, and multiple developmental defects, including pronounced microcephaly, malformed low-set ears, a protruding nape, and characteristic unique facial features. In 60 cases out of 100, embryos with this genetic defect, die.

Edwards syndrome is more common in women than in men. almost 80% of patients - these are women. A child with Edwards syndrome can appear in women over 30 years of age (although there are exceptions, which are much less common). Only 12% of all children born with this defect survive to the age at which the child’s mental capabilities can already be assessed. All surviving babies, as a rule, have serious defects at birth, so they do not live long.

Causes of Edwards syndrome

The causes of Edwards syndrome are not fully understood. This syndrome is associated with a large number of disorders and defects related to the brain, heart, craniofacial structure, stomach and kidneys.

In the human body, each cell contains 23 pairs, inherited from its parents. And in each reproductive cell there is the same number of sets: in men these are XY sperm, in women these are XX eggs. When a fertilized egg divides under the influence of certain factors, a mutation occurs, as a result of which another pair appears in the 18th pair of chromosomes - an additional one. This is the cause of the occurrence and development of Edwards syndrome.

Instead of two copies, children with this syndrome have three copies of chromosomes. This mutation is called trisomy. The name also contains the number of the pair of chromosomes in which the mutation occurred - trisomy 18. This option is a complete trisomy, which is very difficult and has all the signs of the disease.

It must be said that there are two more types of mutations. Of all children with Edwards syndrome, 2% of children have a translocation in pair 18. This means that only part of the extra chromosome appeared in the 18th pair of chromosomes. 3% of children have mosaic trisomy - when the extra chromosome is not present in all cells of the body.

Chromosomal diseases are a large group of congenital hereditary diseases. They occupy one of the leading places in the structure of human hereditary pathology. According to cytogenetic studies among newborn children, the frequency of chromosomal pathology is 0.6-1.0%. The highest frequency of chromosomal pathology (up to 70%) was recorded in the material of early spontaneous abortions.

Consequently, most chromosomal abnormalities in humans are incompatible even with the early stages of embryogenesis. Such embryos are eliminated during implantation (7-14 days of development), which clinically manifests itself as a delay or loss of the menstrual cycle. Some embryos die soon after implantation (early miscarriages). Relatively few variants of numerical chromosome abnormalities are compatible with postnatal development and lead to chromosomal diseases (Kuleshov N.P., 1979).

Chromosomal diseases appear as a result of genomic damage that occurs during gamete maturation, during fertilization, or in the early stages of zygote cleavage. All chromosomal diseases can be divided into three large groups: 1) associated with ploidy disorders; 2) caused by a violation of the number of chromosomes; 3) associated with changes in chromosome structure.

Chromosome abnormalities associated with ploidy disturbances are represented by triploidy and tetraploidy, which are found mainly in the material of spontaneous abortions. There have been only isolated cases of the birth of triploid children with severe developmental defects incompatible with normal life activities. Triploidy can occur both as a result of digeny (fertilization of a diploid egg by a haploid sperm), and as a result of diandry (the reverse version) and dispermia (fertilization of a haploid egg by two sperm).

Chromosomal diseases associated with a violation of the number of individual chromosomes in a set are represented by either a whole monosomy (one of two homologous chromosomes is normal) or a whole trisomy (three homologs). Whole monosomy in live births occurs only on chromosome X (Shereshevsky-Turner syndrome), since most monosomies on the remaining chromosomes of the set (Y chromosome and autosomes) die at very early stages of intrauterine development and are quite rare even in material from spontaneously aborted embryos and fetuses.

It should be noted, however, that monosomy X is also detected with a fairly high frequency (about 20%) in spontaneous abortions, which indicates its high prenatal lethality, amounting to over 99%. The reason for the death of embryos with monosomy X in one case and the live birth of girls with Shereshevsky-Turner syndrome in another is unknown. There are a number of hypotheses to explain this fact, one of which associates the increased death of X-monosomal embryos with a higher probability of manifestation of recessive lethal genes on a single X chromosome.

Whole trisomies in live births occur on chromosomes X, 8, 9, 13, 14, 18, 21 and 22. The highest frequency of chromosomal abnormalities - up to 70% - is observed in early abortions. Trisomies on chromosomes 1, 5, 6, 11 and 19 are rare even in abortive material, which indicates the great morphogenetic significance of these chromosomes. More often, entire mono- and trisomies for a number of chromosomes of the set occur in mosaic condition both in spontaneous abortions and in children with MVD (multiple congenital malformations).

Chromosomal diseases associated with disruption of chromosome structure represent a large group of partial mono- or trisomy syndromes. As a rule, they arise as a result of structural rearrangements of chromosomes present in the germ cells of the parents, which, due to disruption of recombination processes in meiosis, lead to the loss or excess of chromosome fragments involved in the rearrangement. Partial mono- or trisomies are known for almost all chromosomes, but only some of them form clearly diagnosable clinical syndromes.

The phenotypic manifestations of these syndromes are more polymorphic than those of whole mono- and trisomy syndromes. This is partly due to the fact that the size of chromosome fragments and, consequently, their gene composition can vary in each individual case, and also because if one of the parents has a chromosomal translocation, partial trisomy on one chromosome in the child can be combined with partial monosomy on the other.

Clinical and cytogenetic characteristics of syndromes associated with numerical chromosome abnormalities.

1. Patau syndrome (trisomy 13). First described in 1960. Cytogenetic variants can be different: whole trisomy 13 (non-disjunction of chromosomes in meiosis, in 80% of cases in the mother), translocation variant (Robertsonian translocations D/13 and G/13), mosaic forms, additional ring chromosome 13, isochromosomes.

Patients have severe structural anomalies: cleft soft and hard palate, cleft lip, underdeveloped or absent eyes, malformed low-set ears, deformed bones of the hands and feet, numerous disorders of the internal organs, for example, congenital heart defects (septal defects and large vessels) ). Deep idiocy. The life expectancy of children is less than a year, usually 2-3 months. Population frequency is 1 in 7800.

2. Edwards syndrome (trisomy 18). Described in 1960. Cytogenetically, in most cases it is represented by the whole trisomy 18 (a gametic mutation of one of the parents, usually on the maternal side). In addition, mosaic forms are also found, and translocations are observed very rarely. The critical segment responsible for the formation of the main symptoms of the syndrome is the 18q11 segment. No clinical differences were found between cytogenetic forms. Patients have a narrow forehead and a wide protruding back of the head, very low-set deformed ears, underdevelopment of the lower jaw, wide and short fingers. From

internal defects, combined defects should be noted of cardio-vascular system, incomplete intestinal rotation, kidney malformations, etc. Children with Edwards syndrome have low birth weight. There is a delay in psychomotor development, idiocy and imbecility. Life expectancy is up to a year - 2-3 months. Population frequency 1 in 6500.

4.

Down syndrome (trisomy 21). It was first described in 1866 by the English physician Down. Population frequency is 1 case per 600-700 newborns. The frequency of births of children with this syndrome depends on the age of the mother and increases sharply after 35 years. Cytogenetic variants are very diverse, but around Fig. 15. S. Down (6) above (8) below

5.

95% of cases are represented by simple trisomy of chromosome 21, as a result of chromosome nondisjunction in meiosis in the parents. The presence of polymorphic molecular genetic markers makes it possible to determine the specific parent and the stage of meiosis at which nondisjunction occurred. Despite intensive study of the syndrome, the causes of chromosome nondisjunction are still unclear. Etiologically important factors intra- and extrafollicular over-ripening of the egg, a decrease in the number or absence of chiasmata in the first division of meiosis are considered. Mosaic forms of the syndrome (2%), Robertsonian translocation variants (4%) were noted. About 50% of translocation forms are inherited from parents and 50% are mutations de novo. The critical segment responsible for the formation of the main symptoms of the syndrome is the 21q22 region.

Patients have shortened limbs, a small skull, a flat and wide nose bridge, narrow palpebral fissures with an oblique incision, an overhanging fold of the upper eyelid - epicanthus, excess skin on the neck, short limbs, transverse four-finger palmar fold (monkey groove). Among the defects of internal organs, congenital heart defects and gastrointestinal tract, which determine the life expectancy of patients. Characterized by mental retardation of moderate severity. Children with Down syndrome are often affectionate and affectionate, obedient and attentive. Their viability is reduced.

Clinical and cytogenetic characteristics of syndromes associated with sex chromosome abnormalities.

1. Shereshevsky-Turner syndrome (monosomy of the X chromosome). This is the only form of monosomy in humans that can be

detected in live births. In addition to simple monosomy on the X chromosome, which is 50%, there are mosaic forms, deletions of the long and short arms of the X chromosome, iso-X chromosomes, as well as ring X chromosomes. It is interesting to note that 45,X/46,XY mosaicism accounts for 2-5% of all patients with this syndrome and is characterized by a wide range of features: from the typical Shereshevsky-Turner syndrome to the normal male phenotype.

Population frequency is 1 in 3000 newborns. Patients are short in stature, have a barrel-shaped chest, broad shoulders, a narrow pelvis, and shortened lower limbs. A very characteristic feature is a short neck with folds of skin extending from the back of the head (sphinx neck). They experience low hair growth on the back of the head, hyperpigmentation of the skin, and decreased vision and hearing. The inner corners of the eyes are located higher than the outer ones. Congenital heart and kidney defects are common. In patients, ovarian underdevelopment is detected. Infertile. Intellectual development is within normal limits. There is some infantilism of emotions and instability of mood. The patients are quite viable.

2. Polysomy X syndrome ( Trisomy X). Cytogenetically, forms 47,XXXX, 48,XXXX and 49,XXXXXX are detected. As the number of the X chromosome increases, the degree of deviation from the norm increases. Deviations in mental development, skeletal and genital abnormalities have been described in women with tetra- and pentasomy X. Women with karyotype 47,XXX in full or mosaic form generally have normal physical and mental development, and intelligence - within the lower limit of normal. These women have a number of mild deviations in physical development, ovarian dysfunction, and premature menopause, but they can have offspring. Population frequency is 1 per 1000 newborn girls.

3. Klinefelter's syndrome. Described in 1942. Population frequency is 1 in 1000 boys. Cytogenetic variants of the syndrome can be different: 47.XXY: 48.XXYY; 48.XXXY; 49.XXXXY. Both complete and mosaic forms are noted. Patients are tall with disproportionately long limbs. In childhood they are distinguished by a fragile physique, and after 40 years they become obese. They develop an asthenic or eunuch-like body type: narrow shoulders, wide pelvis, female-type fat deposition, poorly developed

muscles, sparse facial hair. Patients have underdevelopment of the testes, lack of spermatogenesis, decreased libido, impotence and infertility. Mental retardation usually develops. IQ below 80.

4. Y-chromosome polysemy syndrome (double-Y or “extra Y chromosome”). Population frequency is 1 in 1000 boys. Cytogenetically marked complete and mosaic forms. Most individuals do not differ from healthy ones in physical and mental development. The gonads are developed normally, growth is usually high, and there are some anomalies of the teeth and skeletal system. Observed psychopathic traits: instability of emotions, antisocial behavior, tendency to aggression, homosexuality. Patients do not exhibit significant mental retardation, and some patients generally have normal intelligence. They can have normal offspring in 50% of cases.

Clinical and genetic characteristics of syndromes associated with structural rearrangements of chromosomes.

Cry of the cat syndrome (monosomy 5p). Described in 1963. Population frequency is 1 in 50,000. Cytogenetic variants vary from partial to complete deletion of the short arm of chromosome 5. For the development of the main signs of the syndrome, the 5p15 segment is of great importance. In addition to simple deletions, ring chromosome 5, mosaic forms, and translocations between the short arm of chromosome 5 (with loss of a critical segment) and another autosome have been noted.

Diagnostic signs of the disease are: microcephaly, an unusual cry or cry reminiscent of a cat's meow (especially in the first weeks after birth); anti-Mongoloid eye shape, squint, moon-shaped face, wide bridge of the nose. The ears are low set and deformed. There is a transverse palmar fold and abnormalities in the structure of the hands and fingers. Mental retardation in the imbecility stage. It should be noted that such signs as a moon-shaped face and a cat's cry smooth out with age, and microcephaly and strabismus are more clearly identified. Life expectancy depends on the severity of congenital malformations of internal organs. Most patients die in the first years of life.

Clinical and cytogenetic characteristics of syndromes and malignant neoplasms associated with microstructural abnormalities of chromosomes.

Recently, clinical cytogenetic studies have begun to rely on high-resolution methods of chromosomal analysis, which has made it possible to confirm the assumption of the existence of microchromosomal mutations, the detection of which is on the verge of the capabilities of a light microscope.

Using standard cytogenetic methods, it is possible to achieve visual resolution of chromosomes with the number of segments not exceeding 400, and using the methods of prometaphase analysis proposed by Younis in 1976, it is possible to obtain chromosomes with the number of segments up to 550-850. Minor abnormalities in the structure of chromosomes can be detected using these methods of chromosome analysis not only among patients with CFPR, but also in some unknown Mendelian syndromes and various malignant tumors. Most syndromes associated with microchromosomal abnormalities are rare - 1 case in 50,000-100,000 newborns.

Retinoblastoma. Patients with retinoblastoma, a malignant tumor of the retina, account for 0.6-0.8% of all patients with cancer. This is the first tumor for which a connection with chromosomal pathology has been established. Cytogenetically, this disease reveals a microdeletion of chromosome 13, segment 13q14. In addition to microdeletions, mosaic forms and translocation variants are also found. Several cases of translocation of a segment of chromosome 13 to the X chromosome have been described.

There was no correlation between the size of the deleted fragment and phenotypic manifestations. The disease usually begins at the age of about 1.5 years and the first signs are glowing pupils, sluggish reaction of the pupil to light, and then decreased vision up to blindness. Complications of retinoblastoma include retinal detachment and secondary glaucoma. In 1986, a tumor suppressor gene was discovered in the critical segment 13ql4 RBI, which was the first antioncogene discovered in humans.

Monogenic diseases manifested by chromosomal instability.

To date, new types of genome variability have been established, differing in frequency and mechanisms from the usual mutation process. One of the manifestations of genome instability at the cellular level is chromosomal instability. Chromosome instability is assessed by an increase in spontaneous and/or induced frequency of chromosomal aberrations and sister chromatid exchanges (SCOs). An increased frequency of spontaneous chromosomal aberrations was first shown in 1964 in patients with Fanconi anemia, and an increased frequency of SCO was found in Bloom's syndrome. In 1968, it was found that xeroderma pigmentosum, a photodermatosis in which the frequency of chromosomal aberrations induced by UV radiation is increased, is associated with a violation of the ability of cells to repair (restore) their DNA from damage caused by UV radiation.

Currently, about one and a half dozen monogenic pathological signs associated with increased chromosome fragility are known. In these diseases, there are no specific areas of chromosomal damage, but the overall frequency of chromosome aberrations increases. The molecular mechanism of this phenomenon is most often associated with defects in individual genes encoding DNA repair enzymes. Therefore, most diseases accompanied by chromosomal instability are also called DNA repair diseases. Despite the fact that these diseases are different in their clinical manifestations, all of them are characterized by an increased tendency to malignant neoplasms, signs of premature aging, neurological disorders, immunodeficiency conditions, congenital malformations, skin manifestations, mental retardation is often observed.

In addition to mutations in DNA repair genes, diseases with chromosomal instability may be based on defects in other genes that ensure genome stability. Recently, more and more evidence has been accumulating that in addition to diseases manifested by instability of chromosome structure, there are also monogenic defects leading to diseases with instability of the number of chromosomes. As such an independent group of monogenic diseases, we can distinguish rare pathological conditions that indicate the non-random, hereditarily determined nature of chromosome nondisjunction in somatic cells during embryogenesis.

During a cytogenetic study in these patients, in a small part of the cells (usually 5-20%), somatic mosaicism is detected on several chromosomes of the set at once, or one married couple may have several siblings with chromosomal mosaicism. It is assumed that such patients are “mitotic mutants” for recessive genes that control individual stages of mitosis. There is no doubt that most of these types of mutations are lethal, and surviving individuals have relatively mild forms of cell division pathology. Despite the fact that the above diseases are caused by defects in individual genes, performing a cytogenetic study in patients with suspected this pathology will help the doctor in the differential diagnosis of these conditions.

Diseases with instability of chromosome structure:

Bloom's syndrome. Described in 1954. The main diagnostic features are: low birth weight, growth retardation, narrow face with butterfly-shaped erythema, massive nose, immunodeficiency, and a tendency to malignancy. Mental retardation is not observed in all cases. Cytogenetically, it is characterized by an increase in the number of sister chromatid exchanges (SEC) per cell to 120-150, although normally their number does not exceed 6-8 exchanges per 1 cell. In addition, chromatid breaks are detected with high frequency, as well as dicentrics, rings and chromosomal fragments. Patients have mutations in the DNA ligase 1 gene, localized on chromosome 19 - 19q13.3, but the Bloom syndrome gene is mapped to the 15q26.1 segment.

Fanconi anemia . A disease with an autosomal recessive type of inheritance. Described in 1927. Main diagnostic signs: hypoplasia radius and thumb, delayed growth and development, hyperpigmentation of the skin in the groin and axillary areas. In addition, bone marrow hypoplasia, a tendency to leukemia, and hypoplasia of the external genitalia are noted. Cytogenetically it is characterized by multiple chromosomal aberrations - chromosome breaks and chromatid exchanges. This is a genetically heterogeneous disease, i.e. a clinically similar phenotype is caused by mutations in different genes. There are at least 7 forms of this disease: A - the gene is localized in the 16q24.3 segment; B - gene localization is unknown; C - 9q22.3; D - Зр25.3; E - 6р22; F - 11р15; G (MIM 602956) - 9р13. The most common form is A - about 60% of patients.

Werner syndrome (premature aging syndrome). A disease with an autosomal recessive type of inheritance. Described in 1904. The main diagnostic signs are: premature graying and baldness, atrophy of subcutaneous fat and muscle tissue, cataracts, early atherosclerosis, endocrine pathology (diabetes mellitus). Characterized by infertility, high voice, and a tendency to malignant neoplasms. Patients die at the age of 30-40 years. Cytogenetically, it is characterized by cell clones with different chromosomal translocations (mosaicism for various translocations). The disease gene is localized in the 8p11-p12 segment.

Fragile X syndrome.

As a rule, chromosome breaks or chromatid gaps that occur with increased frequency in certain specific chromosomal segments (the so-called fragile regions or fragile sites of chromosomes) are not associated with any diseases. However, there is an exception to this rule. In 1969, in patients with a syndrome accompanied by mental retardation, the presence of a specific cytogenetic marker was discovered - in the distal part of the long arm of the X chromosome in the Xq27.3 segment, a chromatid break or gap is recorded in individual cells.

Later it was shown that the first clinical description of a family with a syndrome in which mental retardation is the leading clinical sign was described back in 1943 by English doctors P. Martin and Y. Bell. Martin-Bell syndrome or fragile X syndrome is characterized by a fragile X chromosome in the Xq27.3 segment, which is detected under special cell culture conditions in a folic acid-deficient environment.

The fragile site in this syndrome is designated FRAXA. The main diagnostic signs of the disease are: mental retardation, a wide face with acromegaly features, large protruding ears, autism, hypermobility, poor concentration, speech defects, more pronounced in children. Connective tissue abnormalities with joint hyperextensibility and mitral valve defect are also noted. Only 60% of men with a fragile X chromosome have a relatively full range of clinical signs, 10% of patients have no facial anomalies, 10% have only mental retardation without other signs.

Fragile X syndrome is interesting for its unusual inheritance and high population frequency (1 in 1500-3000). The unusual nature of inheritance is that only 80% of male carriers of the mutant gene have signs of the disease, and the remaining 20% ​​are both clinically and cytogenetically normal, although after passing the mutation to their daughters they may have affected grandchildren. These men are called transmitters, i.e. transmitters of an unexpressed mutant gene that becomes expressed in subsequent generations.

In addition, there are two types of women - heterozygous carriers of the mutant gene:

a) daughters of male transmitters who do not have symptoms of the disease and in whom the fragile X chromosome is not detected;

b) granddaughters of normal male transmitters and sisters of affected males, who show clinical signs of the disease in 35% of cases.

Thus, the gene mutation in Martin-Bell syndrome exists in two forms, differing in their penetrance: the first form is a phenotypically silent premutation, which turns into a complete mutation (the second form) when passing through female meiosis. A clear dependence of the development of mental retardation on the position of the individual in the pedigree was discovered. At the same time, the phenomenon of anticipation is clearly visible - a more severe manifestation of the disease in subsequent generations.

The molecular mechanism of the mutation became clear in 1991, when the gene responsible for the development of of this disease. The gene was named FMR1 (English - Fragile site Mental Retardation 1 - a fragile section of the chromosome associated with the development of type 1 mental retardation). It was found that the clinical manifestations and cytogenetic instability in the Xq27.3 locus are based on a multiple increase in the first exon of the FMR-1 gene of a simple trinucleotide repeat CGG.

In normal people, the number of these repeats in the X chromosome ranges from 5 to 52, and in patients their number is 200 or more. This phenomenon of a sharp, abrupt change in the number of CGG repeats in patients is called expansion of the number of trinucleotide repeats: It has been shown that the expansion of CGG repeats significantly depends on the sex of the descendant; it is noticeably increased when the mutation is transmitted from mother to son. It is important to note that nucleotide repeat expansion is a postzygotic event and occurs very early in embryogenesis.

Edwards syndrome or trisomy 18 is a severe congenital disease caused by chromosomal abnormalities. It is one of the most common pathologies in this category ( second in frequency only to Down syndrome). The disease is characterized by numerous developmental disorders various organs and systems. The prognosis for the child is usually unfavorable, but much depends on the care that the parents are able to provide.

The worldwide prevalence of Edwards syndrome varies from 0.015 to 0.02%. There is no clear dependence on area or race. Statistically, girls get sick 3-4 times more often than boys. A scientific explanation for this proportion has not yet been identified. However, a number of factors have been noted that may increase the risk of this pathology.

Like other chromosomal mutations, Edwards syndrome is, in principle, an incurable disease. The most modern methods of treatment and care can only keep the child alive and contribute to certain progress in his development. There are no uniform recommendations for the care of such children due to the huge variety of possible disorders and complications.

Interesting Facts

• A description of the main symptoms of this disease was made at the beginning of the 20th century.
• Until the mid-1900s, it was not possible to collect sufficient information about this pathology. Firstly, this required an appropriate level of technology development, which would make it possible to detect the extra chromosome. Secondly, most children died in the first days or weeks of life due to the low level of medical care.
• The first complete description of the disease and its underlying cause ( appearance of an extra 18th chromosome) was made only in 1960 by the doctor John Edward, after whom the new pathology was then named.
• The real incidence of Edwards syndrome is 1 case in 2.5 - 3 thousand conceptions ( 0,03 – 0,04% ), however the official data is much lower. This is explained by the fact that almost half of the embryos with this anomaly do not survive and the pregnancy ends in spontaneous abortion or intrauterine death of the fetus. Detailed diagnosis of the cause of miscarriage is rarely carried out.
• Trisomy is a variant of a chromosomal mutation in which a person’s cells contain not 46, but 47 chromosomes. There are only 3 syndromes in this group of diseases. In addition to Edwards syndrome, these are Down syndromes ( trisomy 21 chromosome) and Patau ( trisomy 13 chromosome). In the presence of other additional chromosomes, the pathology is incompatible with life. Only in these three cases is the birth of a living child possible and its further ( albeit slow) growth and development.

Causes of genetic pathology

Edwards syndrome is genetic disease, which is characterized by the presence of an additional chromosome in the human genome. To understand the reasons that cause the visible manifestations of this pathology, it is necessary to find out what the chromosomes themselves and the genetic material as a whole are.

Each human cell has a nucleus, which is responsible for storing and processing genetic information. The nucleus contains 46 chromosomes ( 23 pairs), which are a multiply packaged DNA molecule ( Deoxyribonucleic acid). This molecule contains certain sections called genes. Each gene is the prototype of a specific protein in the human body. If necessary, the cell reads information from this prototype and produces the corresponding protein. Gene defects lead to the production of abnormal proteins, which are responsible for the occurrence of genetic diseases.

A chromosome pair consists of two identical DNA molecules ( one is paternal, the other is maternal), which are interconnected by a small bridge ( centromere). The place of adhesion of two chromosomes in a pair determines the shape of the entire connection and its appearance under a microscope.

All chromosomes store different genetic information (about different proteins) and are divided into the following groups:

• group A includes 1 – 3 pairs of chromosomes, which are large in size and X-shaped;
• group B includes 4–5 pairs of chromosomes, which are also large, but the centromere lies further from the center, which is why the shape resembles the letter X with the center shifted down or up;
• group C includes 6–12 pairs of chromosomes, which in shape resemble the chromosomes of group B, but are inferior to them in size;
• group D includes 13 - 15 pairs of chromosomes, which are characterized by medium size and the location of the centromere at the very end of the molecules, which gives it a resemblance to the letter V;
• group E includes 16–18 pairs of chromosomes, which are characterized by small size and mid-location of the centromere ( letter X shape);
• group F includes 19–20 chromosome pairs, which are somewhat smaller than group E chromosomes and similar in shape;
• group G includes 21–22 pairs of chromosomes, which are characterized by a V-shape and very small size.

The above 22 pairs of chromosomes are called somatic or autosomes. In addition, there are sex chromosomes, which make up the 23rd pair. They are not similar in appearance, so each of them is designated separately. The female sex chromosome is designated X and is similar to group C. The male sex chromosome is designated Y and is similar in shape and size to group G. If a child has both chromosomes female ( type XX), then a girl is born. If one of the sex chromosomes is female and the other is male, then a boy is born ( type XY). The chromosome formula is called a karyotype and can be designated as follows - 46,XX. Here the number 46 denotes the total number of chromosomes ( 23 pairs), and XX is the formula of sex chromosomes, which depends on gender ( The example shows the karyotype of a normal woman).

Edwards syndrome refers to the so-called chromosomal diseases, when the problem is not a gene defect, but a defect in the entire DNA molecule. To be more precise, the classic form of this disease involves the presence of an extra 18th chromosome. The karyotype in such cases is designated as 47,XX, 18+ ( for girl) and 47,ХY, 18+ ( for boy). The last digit indicates the number of the additional chromosome. Excess genetic information in cells leads to the appearance of corresponding manifestations of the disease, which are collectively called “Edwards syndrome”. Availability of additional ( third) chromosome number 18 gave another ( more scientific) the name of the disease is trisomy 18.

Depending on the form of the chromosomal defect, three types of this disease are distinguished:

• Full trisomy 18. The full or classic form of Edwards syndrome involves all cells in the body having an extra chromosome. This variant of the disease occurs in more than 90% of cases and is the most severe.
• Partial trisomy 18. Partial trisomy 18 is a very rare phenomenon ( no more than 3% of all cases of Edwards syndrome). With it, the cells of the body do not contain a whole additional chromosome, but only a fragment of it. This defect can be the result of improper division of genetic material, but it is very rare. Sometimes part of the eighteenth chromosome is attached to another DNA molecule ( is introduced into its structure, lengthening the molecule, or simply “clings” with the help of a bridge). Subsequent cell division leads to the fact that the body has 2 normal chromosomes number 18 and some more genes from these chromosomes ( preserved fragment of a DNA molecule). In this case, the number of birth defects will be much lower. There is an excess not of all the genetic information encoded in the 18th chromosome, but only of its part. Patients with partial trisomy 18 have a better prognosis than children with the full form, but still remain poor.
• Mosaic shape. The mosaic form of Edwards syndrome occurs in 5–7% of cases of this disease. The mechanism of its appearance differs from other species. The fact is that here the defect was formed after the fusion of the sperm and egg. Both gametes ( germ cells) initially had a normal karyotype and carried one chromosome of each species. After fusion, a cell with a normal formula of 46,XX or 46,XY was formed. There was a malfunction in the process of dividing this cell. When the genetic material was doubled, one of the fragments received an additional 18th chromosome. Thus, at a certain stage, an embryo has formed, some of the cells of which have a normal karyotype ( for example, 46,XX), and part is a karyotype of Edwards syndrome ( 47,XX, 18+). The proportion of pathological cells never exceeds 50%. Their number depends on at what stage of division of the initial cell the failure occurred. The later this happens, the lower the proportion of defective cells will be. The form got its name due to the fact that all the cells of the body represent a kind of mosaic. Some of them are healthy, and some have severe genetic pathology. In this case, there is no pattern in the distribution of cells in the body, that is, all defective cells cannot be localized in only one place so that they can be removed. General state The patient is better off than with the classic form of trisomy 18.

The presence of an extra chromosome in the human genome presents many problems. The fact is that human cells are programmed to read genetic information and duplicate only the number of DNA molecules specified by nature. Disturbances in even the structure of one gene can lead to serious diseases. In the presence of an entire DNA molecule, multiple disorders develop even at the stage of intrauterine development before the birth of the child.

According to recent research, chromosome number 18 contains 557 genes that encode at least 289 different proteins. In percentage terms, this is approximately 2.5% of the total genetic material. The disturbances that such a large imbalance causes are very serious. An incorrect amount of proteins determines many anomalies in the development of various organs and tissues. In the case of Edwards syndrome, the bones of the skull, some parts of the nervous system, the cardiovascular and genitourinary systems are most often affected. Apparently, this is due to the fact that the genes located on this chromosome are related to the development of these particular organs and systems.

Thus, the main and only cause of Edwards syndrome is the presence of an additional DNA molecule. Most often ( in the classic form of the disease) it is inherited from one of the parents. Normally, each gamete ( sperm and egg) contain 22 unpaired somatic chromosomes, plus one sex chromosome. A woman always passes the standard set 22+X to the child, and a man can pass 22+X or 22+Y. This determines the sex of the child. The sex cells of the parents are formed by the division of ordinary cells into two sets. Normally, the mother cell is divided into two equal parts, but sometimes not all chromosomes are divided in half. If the 18th pair has not separated at the poles of the cell, then one of the eggs ( or one of the sperm) will be defective in advance. It will have not 23, but 24 chromosomes. If this particular cell is involved in fertilization, the child will receive an additional 18th chromosome.

The following factors can affect improper cell division:

• Parents' age. It has been proven that the likelihood of chromosomal abnormalities increases in direct proportion to the age of the mother. In Edwards syndrome, this relationship is less pronounced than in other similar pathologies ( for example, Down syndrome). But for women over 40 years of age, the risk of having a child with this pathology is on average 6–7 times higher. This dependence on the age of the father is observed to a much lesser extent.
• Smoking and alcohol. Bad habits such as smoking and alcohol abuse can affect reproductive system humans, affecting the division of germ cells. Thus, regular use of these substances ( as well as other narcotic drugs) increases the risk of improper distribution of genetic material.
• Taking medications. Some medications if taken incorrectly in the first trimester, they can affect the division of germ cells and provoke the mosaic form of Edwards syndrome.
• Diseases of the genital area. Previous infections with damage reproductive organs may affect proper cell division. They increase the risk of chromosomal and genetic diseases in general, although similar studies have not been conducted specifically for Edwards syndrome.
• Radiation. Exposure of the genitals to X-rays or other ionizing radiation can cause genetic mutations. Such external influences are especially dangerous during adolescence, when cell division occurs most actively. The particles that form the radiation easily penetrate tissue and subject the DNA molecule to a kind of “bombardment.” If this occurs at the time of cell division, the risk of chromosomal mutation is especially high.

In general, it cannot be said that the causes of the development of Edwards syndrome are completely known and well studied. The above factors only increase the risk of developing this mutation. It is not excluded congenital predisposition some people to the incorrect distribution of genetic material in the germ cells. For example, it is believed that a married couple who has already given birth to a child with Edwards syndrome has a 2–3% chance of having a second child with a similar pathology ( approximately 200 times higher than the average prevalence of the disease).

What do newborns with Edwards syndrome look like?

As you know, Edwards syndrome can be diagnosed before birth, but in most cases this disease is detected immediately after the birth of the child. Newborns with this pathology have a number of pronounced developmental anomalies, which sometimes allow one to immediately suspect the correct diagnosis. Confirmation is carried out later using special genetic analysis.

Newborns with Edwards syndrome have the following characteristic developmental abnormalities:

• change in the shape of the skull;
• change in the shape of the ears;
• anomalies of palate development;
• rocker foot;
• abnormal finger length;
• change in the shape of the lower jaw;
• fusion of fingers;
• abnormal development of the genital organs;
• flexor position of the hands;
• dermatoglyphic signs.

Changing the shape of the skull

A typical symptom of Edwards syndrome is dolichocephaly. This is the name of a characteristic change in the shape of the head of a newborn child, which also occurs in some other genetic diseases. In dolichocephals ( children with this symptom) longer and narrower skull. The presence of this anomaly is precisely confirmed using special measurements. Determine the ratio of the width of the skull at the level of the parietal bones to the length of the skull ( from the protrusion above the bridge of the nose to the occipital protuberance). If the resulting ratio is less than 75%, then the child is a dolichocephalic. This symptom in itself is not a serious disorder. This is just one type of skull shape that is also found in absolutely normal people. Children with Edwards syndrome in 80 - 85% of cases are pronounced dolichocephals, in whom the disproportion of the length and width of the skull can be noticed without special measurements.

Another variant of the abnormal development of the skull is the so-called microcephaly, in which the size of the head as a whole is too small compared to the rest of the body. First of all, this does not apply to the facial skull ( jaws, cheekbones, eye sockets), namely the cranium in which the brain is located. Microcephaly is less common in Edwards syndrome than dolichocephaly, but it also occurs at a higher frequency than among healthy people.

Changing the shape of the ear

If dolichocephaly can be a normal variant, then the pathology of the development of the auricle in children with Edwards syndrome is much more severe. To a certain extent, this symptom is observed in more than 95% of children with the full form of this disease. In mosaic form, its frequency is slightly lower. The pinna is usually located lower than in normal people ( sometimes below eye level). The characteristic bumps of the cartilage that forms the auricle are poorly defined or absent. The lobe or tragus may also be absent ( a small protruding area of ​​cartilage in front of the auditory opening). The ear canal itself is usually narrowed, and in approximately 20–25% it is completely absent.

Anomalies of palate development

The palatine processes of the upper jaw fuse during embryonic development to form the hard palate. In children with Edwards syndrome, this process often remains incomplete. In the place where the median suture is located in normal people ( it can be felt in the middle of the hard palate with the tongue) they have a longitudinal slit.

There are several variants of this defect:

• cleft soft palate ( the back, deep part of the palate that hangs over the throat);
• partial fusion of the hard palate ( the gap does not extend throughout the entire upper jaw);
• complete non-fusion of the hard and soft palate;
• complete nonfusion of the palate and lip.

In some cases, cleft palate is bilateral. The two corners of the upper lip protruding upward are the beginning of pathological fissures. The child cannot close his mouth completely due to this defect. In severe cases, communication between the oral and nasal cavities is clearly visible ( even with your mouth closed). Front teeth may be missing or grow to the side in the future.

These developmental defects are also known as cleft palate, cleft palate, and cleft lip. All of them can occur outside of Edwards syndrome, but in children with this pathology their frequency is especially high ( almost 20% of newborns). Much more often ( up to 65% of newborns) have another feature known as high or gothic skies. It can be classified as a normal variant, since it also occurs in healthy people.

The presence of a cleft palate or upper lip does not confirm Edwards syndrome. This malformation can occur with a fairly high frequency and independently without concomitant disorders from other organs and systems. To correct this anomaly, there are a number of standard surgical interventions.

Rocking foot

This is the name of a characteristic change in the foot that occurs mainly as part of Edwards syndrome. Its frequency in this disease reaches 75%. The defect consists of an incorrect relationship between the talus, calcaneus and navicular bones. It is classified as flat-valgus foot deformity in children.

Externally, the foot of a newborn baby looks like this. The heel tubercle, on which the back of the foot rests, protrudes backwards. The arch may be completely absent. This is easy to notice by looking at the foot with inside. Normally, a concave line appears there, running from the heel to the base of the big toe. With a rocker foot, this line does not exist. The foot is flat or even convex. This is what makes it look like the legs of a rocking chair.

Abnormal finger length

Children with Edwards syndrome may have abnormal proportions in the length of their toes due to changes in the structure of their feet. In particular, we are talking about the thumb, which is normally the longest. In newborns with this syndrome, it is inferior in length to the second finger. This defect can only be noticed when the fingers are straightened and examined carefully. With age, as the child grows, it becomes more noticeable. Because hallux shortening occurs primarily in rocker feet, the prevalence of these symptoms in newborns is approximately the same.

In adults, shortening of the big toe does not have the same diagnostic value. Such a defect may be an individual characteristic of a healthy person or a consequence of the influence of other factors ( deformation of joints, bone diseases, wearing shoes that do not fit properly). In this regard, this sign should be considered as a possible symptom only in newborns in the presence of other developmental anomalies.

Changing the shape of the lower jaw

Changes in the shape of the lower jaw in newborns occur in almost 70% of cases. Normally, the chin in children does not protrude as much as in adults, but in patients with Edwards syndrome it is too retracted. This occurs due to underdevelopment of the lower jaw, which is called micrognathia ( microgeny). This symptom also occurs in other congenital diseases. It is not so rare to find adults with similar facial features. In the absence of concomitant pathologies, this is considered a variant of the norm, although it leads to some difficulties.


Newborns with micrognathia usually quickly develop the following problems:

• inability to keep mouth closed for long ( leakage of saliva);
• feeding difficulties;
• late development of teeth and their incorrect location.

The gap between the lower and upper jaw can be more than 1 cm, which is very large considering the size of the baby's head.

Finger fusion

Fusion of the fingers, or scientifically syndactyly, is observed in approximately 45% of newborns. Most often, this anomaly affects the toes, but syndactyly also occurs on the hands. In mild cases, the fusion is formed by a fold of skin like a short membrane. In more severe cases, fusion of bone tissue by bridges is observed.

Syndactyly occurs not only in Edwards syndrome, but also in many other chromosomal diseases. There are also cases where this developmental defect was the only one, and otherwise the patient was no different from normal children. In this regard, finger fusion is only one of the possible signs of Edwards syndrome, which helps to suspect the diagnosis, but does not confirm it.

Anomalies in the development of the genital organs

Immediately after birth, newborns with Edwards syndrome can sometimes experience abnormalities in the development of the external genitalia. As a rule, they are combined with developmental defects of the entire genitourinary apparatus, but this cannot be established without special diagnostic measures. Most frequent anomalies visible externally are underdevelopment of the penis in boys and hypertrophy ( increase in size) clitoris in girls. They occur in approximately 15–20% of cases. Somewhat less frequently, an abnormal location of the urethra may be observed ( hypospadias) or absence of testicles in the scrotum in boys ( cryptorchidism).

Flexed position of the hands

The flexor position of the hands is a special arrangement of the fingers, caused not so much by structural disorders in the hand area, but by increased muscle tone. The flexors of the fingers and hand are constantly tense, which is why the thumb and little finger seem to cover the other fingers, which are pressed against the palm. This symptom is observed in many congenital pathologies and is not characteristic specifically of Edwards syndrome. However, if a brush of this shape is detected, it is necessary to assume this pathology. With it, flexor position of the fingers is observed in almost 90% of newborns.

Dermatoglyphic signs

Many chromosomal abnormalities in newborns have characteristic dermatoglyphic changes ( abnormal patterns and folds on the skin of the palms). With Edwards syndrome, some signs can be detected in almost 60% of cases. They are important mainly for preliminary diagnosis of mosaic or partial forms of the disease. With complete trisomy 18, dermatoglyphics is not resorted to, since other, more noticeable developmental anomalies are enough to suspect Edwards syndrome.


The main dermatoglyphic signs of Edwards syndrome are:

• arches on the fingertips are located with greater frequency than in healthy people;
• skin fold between the last ( nail) and penultimate ( median) the phalanges of the fingers are absent;
• 30% of newborns have a so-called transverse groove on the palm ( monkey line, Simian line).

Special studies can reveal other deviations from the norm, but immediately after birth, without the involvement of specialized specialists, these changes are enough for doctors.

In addition to the above signs, there is also whole line possible developmental anomalies that can help in the preliminary diagnosis of Edwards syndrome. According to some data, a detailed external examination can detect up to 50 external signs. The combination of the most common symptoms presented above highly likely indicates that the child has this severe pathology. With the mosaic version of Edwards syndrome, there may not be multiple anomalies, but the presence of even one of them is an indication for a special genetic test.

What do children with Edwards syndrome look like?

Children with Edwards syndrome typically develop a variety of comorbidities as they grow older. Their symptoms begin to appear within a few weeks after birth. These symptoms may be the first manifestation of the syndrome, since with the mosaic variant, in rare cases, the disease may go unnoticed immediately after birth. Then diagnosing the disease becomes more complicated.

Most of the external manifestations of the syndrome noticed at birth remain and become more noticeable. We are talking about the shape of the skull, rocker foot, deformation of the auricle, etc. Gradually, others begin to be added to them external manifestations, which could not be noticed immediately after birth. In this case, we are talking about signs that may appear in children in the first year of life.

Children with Edwards syndrome have the following external features:

• retardation in physical development;
• clubfoot;
• abnormal muscle tone;
• abnormal emotional reactions.

Retarded physical development

The delay in physical development is explained by the child’s low birth weight ( only 2000 – 2200 g during normal pregnancy). A significant role also plays genetic defect, which does not allow all body systems to develop normally and harmoniously. The main indicators by which a child’s growth and development are assessed are greatly reduced.

You can notice a child’s lag by the following anthropometric indicators:

• child's height;
• child's weight;
• chest circumference;
• Head circumference ( this indicator may be normal or even increased, but it cannot be relied upon due to congenital deformation of the skull).

Clubfoot

Clubfoot is a consequence of deformation of the bones and joints of the feet, as well as a lack of normal control by the nervous system. Children have difficulty starting to walk ( most do not live to this stage due to congenital malformations). Externally, the presence of clubfoot can be judged by the deformation of the feet and the abnormal position of the legs at rest.

Abnormal muscle tone

Abnormal tone, which at birth causes a flexor position of the hand, begins to appear in other muscle groups as it grows. Most often, children with Edwards syndrome have reduced muscle strength, they are flaccid and lack normal tone. Depending on the nature of the damage to the central nervous system, some groups may have increased tone, which is manifested by spastic contractions of these muscles ( for example, arm flexors or leg extensors). Outwardly, this is manifested by a lack of minimal coordination of movements. Sometimes spastic contractions lead to abnormal bending of the limbs or even dislocations.

Abnormal emotional reactions

The absence or abnormal expression of any emotions is a consequence of abnormalities in the development of certain parts of the brain ( most often the cerebellum and corpus callosum). These changes lead to serious mental retardation, which is observed in all children with Edwards syndrome without exception. Outwardly, a low level of development is manifested by a characteristic “absent” facial expression and lack of emotional response to external stimuli. The child does not maintain eye contact well ( does not follow the finger moving in front of the eyes, etc.). Lack of response to sharp sounds may be a consequence of damage to both the nervous system and the hearing aid. All these signs are revealed as the child grows in the first months of life.

What do adults with Edwards syndrome look like?

In the vast majority of cases, children born with Edwards syndrome do not survive to adulthood. In the full form of this disease, when an extra chromosome is present in every cell of the body, 90% of children die before the age of 1 year due to serious abnormalities in the development of internal organs. Even with surgical correction of possible defects and high-quality care, their body is more susceptible to infectious diseases. This is also facilitated by eating disorders that occur in most children. All this explains the highest mortality rate in Edwards syndrome.

With a milder mosaic form, when only a part of the cells in the body contain an abnormal set of chromosomes, the survival rate is slightly higher. However, even in these cases, only a few patients survive to adulthood. Their appearance is determined by congenital anomalies that were present at birth ( cleft lip, deformed ear, etc.). The main symptom, present in all children without exception, is a severe mental retardation. Having lived to adulthood, a child with Edwards syndrome is profoundly mentally retarded ( IQ less than 20, which corresponds to the most severe degree of mental retardation). In general, the medical literature describes isolated cases in which children with Edwards syndrome survived to adulthood. Because of this, too little objective data has been accumulated to talk about external signs of this disease in adults.

Diagnosis of genetic pathology

Currently, there are three main stages of diagnosing Edwards syndrome, each of which includes several possible methods. Since this disease is incurable, parents should pay attention to the possibilities of these methods and take advantage of them. Most tests are carried out in special prenatal diagnostic centers, where all the necessary equipment is available to search for genetic diseases. However, even a consultation with a geneticist or neonatologist may be useful.

Diagnosis of Edwards syndrome is possible at the following stages:

• diagnosis before conception;
• diagnostics during intrauterine development;
• diagnosis after birth.

Diagnosis before conception

Diagnosis before the child is conceived is ideal option, but, unfortunately, at the present stage of development of medicine, its capabilities are very limited. Doctors can use several methods to suggest an increased likelihood of having a child with a chromosomal disorder, but nothing more. The fact is that with Edwards syndrome, in principle, disorders cannot be detected in the parents. A defective germ cell with 24 chromosomes is only one of many thousands. Therefore, it is impossible to say for sure before the moment of conception whether a child will be born with this disease.

The main diagnostic methods before conception are:

• Family history. A family history is a detailed questioning of both parents about their ancestry. The doctor is interested in any cases of hereditary ( and especially chromosomal) diseases in the family. If at least one of the parents recalls a case of trisomy ( Edwards, Down, Patau syndrome), this greatly increases the likelihood of having a sick child. However, the risk is still no more than 1%. With repeated cases of these diseases in ancestors, the risk increases many times. In essence, the analysis comes down to a consultation with a neonatologist or geneticist. In advance, parents can try to collect more detailed information about their ancestors ( preferably 3 – 4 knees). This will increase the accuracy of this method.
• Detection of risk factors. The main risk factor that objectively increases the risk of chromosomal abnormalities is maternal age. As mentioned above, for mothers after 40 years of age, the likelihood of having a child with Edwards syndrome increases many times over. According to some reports, after 45 years ( mother's age) almost every fifth pregnancy is accompanied by chromosomal pathology. Most of them end in miscarriage. Other factors include previous infectious diseases, chronic diseases, bad habits. However, their role in diagnosis is much lower. This method also does not give an exact answer to the question of whether a child with Edwards syndrome will be conceived.
• Genetic analysis of parents. If previous methods were limited to interviewing parents, then genetic analysis is a full-fledged study that requires special equipment, reagents and qualified specialists. Blood is taken from the parents, from which leukocytes are isolated in the laboratory. After treatment with special substances, chromosomes at the division stage become clearly visible in these cells. In this way, the karyotype of the parents is compiled. In the vast majority of cases it is normal ( with chromosomal abnormalities that can be detected here, the likelihood of procreation is negligible). In addition, using special markers ( fragments of molecular chains) DNA sections with defective genes can be detected. However, what will be found here is not chromosomal abnormalities, but genetic mutations that do not directly affect the likelihood of Edwards syndrome. Thus, genetic analysis of parents before conception, despite the complexity and high cost, also does not provide a clear answer regarding the prognosis for this pathology.

Diagnosis during fetal development

During the period of intrauterine development, there are several methods that can directly or indirectly confirm the presence of chromosomal pathology in the fetus. The accuracy of these methods is much higher, since doctors deal not with the parents, but with the fetus itself. Both the embryo itself and its cells with their own DNA are available for study. This stage is also called prenatal diagnosis and is the most important. At this time, you can confirm the diagnosis, warn parents about the presence of pathology and, if necessary, terminate the pregnancy. If a woman decides to give birth and the newborn is alive, then doctors will have the opportunity to prepare in advance to provide him with the necessary care.

The main research methods within the framework of prenatal diagnosis are:

• Ultrasonography ( Ultrasound) . This method is non-invasive, that is, it does not involve damage to the tissues of the mother or fetus. It is completely safe and recommended for all pregnant women as part of prenatal diagnosis ( regardless of their age or increased risk for chromosomal diseases). The standard program assumes that ultrasound should be done three times ( at 10 – 14, 20 – 24 and 32 – 34 weeks of pregnancy). If the attending physician suspects the possibility of congenital malformations, unscheduled ultrasounds may be performed. Edwards syndrome can be indicated by a lag in fetal size and weight, a large amount of amniotic fluid, and visible developmental anomalies ( microcephaly, bone deformation). These disorders are highly likely to indicate severe genetic diseases, but Edwards syndrome cannot be definitively confirmed.
• Amniocentesis. Amniocentesis is a cytological ( cellular) analysis of amniotic fluid. The doctor carefully inserts a special needle under the control of an ultrasound machine. The puncture is made in a place where there are no loops of the umbilical cord. Using a syringe, the amount of amniotic fluid required for the study is taken. The procedure can be performed in all trimesters of pregnancy, but the optimal period for diagnosing chromosomal disorders is the period after the 15th week of pregnancy. Complication rate ( up to spontaneous abortion) is up to 1%, so the procedure should not be performed in the absence of any indications. After collecting amniotic fluid, the resulting material is processed. These liquids contain cells from the surface of the baby's skin that contain samples of his DNA. They are the ones who are tested for the presence of genetic diseases.
• Cordocentesis. Cordocentesis is the most informative method of prenatal diagnosis. After anesthesia and under the control of an ultrasound machine, the doctor uses a special needle to pierce the vessel passing through the umbilical cord. Thus, a blood sample is obtained ( up to 5 ml) developing child. The technique for performing the analysis is similar to that for adults. This material can be examined with high accuracy for various genetic abnormalities. This includes fetal karyotyping. If there is an additional 18th chromosome, we can talk about confirmed Edwards syndrome. This test is recommended after the 18th week of pregnancy ( optimally 22 – 25 weeks). The frequency of possible complications after cordocentesis is 1.5 – 2%.
• Chorionic villus biopsy. The chorion is one of the embryonic membranes containing cells with the genetic information of the fetus. This study involves puncture of the uterus under anesthesia through the anterior abdominal wall. Using special biopsy forceps, a tissue sample is removed for analysis. Then a standard genetic study of the obtained material is carried out. Karyotyping is done to diagnose Edwards syndrome. The optimal period for performing a chorionic villus biopsy is considered to be 9–12 weeks of pregnancy. The complication rate is 2 – 3%. The main advantage that distinguishes it from other methods is the speed of obtaining results ( within 2 – 4 days).

Diagnosis after birth

Diagnosis of Edwards syndrome after birth is the easiest, fastest and most accurate. Unfortunately, at this moment a child with a severe genetic pathology was already born, effective treatment which does not yet exist in our time. If the disease was not detected at the stage of prenatal diagnosis ( or relevant studies have not been carried out), then suspicion of Edwards syndrome appears immediately after birth. The baby is usually full-term or even post-term, but its weight is still below average. In addition, some of the birth defects mentioned above are noteworthy. If they are noticed, genetic testing is performed to confirm the diagnosis. The child's blood is taken for analysis. However, at this stage, confirming the presence of Edwards syndrome is not the main problem.

The main task when giving birth to a child with this pathology is to detect abnormalities in the development of internal organs, which usually lead to death in the first months of life. Most people are looking for them diagnostic procedures immediately after birth.

To detect defects in the development of internal organs, they are used following methods research:

• ultrasonography abdominal cavity;
• amniocentesis, cordocentesis, etc.) pose a certain risk of complications and are not performed without special indications. The main indications are the presence of cases of chromosomal diseases in the family and the mother's age over 35 years. The diagnostic and management program for the patient at all stages of pregnancy can be changed by the attending physician as necessary.

  Prognosis for children with Edwards syndrome

  Given the multiple developmental disorders that are inherent in Edwards syndrome, the prognosis for newborns with this diagnosis is almost always unfavorable. Statistical data ( from various independent studies) they say that more than half of the children ( 50 – 55% ) do not survive to three months of age. Less than ten percent of babies manage to celebrate their first birthday. Those children who live to an older age have serious health problems and require constant care. To prolong life, complex surgical operations on the heart, kidneys or other internal organs. Correction of birth defects and ongoing skilled care are essentially the only treatment. In children with classic shape Edwards syndrome ( complete trisomy 18) there is practically no chance of a normal childhood or any long life.

  With partial trisomy or mosaic form of the syndrome, the prognosis is slightly better. The average life expectancy increases to several years. This is explained by the fact that developmental anomalies in milder forms do not lead so quickly to the death of the child. However, the main problem, namely serious mental retardation, is common to all patients without exception. Upon reaching adolescence there is no chance of procreation ( puberty usually does not occur), nor on the opportunity to work ( even mechanical, which does not require special skills). There are special centers for the care of children with congenital diseases, where patients with Edwards syndrome are provided care and, if possible, their intellectual development is promoted. With sufficient effort on the part of doctors and parents, a child who has lived for more than a year can learn to smile, respond to movement, independently maintain body position or eat ( in the absence of defects of the digestive system). Thus, signs of development are still observed.

  The high infant mortality rate with this disease is explained by a large number of malformations of internal organs. They are invisible immediately at birth, but are present in almost all patients. In the first months of life, children usually die from cardiac or respiratory arrest.

  Most often, developmental defects are observed in the following organs and systems:

  • musculoskeletal system ( bones and joints, including the skull);
  • the cardiovascular system;
  • central nervous system;
  • digestive system;
  • genitourinary system;
  • other violations.

  Musculoskeletal system

  The main defects in the development of the musculoskeletal system are abnormal position of the fingers and curvature of the feet. At the hip joint, the legs are brought together in such a way that the knees almost touch, and the feet look slightly to the sides. It is not uncommon for children with Edwards syndrome to have an unusually short sternum. This deforms the overall chest and creates breathing problems that get worse as they grow, even if the lungs themselves are not affected.

  Defects in the development of the skull are mainly cosmetic. However, such defects as cleft palate, cleft lip and high palate create serious difficulties with feeding the child. Often, before operations to correct these defects, the child is transferred to parenteral nutrition (in the form of droppers with nutrient solutions). Another option is to use a gastrostomy tube, a special tube through which food goes directly into the stomach. Its installation requires a separate surgical intervention.

  In general, malformations of the musculoskeletal system do not pose a direct threat to the child’s life. However, they indirectly affect its growth and development. The frequency of such changes in patients with Edwards syndrome is about 98%.

  The cardiovascular system

  Malformations of the cardiovascular system are the leading cause of death in early childhood. The fact is that such violations occur in almost 90% of cases. Most often, they seriously disrupt the process of blood transport throughout the body, leading to severe heart failure. Most heart pathologies can be corrected surgically, but not every child can undergo such a complex operation.

  The most common anomalies of the cardiovascular system are:

  • nonunion interatrial septum;
  • non-closure of the interventricular septum;
  • fusion of valve leaflets ( or, conversely, their underdevelopment);
  • coarctation ( narrowing) aorta.
  All these heart defects lead to serious violations blood circulation Arterial blood does not flow to the tissues in the required volume, which is why the body's cells begin to die.

  central nervous system

  The most characteristic defect of the central nervous system is underdevelopment of the corpus callosum and cerebellum. This is the reason for the most various violations, including mental retardation, which is observed in 100% of children. In addition, disturbances at the level of the brain and spinal cord cause abnormal muscle tone and a predisposition to cramps or spastic muscle contractions.

  Digestive system

  The incidence of digestive system defects in Edwards syndrome is up to 55%. Most often, these developmental anomalies pose a serious threat to the child’s life, since they do not allow him to absorb normally. nutrients. Eating bypassing the natural digestive organs greatly weakens the body and aggravates the child’s condition.

  Most frequent vices developments from the digestive system are:

  • Meckel's diverticulum ( cecum in small intestine );
  • esophageal atresia ( overgrowing of its lumen, due to which food does not pass into the stomach);
  • biliary atresia ( accumulation of bile in the bladder).
  All these pathologies require surgical correction. In most cases, surgery only helps to slightly prolong the child's life.

  Genitourinary system

  The most serious defects on the part of genitourinary system associated with impaired renal function. In some cases, ureteral atresia is observed. The kidney on one side can be duplicated or fused with adjacent tissues. If filtration is impaired, toxic waste products begin to accumulate in the body over time. In addition, there may be an increase in blood pressure and disturbances in the functioning of the heart. Serious abnormalities of kidney development pose a direct threat to life.

  Other violations

  Other possible developmental disorders are hernias ( umbilical, inguinal) . Spinal disc herniations may also be detected, which will lead to neurological problems. Microphthalmia is sometimes observed in the eyes ( small eyeball size).

  The combination of these developmental defects predetermines high infant mortality. In most cases, if Edwards syndrome is diagnosed early in pregnancy, doctors will recommend an abortion for medical reasons. However, the final decision is made by the patient herself. Despite the seriousness of the disease and the poor prognosis, many prefer to hope for the best. But, unfortunately, no major changes in the methods of diagnosing and treating Edwards syndrome are expected in the near future.