Chromosomal diseases. trisomy autosomes
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 referred to as "chromosomal abnormalities" for brevity.
The 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's syndrome". In the future, the cause of the syndrome was repeatedly subjected to genetic analysis. Suggestions were made about a dominant mutation, about a congenital infection, about a chromosomal nature.
The first clinical description of the 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. By the name 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 system of sex chromosomes in men (trisomy XXY) as a clinical syndrome was first described by G. Klinefelter in 1942.
These diseases became the object of the first clinical and cytogenetic studies conducted in 1959. Deciphering the etiology of Down syndrome, Shereshevsky-Turner and Klinefelter opened a new chapter in medicine - chromosomal diseases.
In the 60s of the XX century. Thanks to the wide deployment of cytogenetic studies in the clinic, clinical cytogenetics has completely taken shape as a specialty. The role of chro-
* Corrected and supplemented with the participation of Dr. Biol. Sciences I.N. Lebedev.
mosomal and genomic mutations in human pathology, the chromosomal etiology of many syndromes of congenital malformations has been deciphered, the frequency of chromosomal diseases among newborns and spontaneous abortions has been 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.
With the improvement of cytogenetic methods, especially such as differential staining and molecular cytogenetics, new opportunities have opened up for detecting previously undescribed chromosomal syndromes and establishing a relationship between karyotype and phenotype with small changes in chromosomes.
As a result of intensive study of human chromosomes and chromosomal diseases for 45-50 years, a doctrine of chromosomal pathology has developed, which is of great importance in modern medicine. This direction in medicine includes not only chromosomal diseases, but also prenatal pathology (spontaneous abortions, miscarriages), as well as somatic pathology (leukemia, radiation sickness). The number of described types of chromosomal anomalies approaches 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, neuropathologist, 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 anomalies 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 account for a large proportion of reproductive losses (50% among spontaneous abortions of the first trimester), congenital malformations and mental underdevelopment. In general, chromosomal abnormalities occur in 0.7-0.8% of live births, and in women who give birth after 35 years, the probability of having a child with a chromosomal pathology increases to 2%.
ETIOLOGY AND CLASSIFICATION
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 have been found in humans: tetraploidy, triploidy, and aneuploidy. Of all the variants of aneuploidy, only trisomy for autosomes, polysomy for sex chromosomes (tri-, tetra- and pentasomies) are found, and only monosomy X occurs from monosomy.
As for chromosomal mutations, all their types (deletions, duplications, inversions, translocations) have been found in humans. From a clinical and cytogenetic point of view deletion in one of the homologous chromosomes means a lack of a site or partial monosomy for this site, 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 parts 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 of complex mechanisms of crossing over and reduction in the number of chromosomes during the formation of gametes, carriers of balanced translocations and inversions can form unbalanced gametes, those. gametes with partial disomy or with partial nullisomy (normally each gamete is monosomic).
Translocation between two acrocentric chromosomes, with the 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 form 6 types of gametes (Fig. 5.1), but nullisome gametes should lead to monosomy for autosomes in the zygote, and such zygotes do not develop.
Rice. 5.1. Types of gametes in carriers of the 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 - nullisomy 14
The clinical picture of simple and translocation forms of trisomy for acrocentric chromosomes is the same.
In the case of terminal deletions in both arms of the chromosome, ring chromosome. An individual who inherits a ring chromosome from one of the parents will have partial monosomy at the two ends of the chromosome.
Rice. 5.2. Isochromosomes X along the long and short arm
Sometimes a chromosome break passes through the centromere. Each arm, severed after replication, has two sister chromatids connected by the remainder of the centromere. Sister chromatids of the same arm become arms of the same chrono
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 shoulders. Whatever the mechanism of formation of isochromosomes (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 characterization 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 subdivision of chromosomal pathology is thus based 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 on the basis of the clinical picture is not significant, since different chromosomal anomalies are characterized by a large commonality of developmental disorders.
The second principle is determination of the type of cells in which the mutation has 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, in contrast to gametic), then an organism develops with cells of different chromosomal constitutions (two types or more). Such forms of chromosomal diseases are called mosaic.
For the appearance of mosaic forms, which coincide with the full forms in the clinical picture, at least 10% of cells with an abnormal set are needed.
The third principle is identification of 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 family, forms).
O inherited chromosomal diseases they say when the mutation is present in the cells of the parent, including the gonads. It can also be a case of trisomy. For example, individuals with Down syndrome and triplo-X 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 of the 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 in connection with complex rearrangements of chromosomes during meiosis (conjugation, crossing over).
Thus, for an accurate diagnosis of chromosomal disease, it is necessary to determine:
Mutation type;
The chromosome involved in the process;
Form (full or mosaic);
Occurrence in a pedigree is sporadic or inherited.
Such a diagnosis is possible only with a cytogenetic examination of the patient, and sometimes his parents and siblings.
EFFECTS OF CHROMOSOMAL ANOMALIES IN ONTOGENESIS
Chromosomal anomalies cause a violation of the overall genetic balance, the coordination in the work of genes and the systemic regulation that have 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 the cytogenetics of human embryonic development 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 interconnected variants: lethality 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 of 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 neither clinically nor laboratory diagnosed. However, some information about the diversity of chromosomal disorders at the earliest stages of embryonic development can be obtained from the results of pre-implantation genetic diagnosis of chromosomal diseases, carried out as part of artificial insemination procedures. Using molecular cytogenetic methods of analysis, it was shown that the frequency of numerical chromosome disorders in pre-implantation embryos varies within 60-85% depending on the groups of patients examined, their age, indications for diagnosis, and the number of analyzed chromosomes during fluorescent hybridization. in situ(FISH) on the 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 in such embryos carry different variants of numerical chromosome disorders. Among chromosomal abnormalities in pre-implantation embryos, trisomy, monosomy and even nullisomy of autosomes, all possible variants of violations of the number of sex chromosomes, as well as cases of tri- and tetraploidy were revealed.
Such a high level of karyotype anomalies and their diversity, of course, negatively affect the success of the pre-implantation 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 the disruption of the genomic balance due to the development of some particular form of chromosomal anomaly leads to discoordination of the switching on and off of genes at the corresponding stage of development (time factor) or in the corresponding place of the blastocyst (spatial factor). This is quite understandable: since about 1000 genes localized in all chromosomes are involved in the developmental processes in the early stages, the chromosomal abnormality
Malia disrupts the interaction of genes and inactivates some specific developmental processes (intercellular interactions, cell differentiation, etc.).
Numerous cytogenetic studies of the material of spontaneous abortions, miscarriages and stillbirths make it possible to objectively judge the effects of various types of chromosomal abnormalities in the prenatal period of individual development. The lethal or dysmorphogenetic effect of chromosomal abnormalities is found at all stages of intrauterine ontogenesis (implantation, embryogenesis, organogenesis, growth and development of the fetus). 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 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 found in 60-70% of cases. In the first trimester of gestation, chromosomal abnormalities occur in 50% of abortuses. In fetuses of miscarriages of the II trimester, such anomalies are found in 25-30% of cases, and in fetuses that die 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 chromosome imbalance are found in early abortions. These are polyploidies (25%), complete trisomies for autosomes (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 genes in these autosomes. These anomalies interrupt development in the pre-implantation period or disrupt gametogenesis.
The high morphogenetic significance of autosomes is even more pronounced in complete autosomal monosomy. The latter are rarely found even in the material of early spontaneous abortions due to the lethal effect of such an imbalance.
Congenital malformations
If a chromosomal anomaly does not give 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 congenital malformations
development, combinations of which are known as nosological forms of chromosomal diseases and syndromes (Down syndrome, Wolf-Hirshhorn syndrome, cat's cry, etc.).
The effects caused by uniparental disoms can be found in more detail on the CD in the article by S.A. Nazarenko "Hereditary diseases determined by uniparental disoms 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 (nonconception, spontaneous abortion, stillbirth, chromosomal disease). Their effects can be traced throughout life.
Chromosomal abnormalities that occur 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 by the immune system if they manifest themselves as foreign. However, in some cases (activation of oncogenes during translocations, deletions), chromosomal abnormalities cause malignant growth. For example, a translocation between chromosomes 9 and 22 causes myelogenous 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 and bone marrow aplasia. There is experimental evidence for the accumulation of cells with chromosomal aberrations during aging.
PATHOGENESIS
Despite the good knowledge of the clinic and cytogenetics of chromosomal diseases, their pathogenesis, even in general terms, is still unclear. A general scheme for the development of complex pathological processes caused by chromosomal abnormalities and leading to the appearance of the most complex phenotypes of chromosomal diseases has not been developed. A key link in the development of chromosomal disease in any
form was not found. Some authors suggest that this link is an imbalance in the genotype or a violation of the overall gene balance. However, such a definition does not give anything constructive. Genotype imbalance 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 in any trisomy and partial monosomy, 3 types of genetic effects can be distinguished: specific, semi-specific and non-specific.
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 for only 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's syndrome made it possible to identify 3 groups of genes localized on chromosome 21, depending on changes in the level of their activity during trisomy. The first group included genes, the level of expression of which 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, recorded in almost all patients. The second group consisted of genes whose expression level partially overlaps with the expression level in a normal karyotype. It is believed that these genes determine the formation of variable signs of the syndrome, which are not observed in all patients. Finally, the third group included genes whose expression level in disomic and trisomic cells was practically the same. Apparently, these genes are the least likely to be involved in the formation of the clinical features of Down syndrome. It should be noted that only 60% of genes localized 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
The biochemical study of the phenotype of chromosomal diseases has not yet led to an understanding of the pathogenesis pathways of congenital disorders of morphogenesis arising from chromosomal abnormalities in the broad sense of the word. The detected biochemical abnormalities are still difficult to associate 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. In chromosomal disease, the activity of other enzymes or the amount of proteins, the genes of which are localized on chromosomes not involved in the imbalance, always change significantly. In no case was a marker protein found in chromosomal diseases.
Semi-specific effects in chromosomal diseases, they can be due to 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 the key stages of cell metabolism, cell division processes, and intercellular interactions. What are the phenotypic effects of an imbalance in this
groups of genes, how their deficiency or excess is compensated, is still unknown.
Non-specific 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, non-specific and partially semi-specific effects bring us closer to the cellular mechanisms of pathogenesis, which certainly play an important role in congenital malformations.
A large amount of factual material makes it possible to compare the clinical phenotype of the disease with cytogenetic changes (phenokaryotypic correlations).
Common to all forms of chromosomal diseases is the multiplicity of lesions. These are craniofacial dysmorphias, congenital malformations of internal and external organs, slow intrauterine and postnatal growth and development, mental retardation, dysfunctions of the nervous, endocrine and immune systems. With each form of chromosomal diseases, 30-80 different deviations are observed, partially overlapping (coinciding) with different syndromes. Only a small number of chromosomal diseases are manifested by a strictly defined combination of developmental abnormalities, which is used in clinical and pathological-anatomical diagnostics.
The pathogenesis of chromosomal diseases unfolds 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 major malformations are already present (except for malformations of the genital organs). Early and multiple damage to body systems explains some commonality of the clinical picture of various 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 section involved in the anomaly (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 mosaicity of the body in 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. In the study of 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 in autosomes rich in heterochromatin (8; 9; 13; 18; 21). It also explains polysomy (up to pentasomy) on the sex chromosomes, in which the Y chromosome has few genes, and the additional X chromosomes are heterochromatinized.
Clinical comparison of complete and mosaic forms of the disease shows that mosaic forms are on average easier. Apparently, this is due to the presence of normal cells, which partially compensate for the genetic imbalance. In an individual prognosis, there is no direct relationship between the severity of the course of the disease and the ratio of abnormal and normal clones.
As the pheno- and karyotypic correlations are studied for different lengths of the chromosomal mutation, it turns out that the most specific manifestations for a particular syndrome are due to deviations in the content of relatively small segments of chromosomes. An imbalance in a significant amount of chromosomal material makes the clinical picture more nonspecific. Thus, the specific clinical symptoms of Down syndrome are manifested in trisomy along the segment of the long arm of chromosome 21q22.1. For the development of the "cat's cry" syndrome in deletions of the short arm of autosome 5, the middle part of the segment (5p15) is most important. The characteristic features of Edwards syndrome are associated with trisomy of the 18q11 chromosome segment.
Each chromosomal disease is characterized by clinical polymorphism, due to 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 abnormalities. So, 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-
Turner) - this is 10% of all monosomic X-chromosome embryos (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 disease. The frequency of Down syndrome among newborns is 1:700-1:800, does not have any temporal, ethnic or geographical difference with the same age of the parents. The frequency of the birth 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, it is about 3%. A high frequency of children with Down syndrome (about 2%) is observed in women who give birth early (up to 18 years of age). Therefore, for population comparisons of the birth rate of children with Down's 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 of age 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). An increase in the frequency of Down syndrome with increasing maternal age is known, but most children with Down syndrome are still born to mothers younger than 30 years old. This is due to the higher number of pregnancies in this age group compared to older women.
Rice. 5.3. The dependence of the frequency of birth of children with Down syndrome on the age of the mother
The literature describes the "bunching" of the birth of children with Down syndrome at certain intervals in some countries (cities, provinces). These cases can be explained more by stochastic fluctuations in the spontaneous level of nondisjunction of chromosomes than by the influence of supposed etiological factors (viral infection, low doses of radiation, chlorophos).
Cytogenetic variants of Down syndrome are diverse. However, the majority (up to 95%) are cases of complete trisomy 21 due to nondisjunction of chromosomes during meiosis. The contribution of maternal nondisjunction to these gametic forms of the disease is 85-90%, while that of the father is only 10-15%. At the same time, approximately 75% of violations 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 according to the type of 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 occur de novo. The main types of chromosomal disorders found in Down syndrome are presented in Table. 5.4.
Table 5.4. The main types of chromosomal abnormalities in Down syndrome
The ratio of boys and girls with Down syndrome is 1:1.
Clinical symptoms Down syndrome is diverse: these are congenital malformations, disorders of the postnatal development of the nervous system, and secondary immunodeficiency, etc. Children with Down syndrome are born at term, but with moderately severe prenatal hypoplasia (8-10% below average). Many of the symptoms of Down syndrome are noticeable at birth and become more pronounced later on. A qualified pediatrician establishes the correct diagnosis of Down syndrome in the maternity hospital in at least 90% of cases. Of the craniofacial dysmorphias, a Mongoloid incision of the eyes is noted (for this reason, Down syndrome has long been called Mongoloidism), brachycephaly, a round flattened face, a flat back of the nose, epicanthus, a large (usually protruding) tongue, and deformed auricles (Fig. 5.4). Muscular hypoto-
Rice. 5.4.Children of different ages with characteristic features of Down's syndrome (brachycephaly, round face, macroglossia and open mouth, epicanthus, hypertelorism, wide bridge of the nose, carp mouth, strabismus)
nia is combined with looseness of the joints (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 disorders are rare.
Rice. 5.5.Severe hypotension in a patient with Down's syndrome
Rice. 5.6.Palms of an adult male with Down syndrome (increased wrinkling, on the left hand a four-finger, or “monkey”, fold)
Down syndrome is diagnosed based on a combination of several symptoms. The following 10 signs are most important for establishing a diagnosis, the presence of 4-5 of them strongly indicates Down syndrome:
Flattening of the face profile (90%);
Lack of sucking reflex (85%);
Muscular hypotension (80%);
Mongoloid incision of the palpebral fissures (80%);
Excess skin on the neck (80%);
Loose joints (80%);
Dysplastic pelvis (70%);
Dysplastic (deformed) auricles (60%);
Clinodactyly of the little finger (60%);
Four-finger flexion fold (transverse line) of the palm (45%).
Of great importance for diagnosis is the dynamics of the physical and mental development of the child - 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 training methods. Children with Down syndrome are affectionate, attentive, obedient, patient in learning. IQ (IQ) in different children it can be 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's syndrome often suffer from pneumonia and are difficult to tolerate childhood infections. They have a lack of body weight, hypovitaminosis is expressed.
Congenital malformations of internal organs, reduced adaptability of children with Down syndrome often lead to death in the first 5 years. The consequence of altered immunity and insufficiency of repair systems (for damaged DNA) is leukemia, which often occurs in patients with Down syndrome.
Differential diagnosis is carried out with congenital hypothyroidism, other forms of chromosomal abnormalities. Cytogenetic examination of children is indicated not only for suspected Down's syndrome, but also for a clinically established diagnosis, since the patient's cytogenetic characteristics are necessary to predict the health of future children from 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.
recommendations to restrict childbearing in women of the older age group, since the risk by age remains quite low, especially given the possibilities of prenatal diagnosis.
Dissatisfaction among parents is often caused by the form of reporting by a doctor about the diagnosis of Down syndrome in a child. It is usually possible to diagnose Down syndrome by phenotypic features 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 tell parents as soon as possible after the baby is born, at the very least, about your suspicions, but you should not fully inform the baby's parents about the diagnosis. Sufficient information should be given by answering immediate questions and contact with the parents until the day when a more detailed discussion becomes possible. Immediate information should include an explanation of the etiology of the syndrome to avoid recrimination of the spouses and a description of the investigations and procedures necessary to fully assess the health of the child.
A full discussion of the diagnosis should take place as soon as the puerperal has more or less recovered from the stress of delivery, usually on the 1st postpartum day. By this time, mothers have many questions that need to be answered precisely and definitely. It is important to make every effort to have both parents present at this meeting. The child becomes the subject of immediate discussion. During this period, it is too early to load parents with all the information about the disease, as new and complex concepts take time to comprehend.
Don't try to make predictions. It is useless 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 family members.
Medical care for children with Down syndrome is multifaceted and non-specific. Congenital heart defects are eliminated promptly.
General strengthening treatment is constantly carried out. Food must be complete. Careful care is needed for a sick child, protection from the action of harmful environmental factors (colds, infections). Great successes in saving the lives of children with Down syndrome and their development are provided by special methods of education, strengthening physical health from early childhood, 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, create families. The average life expectancy of such patients in industrialized countries is 50-60 years.
Patau syndrome (trisomy 13)
Patau's syndrome was singled out 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 result of nondisjunction of chromosomes in meiosis in one of the parents (mainly in 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 the D/13 and G/13 types. Other cytogenetic variants (mosaicism, isochromosome, non-Robertsonian translocations) have also been found, but they are extremely rare. The clinical and pathological-anatomical picture of simple trisomic forms and translocation forms does not differ.
The sex ratio in 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 (mean 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's syndrome is accompanied by multiple congenital malformations of the brain and face (Fig. 5.7). This is a pathogenetically single group of early (and therefore severe) disorders in the formation of the brain, eyeballs, bones of the brain and facial parts of the skull. The circumference of the skull is usually reduced, and trigonocephaly occurs. Forehead sloping, low; the palpebral fissures are narrow, the bridge of the nose is sunken, the auricles 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) auricles; microgenia (a); flexor position of the hands)
miliated. A typical symptom of Patau's syndrome is cleft lip and palate (usually bilateral). Defects of several internal organs are always found in different combinations: defects in the septa of the heart, incomplete rotation of the intestine, kidney cysts, anomalies of the internal genital organs, defects in the pancreas. As a rule, polydactyly (more often bilateral and on the hands) and flexor position of the hands are observed. The frequency of different symptoms in children with Patau syndrome according to the systems is as follows: face and brain part of the skull - 96.5%, musculoskeletal system - 92.6%, CNS - 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 malformations. If Patau's syndrome is suspected, 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). 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 up to 5 years (about 15% of patients) and even up to 10 years (2-3% of patients).
Other syndromes of congenital malformations (Meckel's and Mohr's syndromes, Opitz's trigonocephaly) coincide with Patau's syndrome in some respects. The decisive factor in diagnosis is the study of chromosomes. A cytogenetic study is indicated in all cases, including in deceased children. Accurate cytogenetic diagnosis is necessary to predict the health of future children in the family.
Medical care for children with Patau syndrome is non-specific: operations for congenital malformations (for health reasons), restorative treatment, careful care, prevention of colds and infectious diseases. Children with Patau syndrome are almost always deep 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 (nondisjunction in the early stages of crushing). Translocational forms are extremely rare, and as a rule, these are partial rather than complete trisomies. There are no clinical differences between cytogenetically distinct forms of trisomy.
The frequency of Edwards syndrome among newborns is 1:5000-1:7000. The ratio of boys and 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). On fig. 5.8-5.11 shows defects in Edwards syndrome. These are multiple congenital malformations of the facial part of the skull, heart, skeletal system, and genital organs. The skull is dolichocephalic; lower jaw and mouth opening small; palpebral fissures narrow and short; auricles deformed and low located. 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 cord
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 2 months)
Rice. 5.10. Rocking foot (heel sticks out, arch sags)
Rice. 5.11. Hypogenitalism in a boy (cryptorchidism, hypospadias)
hernia and cleft lip are rare (5% of cases of Edwards syndrome).
The diverse symptoms of Edwards syndrome in each patient are only partially manifested: the face and brain part of the skull - 100%, the musculoskeletal system - 98.1%, the central nervous system - 20.4%, the eyes - 13.61%, the 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 brain skull and face, the musculoskeletal system, and malformations of the cardiovascular system.
Children with Edwards syndrome die at an early age (90% before 1 year) from complications caused by congenital malformations (asphyxia, pneumonia, intestinal obstruction, cardiovascular insufficiency). Clinical and even pathological-anatomical differential diagnosis of Edwards syndrome is difficult, therefore, in all cases, a cytogenetic study is indicated. 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 on a chromosome from group C or D was ascertained, since there was no individual identification of chromosomes at that time. Complete 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 and girls is 5: 2). Most of the described cases (about 90%) are related to mosaic forms. The conclusion about complete trisomy in 10% of patients was based on the study of one tissue, which in the strict sense is not enough to rule out mosaicism.
Trisomy 8 is the result of a newly occurring mutation (nondisjunction of chromosomes) in the early stages of the blastula, with the exception of rare cases of a new mutation in 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 (mental deficiency, large protruding ears with a simplified pattern)
Rice. 5.14. Contractures of the interphalangeal joints in trisomy 8
The reasons for these variations are unknown. No correlations were found between the severity of the disease and the proportion of trisomic cells.
Babies with trisomy 8 are born full term. The age of the parents is not distinguished from the general sample.
For the disease, deviations in the structure of the face, defects in the musculoskeletal system and urinary system are most characteristic (Fig. 5.12-5.14). These are a protruding forehead (in 72%), strabismus, epicanthus, deep-set eyes, hypertelorism of the eyes and nipples, a high palate (sometimes a cleft), thick lips, an inverted lower lip (in 80.4%), large auricles with a thick lobe, joint contractures (in 74%), camptodactyly, aplasia of the patella (in 60.7%), deep grooves between the interdigital pads (in 85.5%), four-finger fold, anomalies of the anus. Ultrasound reveals anomalies of the spine (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 of 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, anomalies of the hip joint, narrow pelvis, narrow shoulders.
There are no specific treatments. 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, by combinations of different clones. The overall frequency of polysomy on the X or Y chromosomes among newborns is 1.5: 1000-2: 1000. Basically, these are polysomy 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 polysomy on sex chromosomes in humans
Summarized data on the frequency of children with anomalies in sex chromosomes are presented in Table. 5.6.
Table 5.6. Approximate frequency of children with anomalies on sex chromosomes
Triplo-X Syndrome (47,XXX)
Among newborn girls, the frequency of the syndrome is 1: 1000. Women with a XXX karyotype in full or mosaic form have basically normal physical and mental development, they are usually detected by chance during examination. This is explained by the fact that in cells two X chromosomes are heterochromatinized (two bodies of sex chromatin), and only one functions, as in a normal woman. As a rule, a woman with a XXX karyotype has no abnormalities in sexual development, she has normal fertility, although the risk of chromosomal abnormalities in the offspring and the occurrence of spontaneous abortions is increased.
Intellectual development is normal or at the lower limit of normal. Only some women with triplo-X have reproductive disorders (secondary amenorrhea, dysmenorrhea, early menopause, etc.). Anomalies in the development of the external genital organs (signs of dysembryogenesis) are detected only with a thorough examination, they are insignificantly expressed and do not serve as a reason to consult a doctor.
Variants of the 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 pentasomia, mental retardation, craniofacial dysmorphia, anomalies of the teeth, skeleton, and genital organs are 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's syndrome with a set of 47,XXY. This syndrome (in full and mosaic versions) occurs with a frequency of 1: 500-750 newborn boys. Variants of polysomy with a large number of X- and Y-chromosomes (see Table 5.6) are rare. Clinically, they are also referred to as Klinefelter's 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 is clinically manifested during puberty in the form of testicular underdevelopment and secondary male sexual characteristics.
Patients are tall, female body type, gynecomastia, 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).
Disomia Syndrome
on the Y chromosome (47,XYY)
It occurs with a frequency of 1:1000 newborn boys. Most men with this set of chromosomes are slightly different from those with a normal chromosome set in terms of physical and mental development. They are slightly taller than average, mentally developed, not dysmorphic. There are no noticeable deviations in either sexual development, or hormonal status, or fertility in most XYY-individuals. There is no increased risk of having chromosomally abnormal children in XYY individuals. Nearly half of boys aged 47, XYY require additional pedagogical assistance due to delayed speech development, reading and pronunciation difficulties. IQ (IQ) is on average 10-15 points lower. Of the behavioral features, attention deficit, hyperactivity and impulsivity are noted, but without severe aggression or psychopathological behavior. In the 1960s and 70s, it was pointed out that the proportion of XYY males is increased in prisons and psychiatric hospitals, especially among the tall ones. These assumptions are currently considered incorrect. However, the impossibility
Rice. 5.15. Klinefelter syndrome. Tall, gynecomastia, female-type pubic hair
Predicting developmental outcome in individual cases makes XYY fetus identification one of the most difficult tasks in genetic counseling in prenatal diagnosis.
Shereshevsky-Turner syndrome (45,X)
This is the only form of monosomy in live births. At least 90% of conceptions with a 45,X karyotype are spontaneously aborted. Monosomy X accounts for 15-20% of all abnormal abortus karyotypes.
The frequency of Shereshevsky-Turner syndrome is 1: 2000-5000 newborn girls. The cytogenetics of the syndrome is diverse. Along with true monosomy in all cells (45, X), there are other forms of chromosomal abnormalities in the sex chromosomes. These are deletions of the short or long arm of the X chromosome, isochromosomes, ring chromosomes, as well as various types 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 15-20% of paternal origin.
In other cases, the syndrome is caused by a variety of mosaicism (30-40% in general) and rarer variants of deletions, isochromosomes, and ring chromosomes.
Hypogonadism, underdevelopment of the genital organs and secondary sexual characteristics;
Congenital malformations;
Low rise.
On the part of the reproductive system, there is a lack of gonads (gonadal agenesis), hypoplasia of the uterus and fallopian tubes, primary amenorrhea, poor pubic and axillary hair growth, 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 peculiar (although not always). Newborns and infants have a short neck with excess skin and pterygoid folds, lymphatic edema of the feet (Fig. 5.16), shins, hands and forearms. In school and especially in adolescence, growth retardation is detected, in
Rice. 5.16. Lymphedema of the foot in a newborn with Shereshevsky-Turner syndrome. Small protruding 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 dysmorphias, 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, antimongoloid incision of the palpebral fissures, ptosis, epicanthus, retrogeny, low position of the ear shells. The growth of adult patients is 20-30 cm below average. The severity of clinical (phenotypic) manifestations depends on many yet 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 ratio of clones 46XX:45X.
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 (estrogen, growth hormone);
Psychotherapy.
Timely use of all methods of treatment, including the use of genetically engineered growth hormone, gives patients the opportunity to achieve acceptable growth and lead a full life.
Syndromes of partial aneuploidy
This large group of syndromes is caused by chromosomal mutations. Whatever type of chromosomal mutation was originally (inversion, translocation, duplication, deletion), the occurrence of a clinical chromosomal syndrome is determined either by an excess (partial trisomy) or a deficiency (partial monosomy) of genetic material or both by the effect of different altered parts of the chromosome set. To date, about 1000 different variants of chromosomal mutations have been discovered, inherited from parents or arising in early embryogenesis. However, only those rearrangements (there are about 100 of them) are considered clinical forms of chromosomal syndromes, according to which
Several probands have been described with a match between the nature of cytogenetic changes and the clinical picture (correlation of karyotype and phenotype).
Partial aneuploidies occur mainly as a result of inaccurate crossing over in chromosomes with inversions or translocations. Only in a small number of cases, the primary occurrence of deletions in the gamete or in the cell at the early stages of cleavage is possible.
Partial aneuploidy, like complete aneuploidy, causes 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 in partial aneuploidy coincides with that in complete forms (Shereshevsky-Turner syndrome, Edwards syndrome, Down syndrome). In these cases, we are talking about partial aneuploidy in the so-called regions of chromosomes that are critical for the development of the syndrome.
There is no dependence of the severity of the clinical picture of the chromosomal syndrome on the form of partial aneuploidy or on the individual chromosome. The size of the part of the chromosome involved in the rearrangement may be important, but cases of this kind (smaller or greater length) should be considered as different syndromes. It is difficult to identify general patterns of correlations between the clinical picture and the nature of chromosomal mutations, because many forms of partial aneuploidies are eliminated in the embryonic period.
The phenotypic manifestations of any autosomal deletion syndromes consist of two groups of abnormalities: non-specific findings common to many different forms of partial autosomal aneuploidy (prenatal developmental delay, microcephaly, hypertelorism, epicanthus, apparently low-lying ears, micrognathia, clinodactyly, etc.); combinations of findings typical of the syndrome. The most appropriate explanation for the causes of non-specific findings (most of which are of no clinical significance) is the non-specific effects of autosomal imbalance per se, rather than the results of deletions or duplications of specific loci.
Chromosomal syndromes caused by partial aneuploidy have common properties of all chromosomal diseases:
congenital disorders of morphogenesis (congenital malformations, dysmorphias), impaired postnatal ontogenesis, severity of the clinical picture, reduced life expectancy.
Syndrome "cat's cry"
This is 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 cat's demanding meow or cry. For this reason, the syndrome has been termed "Crying 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 the loss of 1/3 to 1/2 of the length of the short arm of chromosome 5. Loss of the entire short arm or, conversely, an insignificant area is rare. For the development of the clinical picture of the 5p syndrome, it is not the size of the lost area that matters, but the specific fragment of the chromosome. Only a small area in the short arm of chromosome 5 (5p15.1-15.2) is responsible for the development of the complete syndrome. In addition to a simple deletion, other cytogenetic variants were found in this syndrome: ring chromosome 5 (of course, 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 the 5p-syndrome varies quite a lot in individual patients in terms of the combination of congenital malformations of organs. The most characteristic sign - "cat's cry" - is due to a change in the larynx (narrowing, softness of the cartilage, a decrease in the epiglottis, unusual folding of the mucous membrane). Almost all patients have certain changes in the brain part of the skull and face: a moon-shaped face, microcephaly, hypertelorism, microgenia, epicanthus, anti-Mongoloid incision of the eyes, high palate, flat back of the nose (Fig. 5.18, 5.19). The auricles are deformed and located low. In addition, there are congenital heart defects and some
Rice. 5.18. A child with pronounced signs of the "cat's cry" syndrome (microcephaly, moon-shaped face, epicanthus, hypertelorism, wide flat bridge of the nose, low-lying auricles)
Rice. 5.19. A child with mild signs of "cat's cry" syndrome
other internal organs, changes in the musculoskeletal system (syndactyly of the feet, clinodactyly of the fifth finger, clubfoot). Reveal muscular hypotension, and sometimes diastasis of the rectus abdominis muscles.
The severity of individual signs and the clinical picture as a whole changes with age. So, "cat's cry", muscular hypotension, moon-shaped face disappear almost completely with age, and microcephaly comes to light more clearly, psychomotor underdevelopment, strabismus become more noticeable. The life expectancy of patients with 5p- syndrome depends on the severity of congenital malformations of the 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 single 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 stage of meiosis, can cause a deletion of the site
5r15.1-15.2.
Wolf-Hirschhorn syndrome (partial monosomy 4p-)
It is caused by a deletion of a segment of the short arm of chromosome 4. Clinically, Wolf-Hirshhorn syndrome is manifested by numerous congenital malformations, 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 a full-term pregnancy is about 2000 g, i.e. prenatal hypoplasia is more pronounced than with other partial monosomies. Children with Wolff-Hirschhorn syndrome have the following signs (symptoms): microcephaly, coracoid nose, hypertelorism, epicanthus, abnormal auricles (often with preauricular folds), cleft lip and palate, anomalies of the eyeballs, anti-Mongoloid incision of the eyes, small
Rice. 5.20. Children with Wolff-Hirschhorn syndrome (microcephaly, hypertelorism, epicanthus, abnormal auricles, strabismus, microgenia, ptosis)
cue mouth, hypospadias, cryptorchidism, sacral fossa, deformity of the feet, 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 viability of children is sharply reduced, most die before the age of 1 year. Only 1 patient aged 25 years has been described.
The cytogenetics of the syndrome is quite characteristic, like many deletion syndromes. In about 80% of cases, the proband has a deletion of a part of the short arm of chromosome 4, and the parents have normal karyotypes. The remaining cases are due to translocation combinations or ring chromosomes, but there is always a loss of the 4p16 fragment.
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 birth of children with Wolff-Hirschhorn syndrome is low (1: 100,000).
Syndrome of partial trisomy 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 slit of the eyes, enophthalmos (deep-set eyes), hypertelorism, rounded tip of the nose, lowered corners of the mouth, low-lying protruding auricles with a flattened pattern, hypoplasia (sometimes dysplasia) of nails (Fig. 5.21). Congenital heart defects were found in 25% of patients.
Less common are other congenital anomalies that are common to all chromosomal diseases: 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). Life prognosis is relatively favorable. Patients live to old and advanced age.
The cytogenetics of the 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-lying auricles, thick lips, short neck): a - 3-year-old child; b - woman 21 years old
The clinical manifestations of the syndrome are the same in different cytogenetic variants, which is quite understandable, since in all cases there is a triple set of genes of a part of the short arm of chromosome 9.
Syndromes due to 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 originally described as dominant diseases (point mutations), but later, using modern high-resolution cytogenetic methods (especially molecular cytogenetic), the true etiology of these diseases was established. With the use of CGH on microarrays, it became possible to detect deletions and duplications of chromosomes 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 approach
understanding of genophenotypic correlations in patients with microstructural aberrations of chromosomes.
It is on the example of deciphering the mechanisms of development of these syndromes that one can see the mutual penetration of cytogenetic methods into genetic analysis, molecular genetic methods into clinical cytogenetics. This makes it possible to decipher the nature of previously incomprehensible hereditary diseases, as well as to clarify the functional relationships between genes. Obviously, the development of microdeletion and microduplication syndromes is based on changes in the dose of genes in the region of the chromosome 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 region 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. For the formation of 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. Sizes 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, resulting from a 4 million bp microdeletion. in the region q11-q13 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 in the homologous chromosome affects the clinical manifestation of microdeletion syndromes. Apparently, the nature of clinical manifestations of different syndromes is different. The pathological process in some of them unfolds through the inactivation of tumor suppressors (retinoblastoma, Wilms tumors), the clinic of other syndromes is due not only to deletions as such, but also to the phenomena of chromosomal imprinting and uniparental disomies (Prader-Willi, Angelman, Beckwith-Wiedemann syndromes). Clinical and cytogenetic characteristics of microdeletion syndromes are constantly being refined. Table 5.8 provides examples of some of the syndromes caused by microdeletions or microduplications of small fragments of chromosomes.
Table 5.8. Overview of Syndromes Due to 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 newborns). Their clinical picture is usually clear. Diagnosis can be made by the combination of symptoms. However, in connection with 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 its parents.
Rice. 5.27. Transverse notches on the earlobe are a typical symptom in Beckwith-Wiedemann syndrome (indicated by an arrow)
The clinical manifestations of the syndromes vary greatly due to the different extent of the deletion or duplication, as well as due to the parental affiliation 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 in the cytogenetic study of two clinically distinct syndromes (Prader-Willi and Angelman). In both cases, the 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 seen in fig. 5.28, maternal disomy 15 causes Prader-Willi syndrome (because the q11-q13 region of the paternal chromosome is missing). The same effect is produced by a deletion of the same site or a mutation in the paternal chromosome with a normal (biparental) karyotype. The exact opposite situation is observed in Angelman's syndrome.
More detailed information about the architecture of the genome and hereditary diseases caused by microstructural disorders of 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 (PWV) and (SA) Angelman: M - mother; O - father; ORD - uniparental disomy
INCREASED RISK FACTORS FOR 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 anomalies (both chromosomal and genomic mutations) occurs spontaneously. The results of experimental genetics were extrapolated and induced mutagenesis in humans (ionizing radiation, chemical mutagens, viruses) was assumed. However, the real reasons for the occurrence of chromosomal and genomic mutations in germ cells or at the early stages of embryo development have not yet been deciphered.
Many hypotheses of non-disjunction of chromosomes were tested (seasonality, racial and ethnic origin, age of mother and father, delayed fertilization, birth order, family accumulation, drug treatment of mothers, bad habits, non-hormonal and hormonal contraception, fluridines, viral diseases in women). In most cases, these hypotheses were not confirmed, but a genetic predisposition to the disease is not excluded. Although in most cases the nondisjunction of chromosomes in humans is sporadic, it can be assumed that it is genetically determined to some extent. The following facts testify to this:
Offspring with trisomy appears in the same women again with a frequency of at least 1%;
Relatives of a proband with trisomy 21 or other aneuploidy have a slightly increased risk of having an aneuploid child;
Consanguinity of parents may increase the risk of trisomy in offspring;
The frequency of conceptions with double aneuploidy may be higher than predicted according to the frequency of individual aneuploidy.
Maternal age is one of the biological factors that increase the risk of chromosome nondisjunction, although the mechanisms of this phenomenon are unclear (Table 5.9, Figure 5.29). As can be seen from Table. 5.9, the risk of having a child with a chromosomal disease due to aneuploidy gradually increases with the age of the mother, but especially sharply after 35 years. In women over 45, every 5th pregnancy ends with the birth of a child with a chromosomal disease. The age dependence is most clearly manifested for triso-
Rice. 5.29. The 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 II trimester; 3 - Down syndrome in the II trimester; 4 - Down syndrome among live births
mi 21 (Down's disease). For aneuploidies on sex chromosomes, 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 birth of children with chromosomal diseases on the age of the mother
On fig. 5.29 shows that with age, the frequency of spontaneous abortions also increases, 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 due (up to 40-45%) to chromosomal abnormalities, the frequency of which is age-dependent.
Above, the factors of increased risk of aneuploidy in children from karyotypically normal parents were considered. In fact, of the many putative factors, only two are relevant for pregnancy planning, or rather, are strong indications for prenatal diagnosis. This is the birth of a child with autosomal aneuploidy and the age of the mother over 35 years.
Cytogenetic study in married couples reveals 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 a 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 trans-
locations 13/13, 21/21), or the birth of children with Patau syndrome (13/13) or Down syndrome (21/21).
Empirical risk tables were compiled to calculate the risk of having a child with a chromosomal disease in the case of an abnormal karyotype in parents. Now there is almost no need for them. Methods of prenatal cytogenetic diagnostics made it possible to move from risk assessment to establishing a diagnosis in an embryo or fetus.
KEY WORDS AND CONCEPTS
isochromosomes
Imprinting at the chromosomal level
History of the discovery of chromosomal diseases
Classification of chromosomal diseases
Ring chromosomes
Pheno- and karyotype correlation
Microdeletion Syndromes
Common Clinical Features of Chromosomal Diseases
Uniparental disomies
The pathogenesis of chromosomal diseases
Indications for cytogenetic diagnosis
Robertsonian translocations
Balanced reciprocal translocations
Types of chromosomal and genomic mutations
Risk factors for chromosomal diseases
Chromosomal abnormalities and spontaneous abortions
Partial monosomy
Partial trisomy
Frequency of chromosomal diseases
Effects of chromosomal abnormalities
Baranov V.S., Kuznetsova T.V. Cytogenetics of human embryonic development: scientific and practical aspects. - St. Petersburg: Scientific literature, 2007. - 640 p.
Ginter E.K. Medical genetics. - M.: Medicine, 2003. -
445 p.
Kozlova S.I., Demikova N.S. Hereditary syndromes and medical genetic counseling: an atlas-handbook. - 3rd ed., add. and reworked. - M.: T-in scientific publications of KMK; Author's Academy, 2007. - 448 p.: 236 ill.
Nazarenko S.A. Chromosome variation and human development. - Tomsk: Publishing House of Tomsk State University, 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 further leads to the expulsion of the fetal egg, which manifests itself in the form of a spontaneous miscarriage. However, in many cases, developmental arrest occurs at a very early stage, 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 fetus.
Spontaneous miscarriages
Spontaneous miscarriages, defined as "spontaneous termination of pregnancy between the term of conception and the viability of the fetus", in many cases are very difficult to diagnose: a large number of miscarriages occur at very early dates: there is no delay in menstruation, or this delay is so small that it the woman is unaware of the pregnancy.
Clinical Data
The expulsion of the ovum may occur suddenly, or it may be preceded by clinical symptoms. Most 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 fetal 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 drastically reduced, indicating a lack of viable fetus. Ultrasound examination allows you to clarify the diagnosis, revealing either the absence of an embryo ("empty fetal egg"), or developmental delay and lack of heartbeat
The clinical manifestations of spontaneous miscarriage vary considerably. 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: spotting from early pregnancy, uterine growth stops, disappearance of signs of pregnancy, a "silent" period for 4-5 weeks, and then expulsion of the fetal egg most often indicate chromosomal abnormalities of the embryo, and the correspondence of the term of the development of the embryo to the term of the miscarriage speaks in favor of the maternal causes of miscarriage.
Anatomical data
Analysis of the material of spontaneous miscarriages, the collection of which was begun 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 a post-mortem study of 1,000 early miscarriages. They ruled out maternal causes of miscarriage in 617 cases. Current data indicate that macerated embryos in apparently normal membranes can also be associated with chromosomal abnormalities, which in total accounts for about 3/4 of all cases in this study.
| Morphological study of 1000 abortions (according to Hertig and Sheldon, 1943) | ||
| Gross pathological disorders of the fetal egg: fertilized egg without embryo or with undifferentiated embryo | 489 | |
| Local anomalies of embryos | 32 | |
| placenta anomalies | 96 | 617 |
| A fertilized egg without gross anomalies | ||
| with macerated germs | 146 | |
| 763 | ||
| with unmacerated embryos | 74 | |
| Uterine anomalies | 64 | |
| Other violations | 99 | |
Further studies by Mikamo and Miller and Polland made it possible to clarify the relationship between the term of miscarriage and the frequency of developmental disorders of the embryo. 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 abnormalities of the fetal egg occur 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 - 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 fetuses up to 17 days after conception. It was the fruit of his 25 years of work.
In 210 women under the age of 40 undergoing hysterectomy (removal of the uterus), the date of the operation was compared with the date of ovulation (possible conception). After the operation, the uterus was subjected to the most thorough histological examination in order to identify a possible short-term pregnancy. Of the 210 women, only 107 were retained in the study due to the discovery of signs of ovulation, and the absence of gross violations of the tubes and ovaries, preventing the onset of pregnancy. Thirty-four gestational sacs were found, of which 21 gestational sacs were externally normal, and 13 (38%) had obvious signs of anomalies that, according to Hertig, would necessarily lead to miscarriage either at the stage of implantation or shortly after implantation. Since at that time it was not possible to conduct a genetic study of fetal 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 of the three fetal eggs has anomalies and is subject to miscarriage before the onset of signs of pregnancy.
Epidemiological and demographic data
The fuzzy clinical symptoms of early spontaneous miscarriages leads to the fact that a fairly large percentage of miscarriages in the short term goes unnoticed by women.
In the case of clinically confirmed pregnancies, about 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 the pregnancy stops, we can say that more than 90% of all spontaneous miscarriages are associated with the first trimester.
Special demographic studies made it possible to clarify the frequency of intrauterine mortality. So, French and Birman in 1953-1956. registered all pregnancies in Kanai women and showed that out of 1000 pregnancies diagnosed after 5 weeks, 237 did not result in a viable baby.
An analysis of the results of several studies allowed Leridon to compile a table of intrauterine mortality, which includes fertilization failures (sexual intercourse at the optimal time - within a day after ovulation).
| Complete table within uterine mortality (per 1000 eggs at risk of fertilization) (according to Leridon, 1973) | ||
|---|---|---|
| weeks after conception | Stopping development followed by expulsion | Percentage of continuing 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 of conception | ||
All these data indicate a huge frequency of spontaneous miscarriages and the important role of developmental disorders of the fetal egg in this pathology.
These data reflect the overall frequency of developmental disorders, without distinguishing among them specific exogenous and endogenous factors (immunological, infectious, physical, chemical, etc.).
It is important to note that, regardless of the cause of the damaging effect, when examining the material of miscarriages, a very high frequency of genetic disorders (chromosomal aberrations (currently best studied) and gene mutations) and developmental anomalies, such as neural tube defects, is found.
Chromosomal Abnormalities Responsible for Stopping Pregnancy Development
Cytogenetic studies of the material of miscarriages made it possible to clarify the nature and frequency of certain chromosomal abnormalities.
Common frequency
When evaluating the results of large series of analyzes, the following should be borne 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 is often not amenable to accurate assessment, the success of culturing abortus cell cultures and chromosomal analysis of the material, subtle methods processing of macerated material.
The overall 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, an analysis based on the stages of development of the embryo makes it possible to draw much more accurate conclusions.
Relative frequency
Almost all large studies of chromosomal aberrations in the material of miscarriages have given strikingly similar results regarding the nature of the violations. 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:
- failure of meiotic division: we are talking about cases of "non-disjunction" (non-separation) of paired chromosomes, which leads to the appearance of either trisomy or monosomy. Non-separation can occur during both the first and second meiotic divisions, and can involve both eggs and sperm.
- failures that occur during fertilization:: cases of fertilization of an egg by two spermatozoa (dyspermia), resulting in a triploid embryo.
- failures that occur during the first mitotic divisions: complete tetraploidy occurs when the first division resulted in a doubling of the chromosomes, but no separation of the cytoplasm. Mosaics arise in the case of such failures at the stage of subsequent divisions.
monosomy
Monosomy X (45,X) is one of the most common anomalies in the material of spontaneous miscarriages. At birth, it corresponds to Shereshevsky-Turner syndrome, and at birth it is less common than other quantitative sex chromosome anomalies. This striking difference between the relatively high incidence of extra X chromosomes in newborns and the relatively rare detection of monosomy X in newborns points to the high mortality rate of monosomy X in the fetus. In addition, the very high frequency of mosaics in patients with Shereshevsky-Turner syndrome attracts attention. In the material of miscarriages, on the contrary, mosaics with monosomy X are extremely rare. Research data have shown that only less than 1% of all X monosomies reach term. Monosomy of autosomes in the material of miscarriages are quite rare. This contrasts greatly with the high frequency of the corresponding trisomies.
Trisomy
In the material of miscarriages, trisomy 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 excess chromosomes, the extra chromosome is most often an autosome.
Accurate identification of the extra chromosome was made possible by the G-banding method. Studies have shown that all autosomes can participate in non-disjunction (see table). It is noteworthy that the three chromosomes most often found in neonatal trisomies (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 timing at which the death of the embryos occurs, since the more lethal the combination of chromosomes is, the earlier the development stops, the less often such an aberration will be detected in the materials of miscarriages (the shorter the stop period development, the more difficult it is to detect such an embryo).
| Extra chromosome in lethal trisomy in the fetus (data from 7 studies: Bue (France), Carr (Canada), Creasy (UK), 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, triploidy is the fifth most common chromosomal abnormality in miscarriage. Depending on the ratio of sex chromosomes, there can be 3 variants of triploidy: 69XYY (the rarest), 69, XXX and 69, XXY (the most frequent). Analysis of sex chromatin shows that in configuration 69, XXX, only one chromatin lump is most often detected, and in configuration 69, XXY, sex chromatin is most often not detected.
The figure below illustrates the various mechanisms leading to the development of triploidy (diandry, digyny, dyspermy). Using special methods (chromosomal markers, tissue compatibility 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 out of 50 cases of observations, triploidy was the result of digyny in 11 cases (22%), deandria or dyspermia in 20 cases (40%), dyspermia in 18 cases (36%).
tetraploidy
Tetraploidy occurs in about 5% of cases of quantitative chromosomal aberrations. The most common tetraploidy 92, XXXX. Such cells always contain 2 clumps of sex chromatin. Cells with tetraploidy 92,XXYY never show sex chromatin, but have 2 fluorescent Y chromosomes.
double aberrations
The high frequency of chromosomal abnormalities in the material of miscarriages explains the high frequency of combined anomalies in the same fetus. In contrast, in newborns, combined anomalies are extremely rare. Usually in such cases there are combinations of anomalies of the sex chromosome and anomalies of the autosome.
Due to the higher frequency of autosomal trisomies in the material of miscarriages, with combined chromosomal abnormalities in abortuses, double autosomal trisomies are most common. It is difficult to say whether such trisomies are due to double non-disjunction in the same gamete, or to the meeting of two abnormal gametes.
The frequency of combinations of different trisomies in the same zygote is random, which suggests that the occurrence of double trisomies is independent of each other.
The combination of two mechanisms leading to the appearance of double anomalies can explain the appearance of other karyotype anomalies that occur in miscarriages. "Non-disjunction" in the formation of one of the gametes in combination with the mechanisms of formation of polyploidy explains the appearance of zygotes with 68 or 70 chromosomes. Failure of the first mitotic division in such a trisomy zygote can result in karyotypes such as 94,XXXX,16+,16+.
Structural chromosomal abnormalities
According to classical studies, the frequency of structural chromosomal aberrations in the material of miscarriages is 4-5%. However, many studies were done prior to the widespread use of the G-banding method. Modern research indicates a higher frequency of structural chromosomal abnormalities in abortuses. A variety of structural anomalies are found. In about half of the cases, these anomalies are inherited from parents, in about half of the cases they occur de novo.
The influence of chromosomal abnormalities on the development of the zygote
Chromosomal abnormalities of the zygote usually appear already in the first weeks of development. Finding out the specific manifestations of each anomaly is associated with a number of difficulties.
In many cases, it is extremely difficult to determine the gestational age when analyzing the material of miscarriages. Usually, the 14th day of the cycle is considered the term of conception, but women with miscarriage often have cycle delays. In addition, it is very difficult to establish the date of "death" of the fetal egg, since a lot of time can pass from the moment of death to miscarriage. In cases of triploidy, this period can be 10-15 weeks. The use of hormonal drugs can further lengthen this time.
Given these reservations, we can say that the shorter the gestational age at the time of the death of the fetal egg, the higher the frequency of chromosome aberrations. According to studies by Creasy and Loritsen, with miscarriages before 15 weeks of gestation, the frequency of chromosome 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 chromosome aberrations in perinatal mortality studies.
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, 5–8 cm in size, does not contain an embryo, but there is a cord-like formation with elements of embryonic tissue, remnants of the yolk sac, and the placenta contains subamniotic blood clots. 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 fetal sac".
With trisomy different types of developmental anomalies are observed, depending on which chromosome is superfluous. However, in the overwhelming majority of cases, development stops at a very early stage, and no elements of the embryo are found. This is a classic case of "empty gestational sac" (anembryony).
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 cavity of the chorion there is a small amniotic vesicle about 5 mm in diameter and an embryonic germ 1–2 mm in size. Most often, development stops at the stage of the embryonic disc.
With some trisomies, for example, with trisomies 13 and 14, the development of the embryo up to a period of about 6 weeks is possible. The embryos are characterized by a cyclocephalic head shape with defects in the closure of the maxillary hillocks. The placentas are hypoplastic.
Embryos with trisomy 21 (Down's syndrome in newborns) do not always have developmental anomalies, and if they do, they are minor, which cannot cause their death. Placentas in such cases are poor in cells, and appear to have stopped in development at an early stage. The death of the embryo in such cases appears to be a consequence of placental insufficiency.
drifts. Comparative analysis of cytogenetic and morphological data allows us to distinguish two types of moles: classic hydatidiform mole and embryonic triploid mole.
Miscarriages in triploidy have a clear morphological picture. This is expressed in a combination of complete or (more often) partial vesicular degeneration of the placenta and an amniotic vesicle with an embryo, the size of which (the embryo) is very small compared to the relatively large amniotic vesicle. Histological examination shows not hypertrophy, but hypotrophy of the vesicularly altered trophoblast, which forms microcysts as a result of numerous intussusceptions.
Against, classic bubble skid does not affect either the amniotic sac or the fetus. In the vesicles, an excessive formation of syncytiotrophoblast with pronounced vascularization is found. Cytogenetically, most classic hydatidiform moles have a 46,XX karyotype. The conducted studies allowed us to establish chromosomal disruptions involved in the formation of hydatidiform mole. The 2 X chromosomes in classic hydatidiform mole have been shown to be identical and paternally derived. The most likely mechanism for the development of hydatidiform mole is true androgenesis, which occurs as a result of fertilization of the egg by a diploid spermatozoon, 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.
Assessment of the frequency of chromosomal disorders 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 the material of miscarriages. However, first of all, it should be noted that the striking similarity of the results of studies of miscarriage material, carried out in different parts of the world, suggests that chromosomal disruptions at the moment of conception are a very characteristic phenomenon in human reproduction. In addition, it can be stated that the least common anomalies (for example, trisomies A, B and F) are associated with developmental arrest at very early stages.
An analysis of the relative frequency of various anomalies that occur when chromosomes do not separate during meiosis allows us to draw the following important conclusions:
1. The only monosomy found in the material of miscarriages 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 performed 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 material of miscarriages is due to the fact that individual chromosome aberrations lead to a halt in development at very early stages and therefore are difficult to detect.
These considerations allow us to approximately calculate the actual frequency of chromosomal abnormalities at the time of conception. Bue's calculations showed that every second conception gives a zygote with chromosomal aberrations.
These figures reflect the average frequency of chromosomal aberrations at conception in the population. However, these figures can vary significantly between couples. Some couples are more likely to experience chromosomal aberrations at conception than the average risk in the population. In such couples, miscarriage at short terms occurs much more often than in other couples.
These calculations are confirmed by other studies conducted using other methods:
1. Hertig's classical studies
2. Determination of the level of chorionic hormone (CH) in the blood of women after 10 years after conception. Often this test turns out to be positive, although the menstruation comes on time or with a slight delay, and the woman does not notice the onset of pregnancy subjectively ("biochemical pregnancy")
3. Chromosome analysis of the material obtained during artificial abortions showed that during abortions at a period of 6–9 weeks (4–7 weeks after conception), the frequency of chromosome aberrations is approximately 8%, and during artificial abortions at a period of 5 weeks (3 weeks after conception ), this frequency increases to 25%.
4. It has been shown that chromosome nondisjunction during spermatogenesis is a very common occurrence. So Pearson et al. found that the probability of nondisjunction in the process of 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 about the same order, then only 40% of all spermatozoa have a normal chromosome set.
Experimental models and comparative pathology
Development arrest frequency
Although differences in type of placentation and number of fetuses make it difficult to compare the risk of miscarriage in pets and humans, certain analogies can be seen. In domestic animals, the percentage of lethal conceptions ranges between 20 and 60%.
A study of lethal mutations in primates has yielded figures comparable to those in humans. Of 23 blastocysts isolated from macaques before conception, 10 had gross morphological abnormalities.
Frequency of chromosomal abnormalities
Only experimental studies make it possible to carry out a chromosomal analysis of zygotes at different stages of development and to estimate the frequency of chromosomal aberrations. Ford's classic studies revealed chromosomal aberrations in 2% of mouse fetuses between 8 and 11 days of age after conception. Further studies have shown that this is too advanced stage of embryonic development, and that the frequency of chromosome aberrations is much higher (see below).
The impact of chromosomal aberrations on development
A great contribution to clarifying the scale of the problem was made by the studies of Alfred Gropp from Lübeck and Charles Ford from Oxford, conducted on the so-called "tobacco mice" ( Mus poschiavinus). Crossing such mice with normal mice gives a wide range of triploidies and monosomies, which makes it possible to evaluate the influence of both types of aberrations on development.
The data of Professor Gropp (1973) are given in the table.
| Distribution of euploid and aneuploid embryos in hybrid mice | |||||
|---|---|---|---|---|---|
| Development stage | 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 allowed us to confirm the hypothesis that monosomies and trisomies are equally likely to occur during conception: autosomal monosomies occur with the same frequency as trisomies, but zygotes with autosomal monosomies die even before implantation and are not found in the material of miscarriages.
In trisomies, the death of the embryos occurs at later stages, but not a single embryo in autosomal trisomies in mice survives to delivery.
Research by the Gropp group showed that, depending on the type of trisomy, embryos die at different times: with trisomies 8, 11, 15, 17 - up to 12 days after conception, with trisomies 19 - closer to the date of birth.
The pathogenesis of developmental arrest in chromosomal abnormalities
A study of the material of 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 fetal eggs", anembryony) (development stops before 2-3 weeks after conception). In other cases, it is possible to detect elements of the embryo, often unformed (stopping development for up to 3-4 weeks after conception). In the presence of chromosomal aberrations, embryogenesis is often or completely impossible, or is severely disturbed from the earliest stages of development. The manifestations of such disorders are much more pronounced in the case of autosomal monosomies, when the development of the zygote stops in the first days after conception, but in the case of trisomies of chromosomes, which are of key importance for embryogenesis, development also stops in the first days after conception. So, for example, trisomy 17 is found only in zygotes that have stopped in development at the earliest stages. In addition, many chromosomal abnormalities are generally associated with a reduced ability to divide cells, as shown by the study of cultures of such cells. in vitro.
In other cases, development can continue up to 5-6-7 weeks after conception, in rare cases longer. As Philip's studies have shown, in such cases, the death of the fetus is due not to a violation of embryonic development (detectable defects in themselves cannot be the cause of the death of the embryo), but to a violation of the formation and functioning of the placenta (the stage of development of the fetus is ahead of the stage of placental formation.
Studies of placental cell cultures with various chromosomal abnormalities have shown that in most cases the division of placental cells occurs much more slowly than with a normal karyotype. This largely explains why newborns with chromosomal abnormalities usually have low body weight and reduced placental mass.
It can be assumed that many developmental disorders in chromosomal aberrations are associated precisely with a reduced ability of cells to divide. In this case, there is a sharp dissynchronization of the processes of development of the embryo, development of the placenta and induction of cell differentiation and migration.
Insufficient and delayed formation of the placenta can lead to malnutrition and hypoxia of the fetus, as well as to a decrease in the hormonal production of the placenta, which may be an additional reason for the development of miscarriages.
Studies of cell lines in trisomies 13, 18 and 21 in newborns have shown that cells divide more slowly than in a normal karyotype, which is manifested in a decrease in cell density in most organs.
It is a mystery why, with the only autosomal trisomy compatible with life (trisomy 21, Down's syndrome), in some cases there is a delay in the development of the embryo in the early stages and spontaneous miscarriage, while in others - unimpaired development of pregnancy and the birth of a viable child. 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 are sharply different, which may explain the different fate of such zygotes.
Causes of quantitative chromosomal aberrations
The study of the causes of chromosomal aberrations is extremely difficult, primarily because of the high frequency, one might say, the universality of this phenomenon. It is very difficult to correctly collect a control group of pregnant women, with great difficulty they lend themselves to the study of disorders of spermatogenesis and oogenesis. Despite this, some etiological factors that increase the risk of chromosomal aberrations have been identified.
Factors directly related to parents
The effect of maternal age on the likelihood of having a child with trisomy 21 suggests a possible effect of maternal age on the likelihood of lethal chromosomal aberrations in the fetus. The table below shows the relationship between the age of the mother and the karyotype of the miscarriage material.
| The average age of the mother with 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 can be seen from the table, no relationship was found between maternal age and spontaneous miscarriages associated with monosomy X, triploidy, or tetraploidy. An increase in the average age of the mother was noted for autosomal trisomies in general, but different numbers were obtained for different groups of chromosomes. However, the total number of observations in the groups is not enough to confidently judge any patterns.
Maternal age is more associated with an increased risk of miscarriages with trisomies of acrocentric chromosomes of groups D (13, 14, 15) and G (21, 22), which also coincides with the statistics of chromosome aberrations in stillbirths.
For some cases of trisomies (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. No relationship was found between paternal age and an increased risk of trisomy.
In the light of animal studies, suggestions have been made about a possible link between gamete aging and delayed fertilization and the risk of chromosomal aberrations. Gamete aging is understood as the aging of spermatozoa in the female genital 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 (late fertilization in the tube). Most likely, similar laws operate in humans, but reliable evidence of this has not yet been received.
environmental factors
It has been shown that the likelihood of chromosomal aberrations at conception is increased in women exposed to ionizing radiation. It is assumed that there is a connection between the risk of chromosomal aberrations and the action of other factors, in particular, chemical ones.
Conclusion
1. Not every pregnancy can be saved for short periods. In a large percentage of cases, miscarriages are due to chromosomal abnormalities in the fetus, and it is impossible to give birth to a live child. Hormonal treatment can delay the moment of 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 can help increase the chance of conceiving a healthy child. In other cases, donor insemination or the use of a donor egg is recommended.
3. In case of miscarriage due to chromosomal factors, a woman's body can "remember" an unfavorable immunological response to a fetal egg (immunological imprinting). In such cases, it is possible to develop a rejection reaction to embryos conceived after donor insemination or using a donor egg. In such cases, a special immunological examination is recommended.
(trisomy 18, or trisomy on the 19th chromosome) is a rare genetic disease in which either part of the 18 human chromosome is duplicated or the entire pair of chromosomes is duplicated. People with such a defect usually have low birth weight, low intelligence, as well as multiple malformations, among which are pronounced microcephaly, malformed low-set auricles, 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 are women. A child with Edwards syndrome can appear in women over 30 years of age (although there are exceptions that are much less common). Only 12% of all children born with this defect live to an age at which it is already possible to assess the mental capabilities of the child. All surviving babies have, as a rule, already have serious defects at birth, so they do not live very long.
Causes of the development 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 has 23 pairs inherited from parents. And in each sex cell - the same number of sets: in men it is XY sperm, in women it is 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. She is the cause of the emergence and development of Edwards syndrome.
Instead of two copies, children with this syndrome have three copies of their 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 variant is a complete trisomy, which is very difficult and has all the signs of the disease.
I must say that there are two more types of mutations. Of all children with Edwards syndrome, 2% of children have a translocation in the 18th pair. This means that only part of the extra chromosome appeared in the 18th pair of chromosomes. 3% of children have mosaic trisomy - when an 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 newborns, 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 is clinically manifested as a delay or loss of the menstrual cycle. Some embryos die shortly after implantation (early miscarriages). Relatively few variants of numerical chromosome anomalies are compatible with postnatal development and lead to chromosomal diseases (Kuleshov N.P., 1979).
Chromosomal diseases appear as a result of damage to the genome 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 impaired ploidy; 2) caused by a violation of the number of chromosomes; 3) associated with changes in the structure of chromosomes.
Chromosome anomalies associated with ploidy disorders are represented by triploidy and tetraploidy, which occur mainly in the material of spontaneous abortuses. Only isolated cases of the birth of triploid children with severe malformations that are incompatible with normal life activity have been noted. Triploidy can occur both as a result of digeny (fertilization of a diploid egg by a haploid spermatozoon), and due to diandry (the reverse version) and dyspermy (fertilization of a haploid egg by two spermatozoa).
Chromosomal diseases associated with a violation of the number of individual chromosomes in a set are represented either by a whole monosomy (one of the two homologous chromosomes in the norm) or a whole trisomy (three homologues). Whole monosomy in live births occurs only on the X chromosome (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 the material of spontaneously aborted embryos and fetuses.
However, it should be noted that monosomy X with a fairly high frequency (about 20%) is detected in spontaneous abortions, which indicates its high prenatal mortality, which is over 99%. The cause of 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 that explain this fact, one of which links 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 disorders - up to 70% is observed in early abortions. Trisomy 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, whole mono- and trisomies on a number of chromosomes of a set occur in mosaic state both in spontaneous abortions and in children with CMHD (multiple congenital malformations).
Chromosomal diseases associated with a violation of the structure of chromosomes represent a large group of syndromes of partial mono- or trisomy. 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 a few of them form clearly diagnosed 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, as well as the fact that in the presence of a chromosomal translocation in one of the parents, partial trisomy on one chromosome in a child can be combined with partial monosomy on the other.
Clinical and cytogenetic characteristics of syndromes associated with numerical chromosome anomalies.
1. Syndrome Patau (trisomy on chromosome 13). First described in 1960. Cytogenetic variants can be different: whole trisomy 13 (nondisjunction of chromosomes during 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 anomalies of the structure: splitting of the soft and hard palate, cleft lips, underdevelopment or absence of eyes, malformed low-set ears, deformed bones of the hands and feet, numerous disorders of the internal organs, for example, congenital heart defects (defects of septa and large vessels) ). Deep idiotic. The life expectancy of children is less than a year, more often 2-3 months. The population frequency is 1 in 7800.
2. Edwards syndrome (trisomy on chromosome 18). Described in 1960. Cytogenetically, in most cases it is represented by a whole trisomy 18 (gametic mutation of one of the parents, more often on the maternal side). In addition, mosaic forms are also encountered, and translocations are observed very rarely. The critical segment responsible for the formation of the main features of the syndrome is the 18q11 segment. Clinical differences between cytogenetic forms were not found. Patients have a narrow forehead and a wide protruding nape, very low deformed ears, underdevelopment of the lower jaw, wide and short fingers. From
internal malformations should be noted combined malformations of the cardiovascular system, incomplete bowel rotation, malformations of the kidneys, etc. Children with Edwards syndrome have low birth weight. There is a delay in psychomotor development, idiocy and imbecility. Life expectancy up to a year - 2-3 months. The population frequency is 1 in 6500.
4. 
Down syndrome (trisomy of chromosome 21). First described in 1866 by the English physician Down. The population frequency is 1 case per 600-700 newborns. The frequency of birth of children with this syndrome depends on the age of the mother and increases sharply after 35 years. Cytogenetic variants are very diverse, but about Fig. 15. S. Downa (6) top (8) bottom
5.
95% of cases are represented by a simple trisomy of chromosome 21, as a result of nondisjunction of chromosomes 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 in which nondisjunction occurred. Despite intensive study of the syndrome, the causes of nondisjunction of chromosomes are still not clear. Etiologically important factors are intra- and extra-follicular over-ripening of the egg, a decrease in the number or absence of chiasmata in the first division of meiosis. 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 features 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, a transverse four-finger palmar fold (monkey furrow). Of the defects of the internal organs, congenital malformations of the heart and gastrointestinal tract are often noted, 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 anomalies of sex chromosomes.
1. Shereshevsky-Turner syndrome (X-chromosome monosomy). This is the only form of monosomy in humans that can be
found 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 arm of the X chromosome, iso-X chromosomes, and also 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 typical Shereshevsky-Turner syndrome to a normal male phenotype.
The population frequency is 1 in 3000 newborns. Patients have small stature, barrel-shaped chest, broad shoulders, narrow pelvis, shortened lower limbs. A very characteristic feature is a short neck with folds of skin extending from the back of the head (the neck of the sphinx). They have low hair growth at the back of the head, hyperpigmentation of the skin, decreased vision and hearing. The inner corners of the eyes are higher than the outer ones. Congenital malformations of the heart and kidneys are common. Patients have underdevelopment of the ovaries. Barren. Intellectual development is within the normal range. There is some infantilism of emotions, instability of mood. Patients are quite viable.
2. Polysomy X syndrome ( Trisomy X). Forms 47,ХХХ, 48,ХХХХ and 49,ХХХХХ are revealed cytogenetically. With an increase in the number of X chromosomes, the degree of deviation from the norm increases. In women with tetra- and pentasomy X, deviations in mental development, anomalies of the skeleton and genital organs are described. Women with a karyotype of 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 non-sharp deviations in physical development, ovarian dysfunction, premature menopause, but they can have offspring. The population frequency is 1 per 1000 newborn girls.
3. Klinefelter's syndrome. Described in 1942. The population frequency is 1 per 1000 boys. Cytogenetic variants of the syndrome may be different: 47.XXY: 48.XXYY; 48.XXXY; 49.XXXXY. Both complete and mosaic forms are noted. Patients of high stature with disproportionately long limbs. In childhood, they are distinguished by a fragile physique, and after 40 years they are obese. They develop an asthenic or eunuchoid body type: narrow shoulders, wide pelvis, female fat deposition, poorly developed
musculature, sparse facial hair. Patients have underdevelopment of the testes, lack of spermatogenesis, decreased sexual desire, impotence and infertility. Mental retardation usually develops. IQ below 80.
4. Syndrome of Y-chromosome polysemy (double-U or "extra Y chromosome"). The population frequency is 1 per 1000 boys. Cytogenetically marked complete and mosaic forms. Most individuals in physical and mental development do not differ from healthy ones. The gonads are developed normally, growth is usually high, there are some anomalies of the teeth and the skeletal system. Psychopathic traits are observed: instability of emotions, antisocial behavior, a tendency to aggression, homosexuality. Patients do not show significant mental retardation, and some patients generally have a normal 
intelligence. They can have normal offspring in 50% of cases.
Clinical and genetic characteristics of syndromes associated with structural rearrangements of chromosomes.
Syndrome "cat's cry" (monosomy 5p). Described in 1963. The population frequency is 1 in 50,000. Cytogenetic variants vary from partial to complete deletion of the short arm of chromosome 5. The 5p15 segment is of great importance for the development of the main features of the syndrome. In addition to a simple deletion, circular chromosomes 5, mosaic forms, as well as translocations between the short arm of chromosome 5 (with the loss of a critical segment) and another autosome were 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 incision of the eyes, strabismus, moon-shaped face, wide bridge of the nose. The auricles are low-set and deformed. There is a transverse palmar fold, anomalies in the structure of the hands and fingers. Mental retardation in the stage of imbecile. It should be noted that such signs as a moon-shaped face and a cat's cry are smoothed out with age, and microcephaly and strabismus come to light more clearly. Life expectancy depends on the severity of congenital malformations of the 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 and cytogenetic studies have begun to rely on high-resolution methods of chromosomal analysis, which 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 no more than 400 segments, and using the methods of prometaphase analysis proposed by Younis in 1976, it is possible to obtain chromosomes with up to 550-850 segments. Minor disorders in the structure of chromosomes can be detected using these methods of chromosomal analysis not only among patients with CMHD, but also in some unknown mendelian syndromes, various malignant tumors. Most of the syndromes associated with chromosomal microabnormalities are rare - 1 case per 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 link with a chromosomal pathology has been established. Cytogenetically, this disease reveals a microdeletion of chromosome 13, segment 13q14. In addition to microdeletions, there are mosaic forms and translocation variants. 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 the glow of the pupils, a sluggish reaction of the pupil to light, and then a decrease in vision up to blindness. Complications of retinoblastoma are retinal detachment, secondary glaucoma. In 1986, a tumor suppressor gene was discovered in the critical segment 13ql4 RBI, which was the first anti-oncogene discovered in humans.
Monogenic diseases manifested by chromosomal instability.
To date, new types of genome variability have been established that differ 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 chromosome aberrations and sister chromatid exchanges (SChO). For the first time, an increased frequency of spontaneous chromosomal aberrations was shown in 1964 in patients with Fanconi anemia, and an increased frequency of CHO was found in Bloom's syndrome. In 1.968, it was found that xeroderma pigmentosa - 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 (repair) their DNA from damage caused by UV radiation.
At present, about one and a half dozen monogenic pathological signs associated with increased fragility of chromosomes are known. In these diseases, there are no specific sites 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 differ in their clinical manifestations, all of them are characterized by an increased tendency to malignant neoplasms, signs of premature aging, neurological disorders, immunodeficiency states, congenital malformations, skin manifestations, and 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 data has been accumulating that, in addition to diseases manifested by instability of the chromosome structure, there are also monogenic defects that lead to diseases with instability in the number of chromosomes. Rare pathological conditions can be distinguished as such an independent group of monogenic diseases, indicating a non-random, hereditarily determined nature of non-disjunction of chromosomes in somatic cells during embryogenesis.
Cytogenetic examination of these patients in a small part of the cells (usually 5-20%) reveals somatic mosaicism on several chromosomes of the set at once, or one married couple may have several sibs with chromosomal mosaicism. It is assumed that such patients are "mitotic mutants" for recessive genes that control individual stages of the passage of mitosis. There is no doubt that most of these mutations are lethal, and surviving individuals have relatively mild forms of pathology of cell division. Despite the fact that the above diseases are caused by defects in individual genes, conducting a cytogenetic study in patients with suspected this pathology will help the doctor in the differential diagnosis of these conditions.
Diseases with instability of the structure of chromosomes:
Bloom syndrome. Described in 1954. The main diagnostic features are: low birth weight, growth retardation, narrow face with butterfly erythema, massive nose, immunodeficiency states, susceptibility to malignant neoplasms. Mental retardation is noted not in all cases. It is cytogenetically characterized by an increase in the number of sister chromatid exchanges (SChO) per cell up to 120-150, although normally their number does not exceed 6-8 exchanges per 1 cell. In addition, chromatid breaks are detected with a high frequency, as well as dicentrics, rings, and chromosome fragments. Patients have mutations in the DNA ligase 1 gene located on chromosome 19 - 19q13.3, but the Bloom syndrome gene is mapped in the 15q26.1 segment.
Anemia Fanconi . A disease with an autosomal recessive mode of inheritance. Described in 1927. The main diagnostic features: hypoplasia of the radius and thumb, growth and developmental delay, hyperpigmentation of the skin in the inguinal and axillary areas. In addition, bone marrow hypoplasia, a tendency to leukemia, and hypoplasia of the external genital organs are noted. It is cytogenetically characterized by multiple chromosomal aberrations - chromosome breaks and chromatid exchanges. This is a genetically heterogeneous disease, i.e. a clinically similar phenotype is due to mutations in different genes. There are at least 7 forms of this disease: A - the gene is localized in the 16q24.3 segment; B - localization of the gene is unknown; C - 9q22.3; D - Зр25.3; E - 6r22; F - 11r15; G (MIM 602956) - 9r13. The most common form is A - about 60% of patients.
Werner syndrome (syndrome of premature aging). A disease with an autosomal recessive mode of inheritance. Described in 1904. The main diagnostic features are: premature graying and baldness, atrophy of subcutaneous adipose tissue and muscle tissue, cataracts, early atherosclerosis, endocrine pathology (diabetes mellitus). Infertility, a high voice, a tendency to malignant neoplasms are characteristic. Patients die at the age of 30-40 years. Cytogenetically characterized by cell clones with different chromosomal translocations (mosaicism for different translocations). The disease gene is located 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 brittle sites 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 found - in the distal part of the long arm of the X chromosome in the Xq27.3 segment, a gap or gap of chromatids 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 as early as 1943 by English doctors P. Martin and Y. Bell. Martin-Bell syndrome or fragile X syndrome is characterized by a fragile (fragil) X chromosome in the Xq27.3 segment, which is detected under special cell culture conditions in a folic acid-deficient medium.
The fragile site in this syndrome was designated FRAXA. The main diagnostic signs of the disease are: mental retardation, a broad face with features of acromegaly, large protruding ears, autism, hypermobility, poor concentration, speech defects, more pronounced in children. There are also connective tissue abnormalities with joint hyperextensibility and mitral valve defect. Only 60% of men with a fragile X chromosome have a relatively complete range of clinical signs, 10% of patients do not have 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). An unusual inheritance is that only 80% of males carrying the mutant gene have signs of the disease, while 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, 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, a gene mutation in Martin-Bell syndrome exists in two forms that differ in their penetrance: the first form is a phenotypically non-manifested premutation that turns into a full mutation (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 found. At the same time, the phenomenon of anticipation is well traced - 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 this disease was characterized. The gene was named FMR1 (English - Fragile site Mental Retardation 1 - a fragile region of the chromosome associated with the development of type 1 mental retardation). It was found that the basis of clinical manifestations and cytogenetic instability in the Xq27.3 locus is a multiple increase in the first exon of the FMR-1 gene of the simple trinucleotide repeat CGG.
In normal people, the number of these repeats on the X chromosome ranges from 5 to 52, while in sick people their number is 200 or more. Such a phenomenon of a sharp, spasmodic change in the number of CGG repeats in patients was called the expansion of the number of trinucleotide repeats: It was shown that the expansion of CGG repeats significantly depends on the sex of the offspring, it is noticeably increased when the mutation is transmitted from mother to son. It is important to note that the expansion of nucleotide repeats is a postzygotic event and occurs at very early stages of 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 only to Down's syndrome in frequency). The disease is characterized by numerous disorders in the development of various organs and systems. The prognosis for a child is usually unfavorable, but much depends on the care that parents are able to provide him.
The prevalence of Edwards syndrome around the globe varies from 0.015 to 0.02%. There is no clear dependence on locality 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 some 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
- The 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. First, this required an appropriate level of technological development that would allow the detection of an 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 ( the appearance of an extra 18th chromosome) was made only in 1960 by the physician John Edward, after whom the new pathology was then named.
- The real frequency of Edwards syndrome is 1 case per 2.5 - 3 thousand conceptions ( 0,03 – 0,04% ), but the official figures are much lower. This is due to 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. A detailed diagnosis of the cause of a 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 chromosomes) and Patau ( trisomy 13 chromosomes). In the presence of other extra chromosomes, the pathology is incompatible with life. Only in these three cases is it possible to have a live child 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 extra 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 couples), which are a multiply packed DNA molecule ( Deoxyribonucleic acid). This molecule contains certain sections called genes. Each gene is the prototype for a specific protein in the human body. If necessary, the cell reads information from this prototype and produces the appropriate 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 linked together 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 pair of chromosomes, which are large 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 pair of chromosomes, which resemble the chromosomes of group B in shape, but are inferior to them in size;
- group D includes 13 - 15 pair of chromosomes, which are characterized by medium size and location of the centromere at the very end of the molecules, which gives a resemblance to the letter V;
- group E includes 16 - 18 pair of chromosomes, which are characterized by small size and median location of the centromere ( X shape);
- group F includes 19-20 chromosome pairs, which are somewhat smaller than the E group chromosomes and similar in shape;
- group G includes 21 - 22 pairs of chromosomes, which are characterized by a V-shape and very small sizes.
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 implies the presence of an extra 18th chromosome. The karyotype in such cases is designated as 47,XX, 18+ ( for girl) and 47,XY, 18+ ( for boy). The last digit indicates the number of the extra chromosome. An excess of genetic information in the cells leads to the appearance of the corresponding manifestations of the disease, which are combined under the name "Edwards syndrome". The presence of an 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:
- Complete trisomy 18. The full or classic form of Edwards syndrome suggests that all cells in the body have 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 extra chromosome, but only a fragment of it. Such a defect may 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 ( penetrates 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 another part of the 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 of not all genetic information encoded in the 18th chromosome, but only part of it. For patients with partial trisomy 18, the prognosis is better than for children with the complete form, but still remains unfavorable.
- 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 spermatozoon and the egg. Both gametes ( sex cells) initially had a normal karyotype and carried one chromosome of each species. After the fusion, a cell with a normal formula 46,XX or 46,XY was formed. In the process of dividing this cell, a failure occurred. When doubling the genetic material, one of the fragments received an additional 18th chromosome. Thus, at a certain stage, an embryo was formed, some of the cells of which have a normal karyotype ( e.g. 46,XX), and part is the 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 smaller will be the proportion of defective cells. The shape got its name due to the fact that all the cells of the body are a kind of mosaic. Some of them are healthy, and some have severe genetic pathology. At the same time, there are no patterns 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. The general condition of the patient is easier than with the classic form of trisomy 18.
According to recent studies, chromosome number 18 contains 557 genes that code for 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 predetermines 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 suffer more often than others. Apparently, this is due to the fact that the genes located on this chromosome are related to the development of these organs and systems.
Thus, the main and only cause of Edwards syndrome is the presence of an additional DNA molecule. most frequently ( in the classical form of the disease) 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 sends a child a standard set of 22+X, and a man can send 22+X or 22+Y. This determines the gender of the child. The germ cells of the parents are formed as a result of the division of ordinary cells into two sets. Normally, the mother cell divides into two equal parts, but sometimes not all chromosomes divide in half. If the 18th pair did not disperse along the poles of the cell, then one of the eggs ( or one of the sperm) will be defective in advance. It will not have 23, but 24 chromosomes. If it is this cell that participates in fertilization, the child will receive an additional 18th chromosome.
The following factors can affect improper cell division:
- Age of parents. It has been proven that the probability of chromosomal abnormalities increases in direct proportion with the age of the mother. In Edwards syndrome, this relationship is less pronounced than in other similar pathologies ( e.g. Down syndrome). But for women over 40, the risk of having a child with this pathology is on average 6-7 times higher. A similar dependence on the age of the father is observed to a much lesser extent.
- Smoking and alcohol. Such bad habits as smoking and alcohol abuse can affect the human reproductive system, affecting the division of germ cells. Thus, regular use of these substances ( as well as other drugs) increases the risk of misallocation of genetic material.
- Taking medicines. Some medications, if taken incorrectly in the first trimester, can affect germ cell division and provoke a mosaic form of Edwards syndrome.
- Diseases of the genital area. Past infections with damage to the reproductive organs can affect the correct division of cells. They increase the risk of chromosomal and genetic disorders in general, although such studies have not been conducted specifically for Edwards syndrome.
- radiation radiation. Exposure of the genital organs to x-rays or other ionizing radiations can cause genetic mutations. Such external influence is especially dangerous in adolescence, when cell division is most active. The particles that form the radiation easily penetrate tissues and expose the DNA molecule to a kind of “bombardment”. If this happens at the time of cell division, the risk of chromosomal mutation is especially high.
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 a child. Newborns with this pathology have a number of pronounced developmental anomalies, which sometimes make it possible to immediately suspect the correct diagnosis. Confirmation is carried out later with the help of a special genetic analysis. Newborns with Edwards syndrome have the following characteristic developmental anomalies:
- change in the shape of the skull;
- change in the shape of the ears;
- anomalies in the development of the sky;
- foot-rocking chair;
- abnormal length of fingers;
- change in the shape of the lower jaw;
- fusion of fingers;
- anomalies in the development of the genital organs;
- flexor position of the hands;
- dermatoglyphic features.
Changing the shape of the skull
A typical symptom in 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) a longer and narrower skull. The presence of this anomaly is precisely confirmed by 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 occiput). If the resulting ratio is less than 75%, then this child belongs to dolichocephals. By itself, this symptom is not a serious violation. This is just one type of skull shape that is also found in completely normal people. Children with Edwards syndrome in 80 - 85% of cases are pronounced dolichocephalic, in which the disproportion in the length and width of the skull can be seen even without special measurements. Another variant of an anomaly in the 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 variant of the norm, then the pathology of the development of the auricle in children with Edwards syndrome is much more severe. To some extent, this symptom is observed in more than 95% of children with the full form of this disease. With a mosaic form, its frequency is somewhat less. The auricle is usually located lower than in normal people ( sometimes below eye level). The characteristic bulges of the cartilage that forms the auricle are poorly defined or absent. The earlobe or tragus may also be absent ( a small protruding area of cartilage in front of the auditory canal). The ear canal itself is usually narrowed, and in about 20-25% it is completely absent. Anomalies in the development of the sky
The palatine processes of the upper jaw fuse together during the development of the embryo, forming a 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 gap. There are several variants of this defect:
- non-occlusion of the soft palate ( back, deep part of the palate that hangs over the pharynx);
- partial non-closure of the hard palate ( the gap does not stretch throughout the entire upper jaw);
- complete non-closure of the hard and soft palate;
- complete non-closure of the palate and lips.
These developmental defects are also known as cleft palate, cleft palate, and cleft lip. All of them can occur outside of Edwards syndrome, however, in children with this pathology, their frequency is especially high ( almost 20% of newborns). Much more frequently ( up to 65% of newborns) have a different feature known as the high or gothic sky. It can be attributed to the variants of the norm, as it is also found in healthy people.
The presence of a cleft palate or upper lip does not yet confirm Edwards syndrome. This malformation can occur with a fairly high frequency and independently without concomitant disorders from other organs and systems. There are a number of standard surgical interventions to correct this anomaly.
Rocking foot
This is the name of a characteristic change in the foot, which occurs mainly in the framework of Edwards syndrome. Its frequency in this disease reaches 75%. The defect lies in the incorrect position of the talus, calcaneus and scaphoid bones. It belongs to the category of flat-valgus deformities of the foot in children. Outwardly, the foot of a newborn child looks like this. The calcaneal tubercle, on which the back of the foot rests, protrudes backwards. In this case, the vault may be completely absent. This is easy to see by looking at the foot from the inside. Normally, a concave line appears there, heading from the heel to the base of the big toe. With a rocking stop, this line is absent. The foot is flat or even convex. This gives it a resemblance to the legs of a rocking chair.
Abnormal finger length
In children with Edwards syndrome, an abnormal proportion in the length of the toes may be observed against the background of changes in the structure of the foot. 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 be seen only when straightening the fingers and carefully examining them. With age, as the child grows, it becomes more noticeable. Since shortening of the big toe occurs mainly with rocking foot, the prevalence of these symptoms in newborns is about the same. In adults, shortening of the big toe does not have such diagnostic value. Such a defect may be an individual feature in a healthy person or a consequence of other factors ( joint deformity, bone disease, 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 forward as in adults, but in patients with Edwards syndrome, it is too much retracted. This is due to the underdevelopment of the lower jaw, which is called micrognathia ( microgenia). This symptom is also found in other congenital diseases. It is not uncommon 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 develop the following problems quickly:
- inability to keep the mouth closed for a long time ( drooling);
- feeding difficulties;
- late development of teeth and their incorrect location.
Finger fusion
Finger fusion, or scientifically syndactyly, occurs in approximately 45% of newborns. Most often, this anomaly affects the toes, but syndactyly on the hands is also found. In mild cases, the fusion is formed by a skin fold like a short membrane. In more severe cases, fusion with bridges of bone tissue is observed. Syndactyly occurs not only in Edwards syndrome, but also in many other chromosomal diseases. There are also cases when this malformation was the only one, and otherwise the patient did not differ in any way from normal children. In this regard, fusion of the fingers 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 childbirth in newborns with Edwards syndrome, abnormalities in the development of the external genital organs can sometimes be observed. As a rule, they are combined with defects in the development of the entire genitourinary apparatus, but this cannot be established without special diagnostic measures. The most common anomalies, visible externally, are underdevelopment of the penis in boys and hypertrophy ( increase in size) clitoris in girls. They occur in about 15-20% of cases. Somewhat less often, an abnormal location of the urethra can be observed ( hypospadias) or absence of testicles in the scrotum in boys ( cryptorchidism).Flexor 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 area of the hand as by increased muscle tone. The flexors of the fingers and hands are constantly tense, which is why the thumb and little finger seem to cover the rest of the fingers, which are pressed to the palm. This symptom is observed in many congenital pathologies and is not characteristic of Edwards syndrome. However, if a brush of a similar shape is found, this pathology must be assumed. With it, the flexor position of the fingers is observed in almost 90% of newborns. Dermatoglyphic features
With many chromosomal abnormalities, newborns have characteristic dermatoglyphic changes ( abnormal patterns and folds on the skin of the palms). With Edwards syndrome, some signs can be found in almost 60% of cases. They are important mainly for preliminary diagnosis in case of a mosaic or partial form of the disease. With complete trisomy 18, dermatoglyphics is not resorted to, since there are enough other, more noticeable developmental anomalies to suspect Edwards syndrome. The main dermatoglyphic features of Edwards syndrome are:
- arches on the fingertips are located more frequently than in healthy people;
- skin fold between the last ( nail) and penultimate ( middle) phalanges of the fingers are absent;
- 30% of newborns have a so-called transverse groove in the palm ( monkey line, simian line).
In addition to the above signs, there are a number of possible developmental anomalies that can help in the preliminary diagnosis of Edwards syndrome. According to some data, with a detailed external examination, up to 50 external signs can be detected. The combination of the most common symptoms presented above indicates with a high probability that the child has this severe pathology. With a mosaic variant 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 usually 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 a mosaic variant, in rare cases, the disease may go unnoticed immediately after birth. Then the diagnosis of the disease becomes more complicated. Most of the outward manifestations of the syndrome seen at birth remain and become more noticeable. We are talking about the shape of the skull, rocking foot, deformity of the auricle, etc. Gradually, other external manifestations begin to add to them that 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:
- lag in physical development;
- clubfoot;
- abnormal muscle tone;
- abnormal emotional reactions.
Lag in physical development
The lag in physical development is explained by the low body weight of the child at birth ( only 2000 - 2200 g at a normal gestational age). A genetic defect also plays a significant role, which does not allow all body systems to develop normally and harmoniously. The main indicators by which the growth and development of the child are assessed are greatly reduced.You can notice the backlog of a child by the following anthropometric indicators:
- child's height;
- child's weight;
- chest circumference;
- Head circumference ( this indicator may be normal or even increased, but cannot be relied upon due to congenital deformity of the skull).
Clubfoot
Clubfoot is the result of deformation of the bones and joints of the feet, as well as the lack of normal control from the nervous system. Children have difficulty walking most do not survive to this stage due to congenital malformations). Outwardly, the presence of clubfoot can be judged by the deformity of the feet, the abnormal position of the legs at rest.Abnormal muscle tone
The abnormal tone, which at birth causes a flexor position of the hand, begins to manifest itself in other muscle groups as it grows. Most often, in children with Edwards syndrome, muscle strength is reduced, they are sluggish and lack normal tone. Depending on the nature of the damage to the central nervous system, some groups may have an increased tone, which is manifested by spastic contractions of these muscles ( e.g. arm flexors or leg extensors). Outwardly, this is manifested by the lack of minimal coordination of movements. Sometimes spastic contractions lead to abnormal kinking of the limbs or even to dislocations.Abnormal emotional reactions
The absence or abnormal manifestation of any emotions is the result of anomalies in the development of some parts of the brain ( most often cerebellum and corpus callosum). These changes lead to a serious mental retardation, which is observed in all, without exception, children with Edwards syndrome. Outwardly, a low level of development is manifested by a characteristic "absent" facial expression, lack of an emotional response to external stimuli. The child is unable to maintain eye contact does not follow a finger moving in front of the eyes, etc.). Lack of response to sharp sounds may be the result of damage to both the nervous system and the hearing aid. All these signs are found 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 anomalies in the development of internal organs. Even with the surgical correction of possible defects and quality care, their body is more susceptible to infectious diseases. This is facilitated by eating disorders that occur in most children. All this explains the highest mortality in Edwards syndrome. With a milder mosaic form, when only a fraction of the cells in the body contain an abnormal set of chromosomes, the survival rate is somewhat greater. 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 auricle, etc.). The main symptom, present in all children without exception, is a serious mental retardation. Having lived to adulthood, a child with Edwards syndrome is a deep oligophrenic ( IQ less than 20, which corresponds to the most severe degree of mental retardation). In general, isolated cases are described in the medical literature when children with Edwards syndrome survived to adulthood. Because of this, too little objective data has been accumulated to talk about the external signs of this disease in adults.
Diagnosis of genetic pathology
Currently, there are three main stages in the diagnosis of 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 use them. Most of the tests are carried out in special centers for prenatal diagnosis, where there is all the necessary equipment to search for genetic diseases. However, even a consultation with a geneticist or neonatologist can be helpful. Diagnosis of Edwards syndrome is possible at the following stages:
- diagnosis before conception;
- diagnosis during fetal development;
- diagnosis after birth.
Diagnosis before conception
Diagnosis before the conception of a child is an ideal option, but, unfortunately, at the present stage of development of medicine, its possibilities are very limited. Doctors can use several methods to suggest an increased chance of having a child with a chromosomal disorder, but no more. The fact is that with Edwards syndrome, in principle, violations in parents cannot be detected. A defective sex cell with 24 chromosomes is just one of many thousands. Therefore, it is impossible to say for sure until 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 syndrome, Down syndrome, Patau), which greatly increases the likelihood of having a sick child. However, the risk is still less than 1%. With repeated cases of these diseases in ancestors, the risk increases many times over. In fact, the analysis comes down to a consultation with a neonatologist or geneticist. Previously, parents can try to collect more detailed information about their ancestors ( preferably 3-4 knees). This will improve the accuracy of this method.
- Detection of risk factors. The main risk factor that objectively increases the risk of chromosomal abnormalities is the age of the mother. As mentioned above, in mothers after 40 years, 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 a chromosomal pathology. Most of them end in miscarriage. Other factors are past 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 the previous methods were limited to interviewing parents, then genetic analysis is a complete 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 in these cells, chromosomes at the division stage become clearly visible. Thus, the karyotype of the parents is compiled. In most cases it is normal with chromosomal disorders that can be found here, the probability of procreation is negligible). In addition, with the help of special markers ( fragments of molecular chains) it is possible to detect sections of DNA with defective genes. However, not chromosomal abnormalities will be found here, but genetic mutations that do not directly affect the likelihood of Edwards syndrome. Thus, the genetic analysis of parents before the moment of conception, despite the complexity and high cost, also does not give an unambiguous answer regarding the prognosis for this pathology.
Diagnosis during fetal development
During fetal development, there are several ways that can directly or indirectly confirm the presence of a chromosomal pathology in the embryo. The accuracy of these methods is much higher, since doctors are not dealing with 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 the woman decides to give birth and the newborn is alive, then the doctors will be able to prepare in advance to provide him with the necessary assistance.The main research methods in the framework of prenatal diagnosis are:
- Ultrasound procedure ( 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 is recommended for all pregnant women as part of prenatal diagnosis ( regardless of their age or increased risk for chromosomal disorders). The standard program suggests that ultrasound should be done three times ( at 10 - 14, 20 - 24 and 32 - 34 weeks of pregnancy). If the attending physician assumes the possibility of congenital malformations, unplanned ultrasound may also be performed. Edwards syndrome can be indicated by the lag of the fetus in size and weight, a large amount of amniotic fluid, visible developmental anomalies ( microcephaly, bone deformity). These disorders are highly likely to indicate severe genetic diseases, but Edwards syndrome cannot be definitively confirmed.
- Amniocentesis. Amniocentesis is a cytologic ( cellular) analysis of amniotic fluid. The doctor gently 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. With the help of a syringe, the amount of amniotic fluid necessary for the study is taken. The procedure can be performed in all trimesters of pregnancy, but the optimal time for the diagnosis of 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 carried out in the absence of any indications. After the amniotic fluid is taken, the obtained material is processed. They contain liquid cells from the surface of the baby's skin, which contain samples of his DNA. It is they 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 pierces a vessel passing through the umbilical cord with a special needle. Thus, a blood sample is obtained ( up to 5 ml) of a developing child. The analysis technique is similar to that for adults. This material can be examined with high accuracy for various genetic anomalies. This includes fetal karyotyping. In the presence of an additional 18th chromosome, we can talk about confirmed Edwards syndrome. This analysis is recommended after the 18th week of pregnancy ( optimal 22 - 25 weeks). The frequency of possible complications after cordocentesis is 1.5 - 2%.
- Chorionic biopsy. The chorion is one of the germinal 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 taken for analysis. Then a standard genetic study of the obtained material is carried out. Karyotyping is done to diagnose Edwards syndrome. The optimal time for a chorion biopsy is considered 9-12 weeks of pregnancy. The frequency of complications is 2 - 3%. The main advantage that distinguishes it from other methods is the speed of obtaining the result ( within 2-4 days).
Diagnosis after birth
Diagnosis of Edwards syndrome after birth is the easiest, fastest and most accurate. Unfortunately, at that moment, a child with a severe genetic pathology was already born, for which there is no effective treatment in our time. If the disease was not detected at the stage of prenatal diagnosis ( or relevant studies have not been conducted), the suspicion of Edwards syndrome appears immediately after birth. The child is usually full-term or even post-term, but his weight is still below the average. In addition, some of the birth defects mentioned above attract attention. If they are noticed, genetic analysis is performed to confirm the diagnosis. The child takes blood for analysis. However, at this stage, confirming the presence of Edwards syndrome is not the main problem.The main task at the birth of a child with this pathology is the detection of anomalies in the development of internal organs, which usually lead to death in the first months of life. It is on their search that most diagnostic procedures are directed immediately after birth.
To detect defects in the development of internal organs, the following research methods are used:
- ultrasound examination of the 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 age of the mother over 35 years. The program of diagnostics and management of the patient at all stages of pregnancy can be changed by the attending physician if 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) say that more than half of the children ( 50 – 55%
) do not live past 3 months of age. Less than ten percent of babies manage to celebrate their first birthday. Those children who survive to older age have serious health problems and need constant care. To prolong life, complex surgical operations on the heart, kidneys, or other internal organs are often necessary. Correction of birth defects and constant skilled care are, in fact, the only treatment. In children with the classic form of Edwards syndrome ( complete trisomy 18) there are practically no chances for a normal childhood or any long life. With partial trisomy or mosaic form of the syndrome, the prognosis is somewhat better. In this case, 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. Nevertheless, the main problem, namely a serious mental retardation, is inherent in all patients without exception. Upon reaching adolescence, there is no chance of either continuing offspring ( puberty usually does not occur), nor the possibility of 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 cared for and, if possible, promote their intellectual development. With enough 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 malformations of the digestive system). Thus, signs of development are still observed.
High infant mortality due to this disease is explained by a large number of malformations of internal organs. They are invisible directly 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, malformations are observed in the following organs and systems:
- musculoskeletal system ( bones and joints, including the skull);
- the cardiovascular system;
- central nervous system;
- digestive system;
- urinary system;
- other violations.
Musculoskeletal system
The main malformations in the development of the musculoskeletal system are the abnormal position of the fingers and curvature of the feet. In 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 chest as a whole and creates breathing problems that get worse with growth, even if the lungs themselves are not affected.Skull malformations are mostly cosmetic. However, vices such as cleft palate, cleft lip and high palate create serious difficulties in feeding the child. Often, prior to surgery 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, a special tube through which food enters directly into the stomach. Its establishment requires a separate surgical intervention.
In general, malformations of the musculoskeletal system do not pose a direct threat to the life of the child. 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 transporting blood through the body, leading to severe heart failure. Most cardiac pathologies can be corrected surgically, but not every child can undergo such a complex operation.The most common anomalies of the cardiovascular system are:
- non-closure of the interatrial septum;
- non-closure of the interventricular septum;
- fusion of the valve leaflets ( or, conversely, their underdevelopment);
- coarctation ( constriction) aorta.
central nervous system
The most characteristic defect from the side of the central nervous system is the underdevelopment of the corpus callosum and cerebellum. This is the cause of a wide variety of disorders, including mental retardation, which is observed in 100% of children. In addition, disorders at the level of the brain and spinal cord cause abnormal muscle tone and a predisposition to convulsions or spastic muscle contractions.Digestive system
The frequency of malformations of the digestive system in Edwards syndrome is up to 55%. Most often, these developmental anomalies pose a serious threat to the life of the child, because they do not allow him to properly absorb nutrients. Eating bypassing the natural digestive organs greatly weakens the body and aggravates the condition of the child.The most common malformations of the digestive system are:
- Meckel's diverticulum caecum in the small intestine);
- esophageal atresia overgrowth of its lumen, due to which food does not pass into the stomach);
- biliary atresia ( accumulation of bile in the bladder).
genitourinary system
The most serious malformations of the genitourinary system are associated with a violation of the kidneys. In some cases, atresia of the ureters is observed. The kidney on one side can be duplicated or fused with adjacent tissues. If there is a violation of filtration, 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 work of the heart. Serious anomalies in the development of the kidneys pose a direct threat to life.Other violations
Other possible developmental disorders are hernias ( umbilical, inguinal) . Disc herniations of the spine can also be detected, which will lead to neurological problems. From the side of the eyes, microphthalmia is sometimes observed ( small eyeballs).The combination of these malformations 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 severity of the disease and the poor prognosis, many people prefer to hope for the best. But, unfortunately, in the near future, major changes in the methods of diagnosis and treatment of Edwards syndrome, apparently, are not expected.
