Trisomy and its causes. Diagnosis after birth

Approximately 1 in 150 children are born with chromosomal abnormality. These abnormalities are caused by errors in the number or structure of chromosomes. Many children with chromosomal problems have mental and/or physical birth defects. Some chromosomal problems eventually lead to miscarriage or stillbirth.

Chromosomes are thread-like structures found in the cells of our body and containing a set of genes. Humans have between 20,000 and 25,000 genes that determine traits such as eye and hair color and are responsible for the growth and development of every part of the body. Each person normally has 46 chromosomes, arranged in 23 chromosome pairs, in which one chromosome is inherited from the mother, and the second from the father.

Causes of chromosomal abnormalities

Chromosomal pathologies are usually the result of an error that occurs during the maturation of the sperm or egg. Why these errors occur is not yet known.

Eggs and sperm cells normally contain 23 chromosomes. When they fuse, they form a fertilized egg with 46 chromosomes. But sometimes during (or before) fertilization, something goes wrong. So, for example, an egg or sperm cell may develop abnormally, as a result of which they may have extra chromosomes, or, conversely, there may not be enough chromosomes.

In this case, cells with the wrong number of chromosomes join a normal egg or sperm cell, as a result of which the resulting embryo has chromosomal abnormalities.

The most common type chromosomal abnormality called trisomy. This means that instead of having two copies of a particular chromosome, a person has three copies. For example, they have three copies of the 21st chromosome.

In most cases, an embryo with the wrong number of chromosomes does not survive. In such cases, a woman has a miscarriage, usually in the early stages. This often happens very early in pregnancy, before a woman can even realize she is pregnant. More than 50% of miscarriages in the first trimester are caused by chromosomal abnormalities in the embryo.

Other errors may occur before fertilization. They can lead to a change in the structure of one or more chromosomes. People with structural chromosomal abnormalities usually have a normal number of chromosomes. However, small pieces of a chromosome (or an entire chromosome) may be deleted, copied, flipped, misplaced, or exchanged with part of another chromosome. These structural rearrangements may not have any effect on a person if he has all the chromosomes, but they are simply rearranged. In other cases, such rearrangements can lead to pregnancy loss or birth defects.

Errors in cell division can occur shortly after fertilization. This can lead to mosaicism, a condition in which a person has cells with different genetic sets. For example, people with a form of mosaicism, Turner syndrome, lack an X chromosome in some, but not all, cells.

Diagnosis of chromosomal abnormalities

Chromosomal abnormalities can be diagnosed before the baby is born by prenatal tests such as amniocentesis or chorion biopsy, or after birth by a blood test.

The cells resulting from these tests are grown in a laboratory and then their chromosomes are examined under a microscope. The laboratory makes an image (karyotype) of all human chromosomes, arranged in order from largest to smallest. A karyotype shows the number, size, and shape of chromosomes and helps doctors identify any abnormalities.

The first prenatal screening consists of taking maternal blood for analysis in the first trimester of pregnancy (between 10 and 13 weeks of pregnancy), as well as a special ultrasound examination of the back of the baby's neck (the so-called collar space).

The second prenatal screening is carried out in the second trimester of pregnancy and consists of a maternal blood test between 16 and 18 weeks. This screening allows you to identify pregnancies that are at higher risk for the presence of genetic disorders.

However, screening tests cannot accurately diagnose Down syndrome or others. Doctors suggest that women who have abnormal screening test results undergo additional tests such as chorionic biopsy and amniocentesis to definitively diagnose or rule out these disorders.

The most common chromosomal abnormalities

The first 22 pairs of chromosomes are called autosomes or somatic (non-sex) chromosomes. The most common disorders of these chromosomes include:

1. Down syndrome (trisomy 21 chromosomes) - one of the most common chromosomal abnormalities, diagnosed in about 1 in 800 babies. People with Down syndrome have varying degrees of intelligence, facial features, and often congenital anomalies in the development of the heart and other problems.

Modern prospects for the development of children with Down syndrome are much brighter than they were before. Most of them have mild to moderate intellectual disability. With early intervention and special education, many of these children learn to read and write and participate in activities from childhood.

The risk of Down syndrome and other trisomies increases with maternal age. The risk of having a child with Down syndrome is approximately:

• 1 in 1300 if the mother is 25 years old;
• 1 in 1000 if the mother is 30 years old;
• 1 in 400 if the mother is 35 years old;
• 1 out of 100 if the mother is 40 years old;
• 1 in 35 if the mother is 45 years old.

2. Trisomy 13 and 18 chromosomes These trisomies are usually more severe than Down's syndrome, but fortunately are quite rare. Approximately 1 in 16,000 babies are born with trisomy 13 (Patau syndrome), and 1 in 5,000 babies are born with trisomy 18 (Edwards syndrome). Children with trisomies 13 and 18 usually suffer from severe abnormalities in mental development and have many congenital physical defects. Most of these children die before the age of one.

The last, 23rd, pair of chromosomes are the sex chromosomes, called X chromosomes and Y chromosomes. As a rule, women have two X chromosomes, while men have one X chromosome and one Y chromosome. Sex chromosome abnormalities can cause infertility, growth disorders, and learning and behavioral problems.

The most common sex chromosome abnormalities include:

1. Turner syndrome - This disorder affects approximately 1 in 2500 female fetuses. A girl with Turner syndrome has one normal X chromosome and is completely or partially missing a second X chromosome. As a rule, such girls are infertile and do not undergo the changes of normal puberty unless they take synthetic sex hormones.

Girls affected by Turner syndrome are very short, although treatment with growth hormone may help increase height. In addition, they have a whole range of health problems, especially with the heart and kidneys. Most girls with Turner syndrome have normal intelligence, although they experience some learning difficulties, especially in mathematics and spatial reasoning.

2. Trisomy X chromosome Approximately 1 in 1000 women have an extra X chromosome. These women are very tall. They usually do not have physical birth defects, they have normal puberty and are capable of childbearing. Such women have a normal intellect, but there may be serious problems with study.

Since such girls are healthy and have a normal appearance, their parents often do not know that their daughter has. Some parents find out that their child has a similar deviation if the mother had one of the invasive methods during pregnancy. prenatal diagnosis(amniocentesis or choriocentesis).

3. Klinefelter syndrome - This disorder affects approximately 1 in 500 to 1000 boys. Boys with Klinefelter syndrome have two (or sometimes more) X chromosomes along with one normal Y chromosome. These boys usually have normal intelligence, although many have learning problems. When such boys grow up, they have a reduced secretion of testosterone and are infertile.

4. Y chromosome disomy (XYY) - Approximately 1 in 1,000 males is born with one or more extra Y chromosomes. These men have normal puberty and are not infertile. Most of them have normal intelligence, although there may be some learning, behavioral, and speech and language problems. As with trisomy X in women, many men and their parents do not know they have the anomaly until prenatal diagnosis is made.

Less common chromosomal abnormalities

New methods for analyzing chromosomes make it possible to identify tiny chromosomal pathologies that cannot be seen even under a powerful microscope. As a result, more and more parents are learning that their child has a genetic anomaly.

Some of these unusual and rare anomalies include:

• Deletion - the absence of a small section of the chromosome;
• Microdeletion - the absence of a very small number of chromosomes, perhaps only one gene is missing;
• Translocation - part of one chromosome joins another chromosome;
• Inversion - part of the chromosome is omitted, and the order of the genes is reversed;
• Duplication (duplication) - part of the chromosome is duplicated, which leads to the formation of additional genetic material;
• Ring chromosome - when genetic material is removed at both ends of the chromosome, and the new ends unite and form a ring.

Some chromosomal pathologies are so rare that only one or a few cases are known to science. Some anomalies (for example, some translocations and inversions) may not affect a person's health in any way if non-genetic material is missing.

Some unusual disorders can be caused by small chromosomal deletions. Examples are:

• crying cat syndrome (deletion on chromosome 5) - sick children in infancy are distinguished by a cry in high tones, as if a cat is screaming. They have significant problems in physical and intellectual development. With such a disease, about 1 out of 20 - 50 thousand babies is born;
• Prader-Will syndromeand (deletion on chromosome 15) - sick children have mental and learning disabilities, short stature and behavioral problems. Most of these children develop extreme obesity. With such a disease, about 1 out of 10 - 25 thousand babies is born;
• DiGeorge Syndrome (deletion on chromosome 22 or deletion 22q11) - about 1 in 4,000 babies are born with a deletion in some part of chromosome 22. This deletion causes a variety of problems that may include heart defects, cleft lip/palate (cleft palate and cleft lip), immune system disorders, abnormal facial features, and learning problems;
• Wolff-Hirshhorn Syndrome (deletion of chromosome 4) - this disorder is characterized by mental retardation, heart defects, poor muscle tone, seizures and other problems. This disorder affects about 1 in 50,000 babies.

With the exception of people with DiGeorge syndrome, people with the above syndromes are infertile. As for people with DiGeorge syndrome, this pathology is inherited by 50% with each pregnancy.

New techniques for analyzing chromosomes can sometimes pinpoint where genetic material is missing, or where an extra gene is present. If the doctor knows exactly where the culprit is chromosomal abnormality, he can assess the full extent of its influence on the child and give an approximate forecast of the development of this child in the future. Often this helps parents make a decision to continue the pregnancy and prepare in advance for the birth of a slightly different baby.

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 due to damage to the genome that occurs during the maturation of gametes, during fertilization, or on early stages cleavage of the zygote. 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 prenatal 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 explaining 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 in meiosis, in 80% of cases in the mother), translocation variant (Robertsonian translocations D / 13 and G / 13), mosaic forms, additional ring chromosome 13, isochromosomes.

Patients have severe anomalies of the structure: splitting of the soft and hard palate, cleft lip, underdevelopment or absence of eyes, malformed low-set ears, deformed bones of the hands and feet, numerous disorders of the internal organs, for example, birth defects heart (defects of partitions 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, short 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, fat deposition female type, underdeveloped

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 sex glands are normally developed, growth is usually high, there are some anomalies of the teeth and 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, ring 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.

AT recent times clinical and cytogenetic studies began 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, visual resolution of chromosomes with no more than 400 segments can be achieved, 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 formations. Most of the syndromes associated with chromosomal microabnormalities are rare - 1 case per 50,000-100,000 newborns.

Retinoblastoma. Patients with retinoblastoma malignant tumor retina, make up 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, a photodermatosis in which the frequency of UV-induced chromosomal aberrations is increased, is associated with a violation of the ability of cells to repair (repair) their DNA from damage caused by UV radiation.

Currently, about a dozen monogenic pathological signs associated with increased fragility of chromosomes. 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 susceptibility to malignant neoplasms, signs premature aging, neurological disorders, immunodeficiency states, congenital malformations, skin manifestations, mental retardation is often observed.

In addition to mutations in DNA repair genes, diseases with chromosomal instability may be based on defects in other genes that ensure genome stability. Recently, more and more data have 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. Main diagnostic features: hypoplasia 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). 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 long shoulder X chromosomes in the Xq27.3 segment individual cells a gap or gap of chromatids is fixed.

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 defect mitral valve. 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 clinical manifestations and cytogenetic instability at the Xq27.3 locus are based on a multiple increase in the CGG simple trinucleotide repeat in the first exon of the FMR-1 gene.

At normal people the number of these repeats in the X chromosome ranges from 5 to 52, and in patients their number is 200 or more. 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.

At the post-implantation stages, no fetuses with trisomy of chromosomes 1 or 19 have been registered. It is assumed that trisomy for these chromosomes is not at all compatible with post-implantation development. 10 blastomeres. One case of mosaic trisomy 1 in cytotrophoblast cells was also registered in our studies. Apparently, at later stages, such embryos either die, or blastomeres with an imbalance of these chromosomes are eliminated.
Trisomy 2 (Tc2) has been described only in spontaneous abortions. At the same time, it is believed that Tc2 is characteristic of cells of the mesenchymal stroma of chorionic villi and is detected only on preparations of cultured chorionic cells. However, we have identified a case of Tc2 in the cytotrophoblast during a developing pregnancy (Table 5.5), and the literature describes cases of prenatal diagnosis and live birth of children with a mosaic form of Tc2.
Tc3 is one of the most common trisomy characteristic of cytotrophoblast cells (8 cases in our study), and the proportion of trisomic cells can vary from single findings to the full form.
Apparently, trisomies of group B chromosomes, as well as most chromosomes of group C, are also lethal and quite rare even in chorion cells. In our studies, one case of the complete form of trisomy 4, limited to the cytotrophoblast, was registered.
Particularly noteworthy are chromosomes 7, 8 and 9, for which a slightly increased frequency of the corresponding trisomies in the material of spontaneous abortions was noted compared to the other chromosomes of group C. Cases of Tc7, Tc8 and Tc9 detected prenatally and in newborns indicate a sublethal effect of an excess of the genetic material of these chromosomes. Therefore, the presence of even a mosaic form of these trisomies in chorion cells requires the study of the fetal karyotype. It is known that Tc7 is one of the trisomies characteristic of the trophoblast (19 cases in our studies). Meanwhile, mosaic forms of trisomy 7 are also described in amniotic fluid cell cultures, as well as in skin fibroblasts in children after birth. Therefore, the opinion that Tc7 is always limited to the cytotrophoblast needs to be corrected. Placental-limited complete forms of trisomy for group C chromosomes
Table 5.5. Frequency (%) and spectrum of chromosomal abnormalities on different stages ontogeny

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 date 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 very early: 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. 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

Clinical manifestations spontaneous miscarriage vary greatly. In some cases, a miscarriage goes unnoticed, in others it is accompanied by bleeding and may require curettage of the uterine cavity. The chronology of symptoms may indirectly indicate the cause of spontaneous miscarriage: bloody issues from early pregnancy, uterine growth stops, disappearance of signs of pregnancy, a "silent" period for 4-5 weeks, and then the expulsion of the fetal egg most often indicate chromosomal abnormalities of the embryo, and the correspondence of the developmental period of the embryo to the miscarriage period speaks in favor of maternal causes of miscarriage pregnancy.

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.

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 fetal arrest in early miscarriages has been shown primarily fundamental research 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 possible pregnancy small term. 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 outwardly 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).

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 the best studied) and gene mutations) and developmental anomalies such as neural tube defects.

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 collection of 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 cultivation cell cultures abortus and chromosomal analysis of the material, fine methods of processing 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 monosomic X in newborns points to the high mortality rate of monosomic 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).

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 various mechanisms leading to the development of triploidy (diandry, diginia, dyspermia). 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 embryo. 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. Application hormonal drugs may 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 chorion cavity 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 the material of miscarriages, conducted in different parts of the world, suggests that chromosomal disruptions at the moment of conception are 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.

Relative frequency analysis various anomalies, arising from the nondisjunction of chromosomes 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 different frequency Anomalies in the material of miscarriages is due to the fact that individual chromosomal 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 allow chromosome analysis zygotes at different stages of development and assess the frequency of chromosome 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.

These studies allowed us to confirm the hypothesis of an equal probability of occurrence of monosomies and trisomies at conception: autosomal monosomies occur with the same frequency as trisomies, but zygotes with autosomal monosomies die 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 drastically 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 can be additional reason 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 possible impact 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.

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 (delayed 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 may 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 anti-mutagenic therapy may help increase the chance of conception. 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.

Course work

on human cytogenetics on the topic:

"TRISOMIES AND THE REASONS FOR THEIR APPEARANCE"

INTRODUCTION

CHAPTER 1. NUMERICAL CHROMOSOMAL MUTATIONS

CHAPTER 2. CLINICAL AND GENETIC CHARACTERISTICS OF TRISOMIA

3.1 Cytogenetic characteristics of Down syndrome

3.2 Clinical manifestations of Down syndrome

CHAPTER 3. EDWARDS SYNDROME - TRISOMY

CHAPTER 4. PATHAU SYNDROME - TRISOMY

CHAPTER 5. VARKANIE SYNDROME - TRISOMY

CHAPTER 6. TRISOMY X (47, XXX)

LIST OF USED LITERATURE

APPENDIX

INTRODUCTION

One of the most actual problems modern medical genetics is to determine the etiology and pathogenesis of hereditary diseases. Cytogenetic and molecular studies are highly informative and valuable in solving this problem, since chromosomal abnormalities occur with a frequency of 4 to 34% in various hereditary syndromes.

Chromosomal syndromes are a large group of pathological conditions resulting from an anomaly in the number and / or structure of human chromosomes. Clinical manifestations in chromosomal disorders are observed from birth and do not have a progressive course, so it is more correct to call these conditions syndromes rather than diseases.

The frequency of chromosomal syndromes is 5-7 per 1000 newborns. Anomalies of chromosomes quite often occur, both in the sex and somatic cells of a person.

The paper deals with hereditary syndromes caused by numerical mutations of chromosomes - trisomy (trisomy 21 - Down syndrome, trisomy 18 - Edwards syndrome, trisomy 13 - Patau syndrome, trisomy 8 - Varkani syndrome, trisomy X 947, XXX).

The aim of the work is: to study the cytogenetic and clinical manifestations of trisomies, possible risks and diagnostic methods.

cause manifestation of trisomy man

CHAPTER 1 NUMERICAL CHROMOSOMAL MUTATIONS

Aneuploidy (other Greek ἀν- - negative prefix + εὖ - completely + πλόος - attempt + εἶδος - view) is a hereditary change in which the number of chromosomes in cells is not a multiple of the main set. It can be expressed, for example, in the presence of an additional chromosome (n + 1, 2n + 1, etc.) or in the lack of any chromosome (n - 1, 2n - 1, etc.). Aneuploidy can occur if, in anaphase I of meiosis, the homologous chromosomes of one or more pairs do not disperse.

In this case, both members of the pair are sent to the same pole of the cell, and then meiosis leads to the formation of gametes containing one or more chromosomes more or less than normal. This phenomenon is known as nondisjunction.

When a gamete with a missing or extra chromosome fuses with a normal haploid gamete, a zygote is formed with an odd number of chromosomes: instead of any two homologues in such a zygote, there may be three or only one.

A zygote in which the number of autosomes is less than the normal diploid usually does not develop, but zygotes with extra chromosomes are sometimes able to develop. However, from such zygotes, in most cases, individuals with pronounced anomalies develop.

Forms of aneuploidy:

Monosomy is the presence of only one of a pair of homologous chromosomes. An example of monosomy in humans is Turner syndrome, which is expressed in the presence of only one sex (X) chromosome. The genotype of such a person is X0, gender is female. Such women lack the usual secondary sexual characteristics, are characterized by short stature and close nipples. The occurrence among the population of Western Europe is 0.03%.

In the case of an extensive deletion in any chromosome, one sometimes speaks of partial monosomy, for example, the syndrome of a cat's cry.

Trisomy Trisomy is the appearance of an extra chromosome in the karyotype. The best-known example of trisomy is Down's disease, which is often called trisomy 21. Trisomy 13 results in Patau syndrome, while trisomy 18 results in Edwards syndrome. All of these trisomies are autosomal. Other autosomal trisomics are not viable, die in utero and, apparently, are lost in the form of spontaneous abortions. Individuals with extra sex chromosomes are viable. Moreover, the clinical manifestations of additional X or Y chromosomes can be quite minor.

Other cases of autosome nondisjunction:

Trisomy 16 miscarriage

Trisomy 9 Trisomy 8 (Varkani syndrome).

Cases of nondisjunction of sex chromosomes:

XXX (women without phenotypic features, 75% have mental retardation of varying degrees, alalia. Often, insufficient development of ovarian follicles, premature infertility and early menopause (endocrinologist observation is necessary). XXX carriers are fertile, although the risk of spontaneous abortions and chromosomal abnormalities in offspring in slightly increased compared to the average; the frequency of manifestation is 1:700)

XXY, Klinefelter's Syndrome (males with some secondary female sex characteristics; infertile; testicles poorly developed, little facial hair, sometimes mammary glands develop; usually a low level of mental development)

XYY: tall men with different levels of mental development.

tetrasomy and pentasomy

Tetrasomy (4 homologous chromosomes instead of a pair in the diploid set) and pentasomy (5 instead of 2) are extremely rare. Examples of tetrasomy and pentasomy in humans are the XXXX, XXYY, XXXY, XYYY, XXXXX, XXXXY, XXXYY, XYYYY, and XXYYY karyotypes. As a rule, with an increase in the number of "extra" chromosomes, the severity and severity of clinical symptoms increase.

The nature and severity of clinical symptoms in various types of chromosomal rearrangements are determined by the degree of violation of the genetic balance and, as a result, homeostasis in the human body. Only a few can be mentioned general patterns clinical manifestations of chromosomal syndromes.

The lack of chromosomal material leads to more pronounced clinical manifestations than its excess. Partial monosomies (deletions) in certain regions of chromosomes are accompanied by more severe clinical manifestations than partial trisomies (duplications), which is due to the loss of a number of genes necessary for cell growth and differentiation. In this case, structural and quantitative rearrangements of chromosomes, in which genes expressed in early embryogenesis are localized, often turn out to be lethal and are found in abortuses and stillborns. Complete monosomy for autosomes, as well as trisomy for chromosomes 1, 5, 6, 11 and 19 lead to the death of an embryo at an early stage of development. The most common trisomies are on chromosomes 8, 13, 18 and 21.

Most chromosomal syndromes caused by abnormalities of the augosomes are characterized by prenatal malnutrition (low weight of the child during full-term pregnancy), malformations of two or more organs and systems, as well as a delay in the rate of early psychomotor development, oligophrenia and a decrease in the physical development of the child. In children with chromosomal pathology, an increase in the number of so-called dysembryogenesis stigmas or minor developmental anomalies is often detected. In the case of five or more such stigmas, they speak of an increase in the threshold of stigmatization in a person. The stigmas of dysembryogenesis include the presence of a sandal-like gap between the first and second toes, diastema (an increase in the distance between the front incisors), splitting of the tip of the nose, and others.

For anomalies of sex chromosomes, in contrast to autosomal syndromes, the presence of a pronounced intellectual deficit is not characteristic, some patients have normal or even above average mental development. Most patients with sex chromosome abnormalities experience infertility and miscarriage. It should be noted that infertility and spontaneous abortion in case of abnormalities of sex chromosomes and augosomes have various causes. With anomalies of autosomes, termination of pregnancy is often due to the presence of chromosomal rearrangements that are incompatible with normal embryonic development, or the elimination of zygotes, embryos, and fetuses that are unbalanced in terms of chromosome material. With anomalies of the sex chromosomes, in most cases, the onset of pregnancy and its bearing is impossible due to anomalies in spermatozoa or aplasia or severe hypoplasia, both of the external and internal genital organs. In general, sex chromosome abnormalities result in less severe clinical symptoms than autosomal abnormalities.

The severity of clinical manifestations depends on the ratio of normal and abnormal cell clones.

Complete forms of chromosomal anomalies are characterized by more severe clinical manifestations than mosaic ones.

Thus, taking into account all the clinical, genetic and genealogical data of patients with chromosomal syndromes, the indications for the study of the karyotype in children and adults are as follows:

Low weight of the newborn during full-term pregnancy;

Congenital malformations of two or more organs and systems;

Congenital malformations of two or more organs and systems in combination with oligophrenia;

Undifferentiated oligophrenia;

Infertility and recurrent miscarriage;

The presence of a balanced chromosomal rearrangement in the parents or sibs of the probands.

CHAPTER 2. CLINICAL AND GENETIC CHARACTERISTICS OF TRISOMIA

The most common type quantitative anomalies chromosomes - trisomy and tetrasomy in one of the pairs. In live births, trisomies of 8, 9, 13, 18, 21, and 22 autosomes are most common. When trisomy occurs in other augosomes (especially large metacentric and submetacentric), the embryo is not viable and dies in the early stages of intrauterine development. Monosomies in all augosomes also have a lethal effect.

There are two ontogenetic variants of trisomies: translocation and regular. The first variant rarely acts as an etiological factor and accounts for no more than 5% of all cases of autosomal trisomies. Translocation variants of chromosomal trisomy syndromes can appear in the offspring of carriers of balanced chromosomal rearrangements (most often, Robertsonian or reciprocal translocations and inversions), as well as denovo.

The remaining 95% of cases of autosomal trisomies are represented by regular trisomies. There are two main forms of regular trisomies: complete and mosaic. In the vast majority of cases (up to 98%), complete forms are found, the occurrence of which may be due to both gametic mutations (nondisjunction or anaphase lagging of the chromosome during the meiotic division of a single gamete) and the presence of balanced chromosomal rearrangements in all cells of the parents.

In rare cases, the inheritance of quantitative chromosomal rearrangements occurs from parents who have a complete form of trisomy (for example, on the X or 21 chromosome).

Mosaic forms of trisomy account for about 2% of all cases and are characterized by a different ratio of normal and trisomic cell clones, which determines the variability of clinical manifestations.

We present the main clinical and cytogenetic characteristics of the three most common variants of complete trisomies for autosomes in humans.

Usually, trisomy occurs due to a violation of the divergence of homologous chromosomes in the anaphase of meiosis I. As a result, both homologous chromosomes get into one daughter cell, and none of the bivalent chromosomes get into the second daughter cell (such a cell is called nulisomal). Occasionally, however, trisomy may be the result of a defect in sister chromatid segregation in meiosis II. In this case, two completely identical chromosomes fall into one gamete, which, if fertilized by normal sperm, will give a trisomic zygote. This type of chromosomal mutation leading to trisomy is called chromosome nondisjunction. Differences in the outcomes of impaired chromosome segregation in meiosis I and II are illustrated in Fig. 1. Autosomal trisomies occur due to nondisjunction of chromosomes, which is observed mainly in oogenesis, but nondisjunction of autosomes can also occur in spermatogenesis. Chromosome nondisjunction can also occur in the early stages of cleavage of a fertilized egg. In this case, a clone of mutant cells is present in the body, which can capture a larger or smaller part of the organs and tissues and sometimes give clinical manifestations similar to those observed with ordinary trisomy.

The reasons for nondisjunction of chromosomes remain unclear. The well-known fact of the connection between the nondisjunction of chromosomes (especially chromosome 21) and the age of the mother still does not have an unambiguous interpretation. Some researchers believe that this may be due to a significant time interval between the conjugation of chromosomes and the formation of chiasmata, which occur in the female fetus, i.e. quite early and with the divergence of chromosomes in diakinesis observed in women in childbearing age. The consequence of oocyte aging may be a violation of spindle formation and other violations of the meiosis I completion mechanisms. A version is also considered about the absence of chiasma formation in meiosis I in female fetuses, which are necessary for subsequent normal chromosome segregation.

Nondisjunction in meiosis I Nondisjunction in meiosis II

Rice. 1. Meiotic nondisjunction

CHAPTER 3

3.1 Cytogenetic characteristics of Down syndrome

Trisomy 21, or Down's syndrome, is the most common of trisomies and, in general, one of the most common hereditary diseases. The cytogenetic nature of Down syndrome was established by J. Lejeune in 1959. The syndrome occurs on average with a frequency of 1 per 700 live births, but the frequency of the syndrome depends on the age of the mothers and increases with its increase. In women older than 45 years, the frequency of birth of patients with Down syndrome reaches 4%.

Cytogenetic causes of Down syndrome are regular trisomy - 95%, translocation of chromosome 21 to other chromosomes - 3% and mosaicism - 2%. Molecular genetic studies have identified the critical region of chromosome 21 responsible for the main clinical manifestations of Down syndrome, -21q22.

Down syndrome can also be caused by a Robertsonian translocation. If chromosomes 21 and 14 are involved, which is not uncommon, the result can be a zygote with trisomy 21, which will result in a baby with Down's disease. For Robertsonian translocations involving chromosome 21, the risk of having such a child is 13% if the mother is the carrier of the translocation, and 3% if the father is the carrier. The possibility of having a child with Down's disease in parents with a Robertsonian translocation, in which chromosome 2 / is involved, must always be kept in mind, since the risk of re-birth of a sick child is different with regular trisomy 21 due to non-disjunction of chromosomes, and trisomy 21 associated with the carrier due to Robertsonian translocation by one of the parents. When a Robertsonian translocation results from the fusion of the long arms of chromosome 21, all gametes will be unbalanced: 50% will have two chromosomes21 and 50% will be nullosomal21. In a family in which one of the parents is a carrier of such a translocation, all children will have Down's disease.

The recurrence risk for regular trisomy21 is approximately 1:100 and depends on the age of the mother. In familial translocation, risk rates range from 1 to 3% if the father is the translocation carrier, and 10 to 15% if the mother is the translocation carrier. As already noted, in rare cases of 21q21q translocation, the recurrence risk is 100%.

Rice. 2 Schematic representation of the karyotype of a man with Down syndrome. Nondisjunction of G21 chromosomes in one of the gametes led to trisomy on this chromosome

Thus, the cytogenetic variants of Down syndrome are varied. However, the majority (94-95%) are cases of simple complete trisomy 21 as a result of chromosome nondisjunction during meiosis. At the same time, the maternal contribution of nondisjunction to these gametic forms of the disease is 80%, and the paternal contribution is only 20%. The reasons for this difference are not clear. A small (about 2%) proportion of children with Down syndrome has mosaic forms (47+21/46). Approximately 3-4% of patients with Down's syndrome have a translocation form of grisomy according to the type of Robertsonian translocations between acroientrics (D/21 and G/21). Nearly 50% of translocation forms are inherited from carrier parents and 50% are denovo-derived translocations.

The ratio of boys and girls among newborns with Down syndrome is 1:1.

3.2 Clinical manifestations of 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 in parents of the same age. 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. 3).

With age, the likelihood of having children with Down syndrome increases significantly. So, at the age of 45, it is about 3%. High frequency children with Down's syndrome (about 2%) is observed in women who give birth early (up to 18 years). Therefore, for population-based comparisons of the birth rate of children with Down syndrome, it is necessary to take into account the distribution of women giving birth by age (the proportion of women giving birth after 30-35 years of age among all those 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). Due to a 2-fold decrease in the number of women giving birth after 35 years, in the last 15 years in Belarus and Russia, the number of children with Down syndrome has decreased by 17-20%. The increase in frequency with increasing maternal age is known, but at the same time it must be understood that most children with Down syndrome are born to mothers under 30 years of age. It's connected with a large number pregnancies in this age group compared with the older group.

Rice. 3 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 chromosome nondisjunction than by the influence of putative etiological factors ( viral infection, low doses of radiation, chlorophos).

The clinical symptoms of Down syndrome are diverse: these are congenital malformations, and disorders of the postnatal development of the nervous system, and secondary immunodeficiency and 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 puts correct diagnosis Down syndrome in maternity hospital not less than

Rice. 4 Children different ages with characteristic features of Down syndrome (brachycephaly, round face, macroglossia and open mouth epicanthus, hypertelorism, wide bridge of the nose, strabismus)

90% of cases. From craniofacial dysmorphias, a Mongoloid incision of the eyes is noted (for this reason, Down syndrome was long called Mongoloidism), a round flattened face, a flat back of the nose, epicanthus, a large (usually protruding) tongue, brachycephaly, and deformed auricles (Fig. 4).

The three figures show photographs of children of different ages, and all of them have characteristic features and signs of dysembryogenesis.

Muscular hypotension is characteristic in combination with looseness of the joints (Fig. 5). Often there are congenital heart disease, clinodactyly, characteristic 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. The frequency of any symptom in 100% of cases, except for short stature, was not noted. In table. 5.2 and 5.3 shows the frequency of external signs of Down's syndrome and the main congenital malformations of internal organs.

The diagnosis of Down's syndrome is based on the frequency of a combination of several symptoms (Tables 1 and 2). The following 10 signs are most important for making a diagnosis, the presence of 4-5 of which reliably indicates Down's syndrome: 1) flattening of the face profile (90%); 2) no sucking reflex (85%); 3) muscular hypotension (80%); 4) Mongoloid eye section (80%); 5) excess skin on the neck (80%); 6) loose joints (80%); 7) dysplastic pelvis (70%); 8) dysplastic (deformed) auricles (40%); 9) clinodactyly of the little finger (60%); 10) four-finger flexion fold (transverse line) on the palm (40%). Of great importance for diagnosis is the dynamics of the physical and mental development of the child. With Down syndrome, both are delayed. The height of adult patients is 20 cm below average. Mental retardation reaches imbecility if special teaching methods are not applied. Children with Down syndrome are affectionate, attentive, obedient, patient in learning. The IQ (10) in different children varies widely (from 25 to 75). The reaction of children with Down syndrome to factors environment often pathological due to weak cellular and humoral immunity, decreased DNA repair, underproduction digestive enzymes, 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, avitaminosis is expressed.

Table 1. The most common external signs of Down syndrome (according to G.I. Lazyuk with add.)

Table 2. The main congenital malformations of internal organs in Down syndrome (according to G. I. Lazyuk with additions)

Congenital malformations of internal organs, reduced adaptability of children with Down syndrome often lead to lethal outcome in the first 5 years.

The consequence of altered immunity and insufficiency of repair systems (for damaged DNA) are leukemias, which are often found in patients with Down syndrome.

Differential diagnosis is carried out with congenital hypothyroidism, other forms of chromosomal abnormalities. A cytogenetic study in children is indicated both for suspected Down syndrome and for clinical established diagnosis, since the patient's cytogenetic characteristics are necessary to predict the health of future children of parents and their relatives.

Ethical issues in Down syndrome are multifaceted. Despite the increased risk of having a child with Down syndrome and other chromosomal syndromes, the doctor should avoid direct recommendations for planning pregnancy in older women. age group, since the age-related risk remains quite low, especially considering the possibilities of prenatal diagnosis.

Dissatisfaction in patients is often caused by the form of reporting about Down syndrome in a child. A diagnosis of Down syndrome based on phenotypic features can usually be made 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 your parents at least your suspicions as soon as possible after delivery. It is impractical to fully inform the parents of a child with Down syndrome immediately after delivery. Enough information should be given to answer their immediate questions and keep them going 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 parents have at least partially recovered from the stress of delivery, usually within 1 day. By this time, they have a set of questions that need to be answered accurately and definitely. Both parents are invited to this meeting. During this period, it is still too early to burden parents with all the information about the disease, as these new and complex concepts take time to absorb.

Don't try to make predictions. It is useless to try to accurately predict the future of any child. The ancient myths like "at least he will always love and enjoy music" are unforgivable. It is important to note that the abilities of each child develop individually.

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. Attentive care is needed for a sick child, protection from the action harmful factors environment (colds, infections). Many patients with trisomy 21 are now able to lead an independent life, master simple professions, create families.

CHAPTER 3. EDWARDS SYNDROME - TRISOMY 18

Cytogenetic examination usually reveals regular trisomy18. As with Down's syndrome, there is an association between the incidence of trisomy18 and maternal age. In most cases, the extra chromosome is of maternal origin. About 10% of trisomy 18 is due to mosaicism or unbalanced rearrangements, more often Robertsonian translocations.

Rice. 7 Karyotype Trisomy 18

There are no clinical differences between cytogenetically distinct forms of trisomy.

The frequency of Edwards syndrome is 1:5000-1:7000 newborns. The ratio of boys and girls is 1:3. The reasons for the predominance of sick girls are still unclear.

With Edwards syndrome, there is a pronounced delay in prenatal development with the full duration of pregnancy (delivery at term). On fig. 8-9 the malformations characteristic of a syndrome of Edwards are presented. First of all, these are multiple congenital malformations of the facial part of the skull, heart, skeletal system, and genital organs.

Rice. 8 Newborn with Fig. 9 Characteristic of Edwards syndrome. Edwards syndrome Prominent occiput; the position of the microgenius fingers; flexor (child's age 2 months) hand position

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 abnormally developed foot (the heel protrudes, sags in a consolidated manner), the first toe is shorter than the second. spinal hernia and cleft lip are rare (5% of cases of Edwards syndrome).

The diverse symptoms of Edwards syndrome in each patient appear only partially. The frequency of individual congenital malformations is given in table. 3.

Table3. The main congenital malformations in Edwards syndrome (according to G. I. Lazyuk)

As can be seen from Table. 3, the most significant in the diagnosis of Edwards syndrome are changes in the brain skull and face, musculoskeletal system, malformations of the cardiovascular system.

Children with Edwards syndrome die in early age(90% - up to 1 year) from complications caused by congenital malformations (asphyxia, pneumonia, intestinal obstruction, cardiovascular insufficiency). Clinical and even pathological differential diagnosis Edwards syndrome is complex. In all cases, a cytogenetic study is indicated. Diagnosis of Edwards syndrome is especially difficult during pregnancy, despite the availability of such an effective method for diagnosing fetal abnormalities as ultrasound. Indirect signs according to ultrasound, indicating Edwards syndrome in the fetus, may be a small placenta, underdevelopment or absence of one of the umbilical arteries in the umbilical cord. In the early stages, ultrasound does not detect any gross developmental anomalies in the case of Edwards syndrome. Due to this combination of diagnostic difficulties, the question of timely termination of pregnancy usually does not arise, and women carry such children to the end. There is no cure for Edwards syndrome.

CHAPTER 4. PATHAU SYNDROME - TRISOMY 13

Patau's syndrome was singled out as an independent nosological form in 1960 as a result of a genetic study conducted in children with congenital malformations. The frequency of Patau syndrome among newborns is 1:5000-1:7000. Cygogenetic variants of this syndrome are as follows. 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 pathoanatomical picture of simple trisomic forms and translocation forms does not differ.

Rice. 10 Karyotype Trisomy 13

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 ( average term gestation 38.3 weeks). A characteristic complication of pregnancy when carrying a fetus with Patau syndrome is polyhydramnios: it occurs in almost 50% of cases of Patau syndrome.

Patau syndrome is characterized by multiple congenital malformations of the brain and face (Fig. 11).

This is a pathogenetically single group of early (and, therefore, severe) disorders in the formation of the brain, eyeballs, brain and front parts skulls. The circumference of the skull is usually reduced, and trigonocephaly occurs. Forehead sloping, low; the palpebral fissures are narrow, the nose bridge is sunken, the auricles are low and deformed.

A typical symptom of Patau's syndrome is clefts upper 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 is presented in Table. 4.

Rice. 11 Newborn 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

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 (95% before the first 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 children) and even up to 10 years (2-3% of children).

Table4. The main congenital malformations in Patau syndrome (according to G. I. Lazyuk)

Medical care for children with Patau syndrome is non-specific: operations for congenital malformations (according to vital indications), restorative treatment, careful care, prevention of colds and infectious diseases. Children with Patau syndrome almost always have a deep idiocy.

CHAPTER 5 VARKANIE SYNDROME - 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 O was ascertained, since there was no individual identification of chromosomes at that time. Complete trisomy 8 is usually fatal. They are often found in prenatally dead embryos and fetuses. Among newborns, trisomy 8 occurs with a frequency of no more than 1:5000, sick 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.

Rice. 12 Trisomy 8 (mosaicism). everted underlip; epicant; abnormal auricle

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. 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. 12-14). At clinical examination a protruding forehead, strabismus, epicanthus, deep-set eyes, hypertelorism of the eyes and nipples, a high palate (sometimes a cleft), thick lips, an inverted lower lip, large auricles with a thick earlobe, joint contractures, camptodactyly, aplasia of the patella, deep grooves between the fingers pads, four-finger fold, anus anomalies. Ultrasound reveals spinal anomalies (accessory vertebrae, incomplete closure spinal canal), anomalies in the shape and position of the ribs or additional ribs. In table. 5.6 summarizes the frequency of individual symptoms (or defects) in trisomy 8.

In newborns, there are from 5 to 15 symptoms or more.

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

There are no specific treatments. Operational interventions produced according to vital indications.

Table4. The main signs of trisomy 8 (according to G. I. Lazyuk)

CHAPTER 6 TRISOMY X (47, XXX)

Trisomy-X. Trisomy-X was first described by P. Jacobs et al. in 1959. Among newborn girls, the frequency of the syndrome is 1:1000 (0.1%), and among the mentally retarded - 0.59%. Women with a karyotype of 47, XXX in full or mosaic form have basically normal physical and mental development. Most often, such individuals are detected by chance during the examination. This is explained by the fact that in cells two X chromosomes are heterochromatinized (two bodies of sex chromatin) and only one, like in normal woman, is functioning. An extra X chromosome doubles the risk of developing some kind of psychosis with age. As a rule, a woman with a XXX karyotype has no abnormalities in sexual development, such individuals have normal fertility, although the risk of chromosomal abnormalities in the offspring and spontaneous abortions is increased. Intellectual development is normal or at the lower limit of normal. Few women with trisomy X have abnormalities reproductive function(secondary amenorrhea, dysmenorrhea, early menopause, etc.). Anomalies in the development of the external genitalia (signs of dysembryogenesis) are found only with a thorough examination, they are not very pronounced, and therefore do not serve as a reason for women to visit a doctor.

The risk of having a child with trisomy X is increased in older mothers. For fertile women with a 47,XXX karyotype, the risk of having a child with the same karyotype is low. There appears to be a protective mechanism that prevents the formation or survival of aneuploid gametes or zygotes.

Variants of the X-polysomy syndrome without a Y chromosome with a number greater than 3 are rare. With an increase in the number of additional X chromosomes, the degree of deviation from the norm increases. In women with tetrasomy and pentasomia, deviations in mental development, craniofacial dysmorphisms, anomalies of the teeth, skeleton and genital organs are described. However, women even with tetrasomy on the X chromosome have offspring.

Rice. 16 Karyotype of a woman with trisomy X syndrome

FINDINGS

In the presented work, trisomy syndromes were considered: Down syndrome - trisomy 21, Edwards syndrome - trisomy 18, Patau syndrome - trisomy 13, Varkani syndrome - trisomy 8 and trisomy X syndrome. Their clinical and genetic manifestations, possible risks are described.

· Among newborns, trisomy on the 21st chromosome, or Down's syndrome, is the most common (2n + 1 = 47). This anomaly, named after the physician who first described it in 1866, is caused by nondisjunction of chromosome 21.

Trisomy 16 is common in humans (more than one percent of pregnancies). However, the consequence of this trisomy is a spontaneous miscarriage in the first trimester.

· Down's syndrome and similar chromosomal abnormalities are more common in children born to older women. The exact reason for this is unknown, but it seems to be related to the age of the mother's eggs.

· Edwards syndrome: regular trisomy is usually found on cytogenetic examination18. About 10% of trisomy 18 is due to mosaicism or unbalanced rearrangements, more often Robertsonian translocations.

· Patau Syndrome: Simple complete trisomy 13 due to nondisjunction of chromosomes during meiosis in one of the parents.

Other cases are mainly due to the transfer of an additional chromosome (more precisely, its long arm) in Robertsonian translocations. Other cytogenetic variants (mosaicism, isochromosome, non-Robertsonian translocations) have also been found, but they are extremely rare.

Varkani syndrome: 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. Mosaicism on chromosome 8 was cytogenetically stated.

· Trisomy XXX syndrome of a woman without phenotypic features, 75% have mental retardation of varying degrees, alalia.

LIST OF USED LITERATURE

1. Bokov N. P. Clinical genetics: Textbook. - 2nd ed. revised and additional - M .: GEOTAR-MED, 2002 - 448 .: ill. – (XXI century)

2. Ginter E.K. Medical genetics: Textbook. - M .: Medicine, 2003 - 448 pp.: ill. (Study literature for students of medical universities)

Z. Genetics. Textbook for universities / Ed. Academician of the Russian Academy of Medical Sciences V.I. Ivanov. - M .: ICC "Akademkniga", 2006. - 638 p.: ill.

4. Vogel F., Motulski A. Human genetics: In 3 vols.: Per. from English. - M .: Mir, 1989., ill.

5. Limarenko M.P. Hereditary diseases and congenital heart defects in children // Vracheb. practice. - 2005. - No. 5. - P. 4-7.

6. Shevchenko V.A. Human genetics: a textbook for universities / V.A. Shevchenko, N.A. Topornina, N.S. Stvolinskaya. – M.: Vlados, 2002.

7. Shchipkov V.P., Krivosheina G.N. General and medical genetics. M.: Academy, 2003. 256c.

8. M.P. Limarenko, N.G. Logvinenko, T.V. Artyukh Donetsk National Medical University. M. Gorky "Atrioventricular communication as the most common congenital heart disease in children with Down syndrome". Access mode: http://www.ukrcardio.org/journal.php/article/385

9. N.A. Scriabin, T.D. Pavlova, A.V. Alekseeva, A.N. Nogovitsyna, A.L. Sukhomyasova "Information about patients with syndromes associated with the pathology of sex chromosomes" 2007-2(18)-p.48-52. Access mode: http://mednauka.com/index.php?option=com_content&task=view&id=35&Itemid=47

10. Tiganov A.S. - Pathology of mental development. Syndromes due to chromosomal aberrations. Access mode: http://www.psychiatry.ru/book_show.php?booknumber=36&article_id=11

11. Sklyarenko E. O. "Genetic diseases: Down syndrome". Access mode: http://uaua.info/content/articles/4522.html

12. Big reference book of health. Edwards Syndrome. Access mode: http://spravzdrav.ru/spravochnik-boleznej/hereditary-diseases/e1/edvardsa_sindrom/

13. Big reference book of health. Patau syndrome. Access mode: http://spravzdrav.ru/spravochnik-boleznej/hereditary-diseases/p/patau_sindrom/

14. Syndrome (disease) Down (SD). Website "Human Biology". Access mode: http://humbio.ru/Humbio/01122001/medgen/0005114e.htm

15. Trisomy 8. Clinical picture of trisomy syndrome 8. Main signs of trisomy 8. Access mode: http://www.eurolab.ua/encyclopedia/505/4354/

16. Sakaki, Y. et al. The complete sequence and gene catalog of human chromosome 21. Nature 405, 921-923 (2000). Access Mode: www.nature.com/genomics

17. SchaumannB, AlterM: Dermatoglyphics in Medical Disorders. Springer-Verlag, New York, 1976

APPENDIX

Dermatoglyphics and Syndromes

Rice. 1 Dermatoglyphics in Down syndrome

1. The predominance of ulnar loops on the fingers, often 10 loops, high loops in the form of the letter L;

2. radial loops on 4-5 fingers;

3. large ulnar loops in the hypothenar area in association with (4);

4. high axial triradii;

5. increased frequency of thenar patterns;

7. reduced frequency (occurrence) of patterns on the 4th interdigital pad;

8. transverse orientation of the main palmar lines;

9. the end of the main palmar line "D" in field 11 or on the radial edge of the palm;

10. main palmar line "C" forms a loop on the 3rd interdigital pad;

11. often the absence of the main palmar line "C" or its abortive variant (X);

12. single flexion fold of the palm;

13. Sydney flexion fold;

14. The only flexion crease of the little finger;

15. Fibular loop on the foot;

16. tibial arch configuration on the ball of the big toe; (extremely rare sign in the norm);

17. distal loop with a low score (narrow loop) on the ball of 1 finger;

18. feet (normally this loop has a large ridge count);

19. distal loop on the 4th interdigital pad of the foot;

20. dissociation of scallops.

Rice. 2 Dermatoglyphics in Patau syndrome (trisomy 13)

1. Increased frequency of arcs;

2. increased frequency of radial loops;

3. increased frequency of the pattern on the 3rd interdigital pad;

4. reduced frequency of patterns on the 4th interdigital pad;

5. high axial triradius of the palm;

6. frequent patterns in the thenar area;

7. radial displacement of the triradius "a", which is related to (8);

8. increased comb score "a-b";

9. radial ending of the main palmar lines;

10. the only flexion fold of the palms is very common;

11. frequent patterns such as fibular arch and S-shaped fibular arch on the foot;

12 dissociation of ridges.

Rice. 3 Dermatoglyphics in the syndrome of "trisomy 8 mosaicism"

1. increased arc frequency;

2. curls are less common, but often present simultaneously with the presence of arc patterns on the fingers;

3. increased the frequency of patterns on the thenar;

4. reduced frequency of patterns on the hypothenar;

5. increased frequency of patterns on the 2nd interdigital pad;

6. increased frequency of patterns on the 3rd interdigital pad;

7. increased frequency of patterns on the 4th interdigital pad;

8. the only flexion fold of the palm;

9. increased frequency of arches on 1 toe;

10. increased frequency of curls on the ball of 1 toe;

11. increased complexity of foot patterns;

12 deep longitudinal flexion folds of the foot.