Unlike patients with other sex chromosomal aneuploidies, girls with Turner syndrome are often identified at birth or before puberty due to distinct phenotypic features. Turner syndrome is much rarer than other sex chromosome aneuploidies. The incidence of the Turner syndrome phenotype is approximately 1 in 4000 female births, although some studies have reported significantly higher figures.
Most common chromosomal constitution- 45,X (sometimes incorrectly written 45,X0), without a second sex chromosome. However, up to 50% of cases have other karyotypes. About a quarter of Turner syndrome cases have mosaic karyotypes, in which only a portion of the cells contain 45.X. The most common karyotypes and their approximate relative frequencies are as follows:
1) 45.X: 50%
2) 46,X,i(Xq): 15%
3) Mosaics 45,Х/46,XX: 15%
4) Mosaics 45,X/46,X,i (Xq): about 5%
5) 45.X, other anomaly X: about 5%
6) Other mosaics 45.X/?: about 5%
Compound chromosomes clinically significant. For example, patients with i(Xq) are similar to women with classic 45,X, patients with Xp deletion have short stature and congenital malformations, and those with Xq deletion often have only gonadal dysfunction.
Typical anomalies during Turner syndrome include short stature, gonadal dysgenesis (due to a defect in their formation, the ovaries are usually represented by bands of connective tissue), a characteristic unusual face, a folded neck, low hair growth at the back of the head, a broad chest with widely spaced nipples, and a high incidence of renal and cardiovascular anomalies.
At birth babies with this syndrome often have an important diagnostic sign - swelling of the back of the feet and hands.
For many patients find coarctation of the aorta, women with Turner syndrome have an increased risk of cardiovascular abnormalities. Lymphoedema can occur in utero, causing fetal cystic hygroma (detected by ultrasound), causing cervical folds visible after birth.
Turner syndrome should be suspected in any newborn girl with swelling of the hands and feet or hypoplastic left heart or coarctation of the aorta. The possibility of this diagnosis should also be considered in adolescence in girls with primary or secondary amenorrhea, especially if they are short. Growth hormone therapy is indicated for all girls with Turner syndrome and can add 6 to 12 cm in height.
It is generally believed that intelligence is women with Turner syndrome will be normal, although approximately 10% of patients have significant developmental delay requiring special education. Even among those who have normal intelligence, deficits in spatial perception, motor and fine motor skills are often identified.
As a consequence, nonverbal assessment IQ significantly lower than verbal, and most patients need pedagogical support, especially in mathematics. Women with Turner syndrome are at high risk of poor social adaptation. A comparison of 45,X girls with maternal and paternal X chromosome ancestry showed significantly worse social skills with maternal X chromosome ancestry. Since the effect of parental origin can be explained by imprinting, this possibility is being explored for genes on the X chromosome that influence phenotype.
High occurrence karyotype 45.X with spontaneous abortions has already been mentioned. The anomaly is present presumably in 1-2% of all conceptions; Survival to term is rare, and more than 99% of such pregnancies abort spontaneously. The single X chromosome is of maternal origin in approximately 70% of cases; in other words, a chromosomal error leading to the loss of a sex chromosome usually occurs in the father.
The basis for unusually high frequency loss of X or Y chromosome unknown. In addition, it is unclear why the 45,X karyotype, so often lethal in utero, is apparently completely compatible with life after birth. The lost genes responsible for the Turner syndrome phenotype must be located on both the X and Y chromosomes. It is believed that these genes are among the genes that escape X-inactivation, in particular those located on the short arm, including the pseudoautosomal region.
Sometimes in patients with low height, gonadal dysgenesis and mental retardation reveal small ring X chromosomes. Since mental retardation is not typical for Turner syndrome, the presence of such a delay with other anomalies in patients with karyotype 46,X,r(X) is associated with the fact that small ring X chromosomes lose the X-inactivation center.
Inability to inactivate ring X chromosome leads to overexpression of genes that are normally subject to inactivation. Detection of a ring X chromosome during prenatal diagnosis can lead to great uncertainty, in which case a study of XIST gene expression is indicated. Large rings containing an X-inactivation center and expressing the XIST gene lead to the development of the Turner syndrome phenotype; with small ring chromosomes without XIST gene expression, a more severe phenotype can be expected.
Chromosomal diseases are a large group of congenital hereditary diseases caused by abnormalities in the number or structure of chromosomes, that is, mutations. Diseases that are caused by genomic and chromosomal mutations are called chromosomal diseases.
Pathological changes occur both with the loss of genetic material and with the addition of new chromosomes.
Diseases caused by autosomal mutations(Fig. 1):
Rice. 1. Diseases caused by autosomal mutations ()
A deletion in the 5th chromosome causes cry-of-the-cat syndrome; in newborn patients there is a disturbance in the structure of the larynx, a mewing timbre of the voice, dementia, psychomotor retardation; such patients rarely survive to adulthood;
A deletion in chromosome 3 usually leads to miscarriage; at birth, children are unable to sit up and eat solid food;
A deletion on chromosome 21 causes chronic leukemia, a lack of red blood cells;
Trisomy on the 21st chromosome (Down's disease) (Fig. 2) - in the karyotype in patients there are not two, but three 21st chromosomes - this is the most common anomaly, the birth rate is 1:500, depends on the age of the mother and increases sharply after 35 years. Up to 40% of children with this disease are born to older mothers.
Rice. 2. Down syndrome ()
Such patients have a Mongoloid type of face, shortened limbs, and mental retardation.
Trisomy on the 13th chromosome (Patau syndrome) is a rather rare syndrome, the incidence is 1:14,500, patients have abnormalities of the heart and kidneys, serious disturbances in appearance, life expectancy is no more than a year;
Trisomy on chromosome 18 (Edwards syndrome) - patients have multiple organ defects, mental retardation, early mortality.
There are trisomies on the 8th, 9th, 14th and 22nd chromosomes, they are all lethal at an early stage.
There is a single description of even tetrosomy (mental retardation of varying degrees) and pentosomy (severe damage to the body and mental abilities) of autosomes.
Rice. 3. Diseases associated with sex chromosome disorders in women ()
Trisomy XXX (triple-X syndrome) - frequency of occurrence is 1:700, not sharp deviations in physical development, ovarian dysfunction, premature menopause. Patients with such a mutation are not even aware of their karyotype;
Tetrosomy XXXX leads to varying degrees of mental disability;
Pentosomy XXXXX is accompanied by severe damage to organs and consciousness;
Monosomy X0 (Turner syndrome) is the only one compatible with life, incidence 1:4000, underdeveloped ovaries and uterus, physical and mental retardation.
- Klinefelter syndrome occurs in two forms - polysomy on the X chromosome and polysomy on the Y chromosome; patients with the XX Y karyotype are effeminate men, they have developed breasts, a female voice, long legs, and underdeveloped testes. They are sterile, but mentally completely normal;
Rice. 4. Diseases associated with sex chromosome disorders in men ()
Patients with karyotype X Y Y are normal tall men, mentally and mentally healthy, but prone to aggression and asocial.
The above mutations do not cause the death of the organism; others, as a rule, lead to death even at the stage of intrauterine development. Disorders caused by these pathologies are usually incompatible with the sexual process; such patients do not survive to reproductive age or are sterile. Therefore, chromosomal diseases, unlike genetic diseases, are much less likely to be inherited, but there is an exception - patients with Down syndrome are capable of reproducing.
As a result of intensive study of human chromosomes and chromosomal diseases over the course of 35-40 years, the doctrine of chromosomal pathology has emerged, which is of great importance in modern medicine.
Bibliography
- Belyaev D.K. General biology. A basic level of. - 11th edition, stereotypical. - M.: Education, 2012.
- Pasechnik V.V., Kamensky A.A., Kriksunov E.A. General biology, grades 10-11. - M.: Bustard, 2005.
- Agafonova I.B., Zakharova E.T., Sivoglazov V.I. Biology 10-11 grade. General biology. A basic level of. - 6th ed., add. - Bustard, 2010.
- Bibliofond.ru ().
- Rh-conflict.narod.ru ().
- Vse-pro-geny.ru ().
Homework
- Define chromosomal diseases.
- What are the main diseases caused by autosomal mutations?
- What determines the likelihood of having a child with Down syndrome?
Chromosomal abnormalities that occur in germ cells during fertilization and early embryogenesis,- the most important cause of intrauterine development disorders, stillbirths, spontaneous abortions in the 8-11th week of pregnancy or later.
Mutations in somatic cells- a common cause of malignant neoplasms.
Basic Concepts
Normal in humans 44 (22 pairs) autosomes (non-sex chromosomes)and two sex chromosomes(a pair). Autosomes are designated by numbers 1-22, and sex chromosomes are designated X, Y.
A normal male karyotype is designated "46, XY", and a female- "46, XX".
Chromosomal abnormalities are classified:
- by type of affected cells (somatic or gametes);
- by disruption of chromosome structure;
- by changes in the number of chromosomes.
Regardless of the type of anomaly, all chromosomal disorders manifest themselves in a similar way: mental retardation, short stature, abnormal shape of the ears, nose and mouth, fingers, congenital heart defects, abnormalities of the papillary lines and palmar folds, multiplicity of lesions. Characterized by high mortality.
The reasons why disturbances in different regions of chromosomes manifest themselves in similar ways are unknown.
Trisomy
Most common chromosomal disorder- these are trisomy (47 chromosomes), followed by monosomy (45 chromosomes) and triploidy (69 chromosomes). All these disorders relate to changes in the number of chromosomes. In spontaneous abortions, trisomy is detected on all chromosomes, but more often on the 16th chromosome, but a small number of children are born with trisomy, and, as a rule, this is trisomy 21, 18 or 13 chromosomes.
If trisomy occurs on the sex chromosome (XXY, XYY, XXX), it does not interfere with intrauterine development. Since children with trisomy on the 18th and 13th chromosomes die in infancy, in light of the above, in sick adults, trisomy on the 21st chromosome and karyotypes 47, XXY can most often be diagnosed; 47,XYY; 47, XXX.
Other autosomal trisomies are occasionally found, but they are associated with mosaicism- when the body's cell populations are genetically heterogeneous. The mechanisms responsible for changes in the number of chromosomes have not been established.
The main pathologies that trisomy leads to:
- by X, karyotype 47, XXX- secondary amenorrhea, mild mental retardation, behavioral disorders;
- by X, karyotype 47, XXY- Klinefelter's syndrome (hypogonadism, infertility, gynecomastia, testicular hypoplasia), in the case of mosaicism, the manifestations are softened, and in the presence of a larger number of chromosomes (48, XXXY; 49, XXXXXY), the symptoms are more pronounced;
- by X, karyotype 47, ХYY- high growth, reduced fertility, behavioral disorders;
- on the 8th - malformations of the skeleton, face, moderate mental retardation;
- 13 each -th -Patau syndrome (cleft lip and palate, eye malformations, polydactyly, malformations of internal organs);
- on the 18th - Edwards syndrome (malformations of the skull, face, brain, deformation of the ears, severe mental retardation);
- on 21st - Down syndrome.
Other chromosomal disorders
Of the detected monosomies, monosomies on the sex chromosome (karyotype 45, X0) are most often observed.
In rare surviving newborns, due to a chromosomal disorder, the normal development of the ovaries, oviducts, uterus, and vagina does not occur, and during puberty there is an absence of secondary sexual characteristics and primary amenorrhea
Patients are characterized by short stature, low-set ears, low hairline on the back of the head, skin folds, underdevelopment of the upper jaw, shortening of the phalanges of the fingers, congenital heart defects, disorders in the development of the kidneys- all this is called Turner syndrome.
Triploidy (69, XXY) is accompanied by hydrocephalus, mental retardation, congenital heart defects, malformations of the external genitalia, and syndactyly. Death occurs in childhood.
Structural chromosomal abnormalities are called aberrations, and most of them occur in the chromosomes received from the father. They can be genetically compensated and do not cause adverse effects on the fetus, otherwise they lead to developmental defects.
Structural damage includes deletions (partial monosomies) and duplications (partial trisomies) of chromosomes, inversions and translocations.
When diagnosing chromosomal diseases, it is important to determine the chromosome involved in the process, the form of cell damage (complete or mosaic), the type of mutation, whether it is inherited or an accidental breakdown.
The pathogenesis of chromosomal diseases has not been studied, and there is no treatment.
Numerical disorders in the sex chromosome system (monosomy and trisomy) do not cause such severe consequences as autosomal abnormalities. There are few or no pronounced changes in phenotype (for example, in women with a karyotype of 47,XXX). In the preliminary diagnosis of diseases caused by abnormalities of sex chromosomes, anamnesis is of primary importance: delayed sexual development, impaired formation of secondary sexual characteristics, infertility, spontaneous abortions. Express methods of cytogenetic analysis (for example, determination of sex chromatin in scrapings from the buccal mucosa) do not always provide reliable results. Therefore, if a sex chromosome abnormality is suspected, a detailed cytogenetic study of a large number of cells is required. One of the main objectives of such a study is to exclude mosaicism in gonadal dysgenesis. The presence of a clone of cells carrying the Y chromosome in a patient with mosaicism indicates an increased risk of gonadoblastoma. In cases where the likelihood of an abnormality of the sex chromosomes is high, but the anomaly is not detected in lymphocytes, cells of other tissues (usually skin fibroblasts) need to be examined.
1. Turner syndrome is a clinical manifestation of an abnormality of one of the X chromosomes in women. Turner syndrome in 60% of cases is caused by monosomy of the X chromosome (karyotype 45,X), in 20% of cases by mosaicism (for example, 45,X/46,XX) and in 20% of cases by an aberration of one of the X chromosomes (for example, 46,X). The prevalence of Turner syndrome, caused by complete monosomy of the X chromosome (45,X), among children born alive is 1:5000 (for girls 1:2500). Fetuses with a karyotype of 45.X are spontaneously aborted in 98% of cases. The syndrome is characterized by multiple malformations of the skeleton and internal organs. The most important phenotypic characteristics: short stature and dysgenesis or complete absence of gonads (in place of the ovaries, undifferentiated connective tissue cords are found that do not contain germ cells and follicles). Other signs: short neck with wing-shaped skin folds, low hairline at the back of the head, barrel-shaped chest, imbalance in facial proportions, O-shaped curvature of the arms (deformation of the elbow joints), X-shaped curvature of the legs.
A. Cytogenetic variants of the syndrome. Patients with a 45.X karyotype usually lack the paternal X chromosome; maternal age is not a risk factor. Karyotype 45,X in most cases is caused by non-disjunction of sex chromosomes in the 1st division of meiosis (as a result, only one X chromosome enters the zygote), less often - by mitotic disorders in the early stages of zygote fragmentation. In patients with mosaicism, there are clones of cells containing two X chromosomes (45,X/46,XX), X and Y chromosomes (45,X/46,XY) or clones with polysomy of the X chromosome (for example, 45, X/47,XXX). Translocations between the X chromosome and autosomes are sometimes observed. Translocations and the presence of additional cell lines in patients with mosaicism greatly influence the formation of the phenotype. If there is a clone of cells bearing the Y chromosome, then hormonally active testicular tissue may be present in the primordia of the gonads on one or both sides; external genitalia of an intermediate type are observed (from a hypertrophied clitoris to an almost normal penis). Possible aberrations of the X chromosome in Turner syndrome: isochromosome along the long arm, in rare cases isochromosome along the short arm; terminal deletion of the long arm or deletion of the entire long arm (Xq -), terminal deletion of the short arm or deletion of the entire short arm (Xp -); terminal rearrangement of the X chromosome; ring X chromosome. If an aberrant X chromosome is inactivated, the aberration may not appear in the phenotype at all or may not be fully expressed. In the latter case, the aberration is partially compensated by the presence of a normal X chromosome (gene dosage effect). Aberrations of the X chromosome are often combined with mosaicism, i.e., with the presence of a clone of 45,X cells [for example, 45,X/46X,i(Xp)]. With a translocation between the X chromosome and an autosome, the karyotype can be balanced or unbalanced. Even if the translocation is balanced, the incidence of malformations or mental retardation is increased. The normal X chromosome is usually inactivated during X-autosomal translocation. In rare cases, in patients with Turner syndrome (including patients with mosaicism with cell clone 45,X), an aberrant Y chromosome is detected. The risk of having a child with Turner syndrome again is low unless one or both parents have an inherited X autosomal translocation or the mother carries a 45.X cell clone.
b. Characteristic signs of Turner syndrome in newborns are lymphedema of the extremities and heart defects (occurring in approximately 20% of patients). The defects in 75% of cases are ventricular septal defects or coarctation of the aorta. Any girl or woman with severe growth retardation should be evaluated, even if there are no other signs of the syndrome. Other indications for examination: delayed sexual development, isolated delayed menarche, dysmenorrhea, infertility, repeated spontaneous abortions (3 or more), premature menopause. Important information is provided by determining the level of gonadotropic hormones (especially in young and prepubertal girls). The final diagnosis of Turner syndrome should be based on cytogenetic analysis. At least 50 cells should be viewed.
V. Management of patients with Turner syndrome. The primary task is a detailed examination of patients, especially young girls. The purpose of the examination is to identify heart defects, aortic dissection, gastrointestinal and kidney abnormalities, and hearing impairment. Surgery may be required. In older girls and women, chronic lymphocytic thyroiditis, chronic inflammatory bowel disease and arterial hypertension are common; these diseases require long-term conservative treatment. Treatment somatropin(sometimes in combination with anabolic steroids) accelerates growth in childhood and increases the height of adult patients. Treatment with somatropin can begin at 2 years of age (but only in cases where the girl’s height is less than the 5th percentile). Replacement therapy low doses estrogen begin, as a rule, after ossification of the epiphyses (from 14 years of age). If the patient has a hard time experiencing the absence of pubertal changes, estrogens are prescribed earlier. Even with hormonal treatment, secondary sexual characteristics are often not fully formed. Women with Turner syndrome are usually infertile, but in rare cases spontaneous ovulation occurs and pregnancy can occur. Some patients experience menstruation and normalize gonadotropin levels in the absence of hormone replacement therapy. The risk of developmental defects in the offspring of patients is increased. Women with Turner syndrome are warned about the risk of spontaneous abortion and premature menopause, and if pregnancy is suspected, they are offered prenatal diagnosis.
2. Trisomy X chromosome (47,XXX) occurs in newborn girls with a frequency of 1:1000; rarely diagnosed in early childhood; adult patients usually have a normal female phenotype.
A. A few prospective studies have shown that women with a karyotype of 47.XXX are most often noted to be: tall; mental retardation (usually mild); late speech development; epilepsy; dysmenorrhea; infertility. The risk of having a child with trisomy X is increased in older mothers. For fertile women with a karyotype of 47.XXX, 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.
b. With polysomy of the X chromosome with more than three X chromosomes (for example, 48,ХХХХ, 49,ХХХХХ) there is a high probability of severe mental retardation, abnormal facial proportions, malformations of the skeleton or internal organs. Syndromes of this kind are rare and usually sporadic.
3. Klinefelter syndrome is a clinical manifestation of polysomy on the X chromosome in men (prevalence approximately 1:500). The most commonly observed karyotype 47.XXY(classic variant of the syndrome), but rarer karyotypes are also found: 48,XXXY; 49,XXXXY; 48,XXYY; 49,XXXYY. The presence of at least two X chromosomes and one Y chromosome in the karyotype is the most common cause primary hypogonadism in men.
A. Approximately 10% of patients with Klinefelter syndrome experience mosaicism 46,XY/47,XXY. Since a clone of cells with a normal karyotype is involved in the formation of the phenotype, patients with 46,XY/47,XXY mosaicism can have normally developed gonads and be fertile. The extra X chromosome is inherited from the mother in 60% of cases, especially during late pregnancy. The risk of inheriting the paternal X chromosome does not depend on the father's age.
b. Klinefelter syndrome is characterized by phenotypic polymorphism. The most common signs: tall stature, disproportionately long legs, eunuchoid build, small testicles (long axis< 2 см). Производные вольфова протока формируются нормально. В детском возрасте нарушения развития яичек незаметны и могут не выявляться даже при биопсии. Эти нарушения обнаруживают в пубертатном периоде и позднее. В типичных случаях при биопсии яичка у взрослых находят гиалиноз извитых семенных канальцев, гиперплазию клеток Лейдига, уменьшение численности или отсутствие клеток Сертоли; сперматогенез отсутствует. Больные, как правило, бесплодны (даже если есть признаки сперматогенеза). Формирование вторичных половых признаков обычно нарушено: оволосение лица и подмышечных впадин скудное или отсутствует; наблюдается гинекомастия; отложение жира и рост волос на лобке по женскому типу. Как правило, психическое развитие задерживается, но у взрослых нарушения интеллекта незначительны. Нередко встречаются нарушения поведения, эпилептическая активность на ЭЭГ , эпилептические припадки. Сопутствующие заболевания: рак молочной железы, сахарный диабет, болезни щитовидной железы, ХОЗЛ .
V. Treatments for infertility in Klinefelter syndrome have not yet been developed. Testosterone replacement therapy usually begins between 11 and 14 years of age; with androgen deficiency, it significantly accelerates the formation of secondary sexual characteristics. In adult patients, testosterone treatment increases libido. Gynecomastia may require surgery. Psychotherapy promotes social adaptation of patients with Klinefelter syndrome and patients with other sex chromosome abnormalities.
4. Karyotype 47,XYY. This variant of aneuploidy is the least studied, attracts the attention of doctors and arouses the interest of the general public.
A. This chromosomal abnormality occurs in men with a frequency of 1:800 and rarely occurs in childhood. Adult carriers of the 47,XYY karyotype in most cases have a normal male phenotype. An additional (paternal) Y chromosome most often appears as a result of chromatid nondisjunction in the 2nd division of meiosis. Father's age is not a risk factor.
b. Carriers of the 47,XYY karyotype are characterized by high growth; Pubertal growth acceleration occurs earlier and lasts longer than usual. Minor malformations are common; the connection of the 47,XYY karyotype with major malformations has not been proven. ECG changes, globular or abscessed acne, and varicose veins are sometimes observed, but an increased risk of these disorders in individuals with a 47,XYY karyotype has not been confirmed. Mental development is within normal limits, but speech development is delayed. Often adolescents and men with karyotype 47,XYY are very aggressive, prone to criminal acts and poorly adapt to life in society. In most, the development and function of the gonads are normal, but there are cases of testicular underdevelopment, infertility, or reduced fertility.
V. No treatment required. If a 47,XYY karyotype is detected during prenatal testing or in a prepubertal child, parents should be counseled truthfully and thoroughly. An adult man who has been diagnosed with a 47,XYY karyotype for the first time needs psychological support; Medical genetic consultations may be required. Married couples in which the man carries a 47,XYY karyotype are recommended to undergo prenatal diagnosis, although in such families the children usually have a normal karyotype.
Chromosomal diseases are a large group of congenital hereditary diseases. They occupy one of the leading places in the structure of human hereditary pathology. According to cytogenetic studies among newborn children, the frequency of chromosomal pathology is 0.6-1.0%. The highest frequency of chromosomal pathology (up to 70%) was recorded in the material of early spontaneous abortions.
Consequently, most chromosomal abnormalities in humans are incompatible even with the early stages of embryogenesis. Such embryos are eliminated during implantation (7-14 days of development), which clinically manifests itself as a delay or loss of the menstrual cycle. Some embryos die soon after implantation (early miscarriages). Relatively few variants of numerical chromosome abnormalities are compatible with postnatal development and lead to chromosomal diseases (Kuleshov N.P., 1979).
Chromosomal diseases appear as a result of genomic damage that occurs during gamete maturation, during fertilization, or in the early stages of zygote cleavage. All chromosomal diseases can be divided into three large groups: 1) associated with ploidy disorders; 2) caused by a violation of the number of chromosomes; 3) associated with changes in chromosome structure.
Chromosome abnormalities associated with ploidy disturbances are represented by triploidy and tetraploidy, which are found mainly in the material of spontaneous abortions. There have been only isolated cases of the birth of triploid children with severe developmental defects incompatible with normal life activities. Triploidy can occur both as a result of digeny (fertilization of a diploid egg by a haploid sperm), and as a result of diandry (the reverse version) and dispermia (fertilization of a haploid egg by two sperm).
Chromosomal diseases associated with a violation of the number of individual chromosomes in a set are represented by either a whole monosomy (one of two homologous chromosomes is normal) or a whole trisomy (three homologs). Whole monosomy in live births occurs only on chromosome X (Shereshevsky-Turner syndrome), since most monosomies on the remaining chromosomes of the set (Y chromosome and autosomes) die at very early stages of intrauterine development and are quite rare even in material from spontaneously aborted embryos and fetuses.
It should be noted, however, that monosomy X is also detected with a fairly high frequency (about 20%) in spontaneous abortions, which indicates its high prenatal lethality, amounting to over 99%. The reason for the death of embryos with monosomy X in one case and the live birth of girls with Shereshevsky-Turner syndrome in another is unknown. There are a number of hypotheses that explain this fact, one of which associates the increased death of X-monosomal embryos with a higher probability of manifestation of recessive lethal genes on a single X chromosome.
Whole trisomies in live births occur on chromosomes X, 8, 9, 13, 14, 18, 21 and 22. The highest frequency of chromosomal abnormalities - up to 70% - is observed in early abortions. Trisomies on chromosomes 1, 5, 6, 11 and 19 are rare even in abortive material, which indicates the great morphogenetic significance of these chromosomes. More often, entire mono- and trisomies for a number of chromosomes of the set occur in mosaic condition both in spontaneous abortions and in children with MVD (multiple congenital malformations).
Chromosomal diseases associated with disruption of chromosome structure represent a large group of partial mono- or trisomy syndromes. As a rule, they arise as a result of structural rearrangements of chromosomes present in the germ cells of the parents, which, due to disruption of recombination processes in meiosis, lead to the loss or excess of chromosome fragments involved in the rearrangement. Partial mono- or trisomies are known for almost all chromosomes, but only some of them form clearly diagnosable clinical syndromes.
The phenotypic manifestations of these syndromes are more polymorphic than those of whole mono- and trisomy syndromes. This is partly due to the fact that the size of chromosome fragments and, consequently, their gene composition can vary in each individual case, and also because if one of the parents has a chromosomal translocation, partial trisomy on one chromosome in the child can be combined with partial monosomy on the other.
Clinical and cytogenetic characteristics of syndromes associated with numerical chromosome abnormalities.
1. Patau syndrome (trisomy 13). First described in 1960. Cytogenetic variants can be different: whole trisomy 13 (non-disjunction of chromosomes in meiosis, in 80% of cases in the mother), translocation variant (Robertsonian translocations D/13 and G/13), mosaic forms, additional ring chromosome 13, isochromosomes.
Patients have severe structural anomalies: cleft soft and hard palate, cleft lip, underdeveloped or absent eyes, malformed low-set ears, deformed bones of the hands and feet, numerous disorders of the internal organs, for example, congenital heart defects (septal defects and large vessels) ). Deep idiocy. The life expectancy of children is less than a year, usually 2-3 months. Population frequency is 1 in 7800.
2. Edwards syndrome (trisomy 18). Described in 1960. Cytogenetically, in most cases it is represented by the whole trisomy 18 (a gametic mutation of one of the parents, usually on the maternal side). In addition, mosaic forms are also found, and translocations are observed very rarely. The critical segment responsible for the formation of the main symptoms of the syndrome is the 18q11 segment. No clinical differences were found between cytogenetic forms. Patients have a narrow forehead and a wide protruding back of the head, very low-set deformed ears, underdevelopment of the lower jaw, wide and short fingers. From
internal defects should be noted combined defects of the cardiovascular system, incomplete intestinal rotation, kidney malformations, etc. Children with Edwards syndrome have low birth weight. There is a delay in psychomotor development, idiocy and imbecility. Life expectancy is up to a year - 2-3 months. Population frequency 1 in 6500.
Down syndrome (trisomy 21). It was first described in 1866 by the English physician Down. Population frequency is 1 case per 600-700 newborns. The frequency of births of children with this syndrome depends on the age of the mother and increases sharply after 35 years. Cytogenetic variants are very diverse, but around Fig. 15. S. Down (6) above (8) below
95% of cases are represented by simple trisomy of chromosome 21, as a result of chromosome nondisjunction in meiosis in the parents. The presence of polymorphic molecular genetic markers makes it possible to determine the specific parent and the stage of meiosis at which nondisjunction occurred. Despite intensive study of the syndrome, the causes of chromosome nondisjunction are still unclear. Etiologically important factors are intra- and extrafollicular 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 symptoms of the syndrome is the 21q22 region.
Patients have shortened limbs, a small skull, a flat and wide nose bridge, narrow palpebral fissures with an oblique incision, an overhanging fold of the upper eyelid - epicanthus, excess skin on the neck, short limbs, a transverse four-fingered palmar fold (monkey groove). Among the defects of internal organs, congenital defects 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 sex chromosome abnormalities.
1. Shereshevsky-Turner syndrome (monosomy of the X chromosome). This is the only form of monosomy in humans that can be
detected in live births. In addition to simple monosomy on the X chromosome, which is 50%, there are mosaic forms, deletions of the long and short arms of the X chromosome, iso-X chromosomes, as well as ring X chromosomes. It is interesting to note that 45,X/46,XY mosaicism accounts for 2-5% of all patients with this syndrome and is characterized by a wide range of features: from the typical Shereshevsky-Turner syndrome to the normal male phenotype.
Population frequency is 1 in 3000 newborns. Patients are short in stature, have a barrel-shaped chest, broad shoulders, a narrow pelvis, and shortened lower limbs. A very characteristic feature is a short neck with folds of skin extending from the back of the head (sphinx neck). They experience low hair growth on the back of the head, hyperpigmentation of the skin, and decreased vision and hearing. The inner corners of the eyes are located higher than the outer ones. Congenital heart and kidney defects are common. In patients, ovarian underdevelopment is detected. Infertile. Intellectual development is within normal limits. There is some infantilism of emotions and instability of mood. The patients are quite viable.
2. Polysomy X syndrome ( Trisomy X). Cytogenetically, forms 47,ХХХ, 48,ХХХХ and 49,ХХХХХ are detected. As the number of the X chromosome increases, the degree of deviation from the norm increases. In women with tetra- and pentasomy X, abnormalities in mental development, skeletal and genital abnormalities have been described. Women with karyotype 47,XXX in full or mosaic form generally have normal physical and mental development, and intelligence - within the lower limit of normal. These women have a number of mild deviations in physical development, ovarian dysfunction, and premature menopause, but they can have offspring. Population frequency is 1 per 1000 newborn girls.
3. Klinefelter's syndrome. Described in 1942. The population frequency is 1 in 1000 boys. Cytogenetic variants of the syndrome can be different: 47.XXY: 48.XXYY; 48.XXXY; 49.XXXXY. Both complete and mosaic forms are noted. Patients are tall with disproportionately long limbs. In childhood they are distinguished by a fragile physique, and after 40 years they become obese. They develop an asthenic or eunuch-like body type: narrow shoulders, wide pelvis, female-type fat deposition, poorly developed
muscles, sparse facial hair. Patients have underdevelopment of the testes, lack of spermatogenesis, decreased libido, impotence and infertility. Mental retardation usually develops. IQ below 80.
4. Y-chromosome polysemy syndrome (double-Y or “extra Y chromosome”). The population frequency is 1 in 1000 boys. Cytogenetically marked complete and mosaic forms. Most individuals do not differ from healthy ones in physical and mental development. The gonads are developed normally, growth is usually high, and there are some anomalies of the teeth and skeletal system. Psychopathic traits are observed: instability of emotions, antisocial behavior, tendency towards aggression, homosexuality. Patients do not exhibit significant mental retardation, and some patients generally have normal intelligence. They can have normal offspring in 50% of cases.
Clinical and genetic characteristics of syndromes associated with structural rearrangements of chromosomes.
Cry of the cat syndrome (monosomy 5p). Described in 1963. Population frequency is 1 in 50,000. Cytogenetic variants vary from partial to complete deletion of the short arm of chromosome 5. For the development of the main signs of the syndrome, the 5p15 segment is of great importance. In addition to simple deletions, ring chromosome 5, mosaic forms, and translocations between the short arm of chromosome 5 (with loss of a critical segment) and another autosome have been noted.
Diagnostic signs of the disease are: microcephaly, an unusual cry or cry reminiscent of a cat's meow (especially in the first weeks after birth); anti-Mongoloid eye shape, squint, moon-shaped face, wide bridge of the nose. The ears are low set and deformed. There is a transverse palmar fold and abnormalities in the structure of the hands and fingers. Mental retardation in the imbecility stage. It should be noted that such signs as a moon-shaped face and a cat's cry smooth out with age, and microcephaly and strabismus are more clearly identified. Life expectancy depends on the severity of congenital malformations of internal organs. Most patients die in the first years of life.
Clinical and cytogenetic characteristics of syndromes and malignant neoplasms associated with microstructural abnormalities of chromosomes.
Recently, clinical cytogenetic studies have begun to rely on high-resolution methods of chromosomal analysis, which has made it possible to confirm the assumption of the existence of microchromosomal mutations, the detection of which is on the verge of the capabilities of a light microscope.
Using standard cytogenetic methods, it is possible to achieve visual resolution of chromosomes with the number of segments not exceeding 400, and using the methods of prometaphase analysis proposed by Younis in 1976, it is possible to obtain chromosomes with the number of segments up to 550-850. Minor abnormalities in the structure of chromosomes can be detected using these methods of chromosome analysis not only among patients with CFPR, but also in some unknown Mendelian syndromes and various malignant tumors. Most syndromes associated with microchromosomal abnormalities are rare - 1 case in 50,000-100,000 newborns.
Retinoblastoma. Patients with retinoblastoma, a malignant tumor of the retina, account for 0.6-0.8% of all patients with cancer. This is the first tumor for which a connection with chromosomal pathology has been established. Cytogenetically, this disease reveals a microdeletion of chromosome 13, segment 13q14. In addition to microdeletions, mosaic forms and translocation variants are also found. Several cases of translocation of a segment of chromosome 13 to the X chromosome have been described.
There was no correlation between the size of the deleted fragment and phenotypic manifestations. The disease usually begins at the age of about 1.5 years and the first signs are glowing pupils, sluggish reaction of the pupil to light, and then decreased vision up to blindness. Complications of retinoblastoma include retinal detachment and secondary glaucoma. In 1986, a tumor suppressor gene was discovered in the critical segment 13ql4 RBI, which was the first antioncogene discovered in humans.
Monogenic diseases manifested by chromosomal instability.
To date, new types of genome variability have been established, differing in frequency and mechanisms from the usual mutation process. One of the manifestations of genome instability at the cellular level is chromosomal instability. Chromosome instability is assessed by an increase in spontaneous and/or induced frequency of chromosomal aberrations and sister chromatid exchanges (SCOs). An increased frequency of spontaneous chromosomal aberrations was first shown in 1964 in patients with Fanconi anemia, and an increased frequency of SCO was found in Bloom's syndrome. In 1968, it was found that xeroderma pigmentosum, a photodermatosis in which the frequency of chromosomal aberrations induced by UV radiation is increased, is associated with a violation of the ability of cells to repair (restore) their DNA from damage caused by UV radiation.
Currently, about one and a half dozen monogenic pathological signs associated with increased chromosome fragility are known. In these diseases, there are no specific areas of chromosomal damage, but the overall frequency of chromosome aberrations increases. The molecular mechanism of this phenomenon is most often associated with defects in individual genes encoding DNA repair enzymes. Therefore, most diseases accompanied by chromosomal instability are also called DNA repair diseases. Despite the fact that these diseases are different in their clinical manifestations, they are all characterized by an increased tendency to malignant neoplasms, signs of premature aging, neurological disorders, immunodeficiency states, congenital malformations, skin manifestations, and mental retardation is often observed.
In addition to mutations in DNA repair genes, diseases with chromosomal instability may be based on defects in other genes that ensure genome stability. Recently, more and more evidence has been accumulating that in addition to diseases manifested by instability of chromosome structure, there are also monogenic defects leading to diseases with instability of the number of chromosomes. As such an independent group of monogenic diseases, we can distinguish rare pathological conditions that indicate the non-random, hereditarily determined nature of chromosome nondisjunction in somatic cells during embryogenesis.
During a cytogenetic study in these patients, in a small part of the cells (usually 5-20%), somatic mosaicism is detected on several chromosomes of the set at once, or one married couple may have several siblings with chromosomal mosaicism. It is assumed that such patients are “mitotic mutants” for recessive genes that control individual stages of mitosis. There is no doubt that most of these types of mutations are lethal, and surviving individuals have relatively mild forms of cell division pathology. Despite the fact that the above diseases are caused by defects in individual genes, conducting a cytogenetic study in patients suspected of having this pathology will help the doctor in the differential diagnosis of these conditions.
Diseases with instability of chromosome structure:
Bloom's syndrome. Described in 1954. The main diagnostic features are: low birth weight, growth retardation, narrow face with butterfly-shaped erythema, massive nose, immunodeficiency, and a tendency to malignancy. Mental retardation is not observed in all cases. Cytogenetically, it is characterized by an increase in the number of sister chromatid exchanges (SEC) per cell to 120-150, although normally their number does not exceed 6-8 exchanges per 1 cell. In addition, chromatid breaks are detected with high frequency, as well as dicentrics, rings and chromosomal fragments. Patients have mutations in the DNA ligase 1 gene, localized on chromosome 19 - 19q13.3, but the Bloom syndrome gene is mapped to the 15q26.1 segment.
Fanconi anemia . A disease with an autosomal recessive type of inheritance. Described in 1927. The main diagnostic signs: hypoplasia of the radius and thumb, delayed growth and development, hyperpigmentation of the skin in the groin and axillary areas. In addition, bone marrow hypoplasia, a tendency to leukemia, and hypoplasia of the external genitalia are noted. Cytogenetically it is characterized by multiple chromosomal aberrations - chromosome breaks and chromatid exchanges. This is a genetically heterogeneous disease, i.e. a clinically similar phenotype is caused by mutations in different genes. There are at least 7 forms of this disease: A - the gene is localized in the 16q24.3 segment; B - gene localization is unknown; C - 9q22.3; D - Зр25.3; E - 6р22; F - 11р15; G (MIM 602956) - 9р13. The most common form is A - about 60% of patients.
Werner syndrome (premature aging syndrome). A disease with an autosomal recessive type of inheritance. Described in 1904. The main diagnostic signs are: premature graying and baldness, atrophy of subcutaneous fat and muscle tissue, cataracts, early atherosclerosis, endocrine pathology (diabetes mellitus). Characterized by infertility, high voice, and a tendency to malignant neoplasms. Patients die at the age of 30-40 years. Cytogenetically, it is characterized by cell clones with different chromosomal translocations (mosaicism for various translocations). The disease gene is localized in the 8p11-p12 segment.
Fragile X syndrome.
As a rule, chromosome breaks or chromatid gaps that occur with increased frequency in certain specific chromosomal segments (the so-called fragile regions or fragile sites of chromosomes) are not associated with any diseases. However, there is an exception to this rule. In 1969, in patients with a syndrome accompanied by mental retardation, the presence of a specific cytogenetic marker was discovered - in the distal part of the long arm of the X chromosome in the Xq27.3 segment, a chromatid break or gap is recorded in individual cells.
Later it was shown that the first clinical description of a family with a syndrome in which mental retardation is the leading clinical sign was described back in 1943 by English doctors P. Martin and Y. Bell. Martin-Bell syndrome or fragile X syndrome is characterized by a fragile X chromosome in the Xq27.3 segment, which is detected under special cell culture conditions in a folic acid-deficient environment.
The fragile site in this syndrome is designated FRAXA. The main diagnostic signs of the disease are: mental retardation, a wide face with acromegaly features, large protruding ears, autism, hypermobility, poor concentration, speech defects, more pronounced in children. Connective tissue abnormalities with joint hyperextensibility and mitral valve defect are also noted. Only 60% of men with a fragile X chromosome have a relatively full range of clinical signs, 10% of patients have no facial anomalies, 10% have only mental retardation without other signs.
Fragile X syndrome is interesting for its unusual inheritance and high population frequency (1 in 1500-3000). The unusual nature of inheritance is that only 80% of male carriers of the mutant gene have signs of the disease, and the remaining 20% are both clinically and cytogenetically normal, although after passing the mutation to their daughters they may have affected grandchildren. These men are called transmitters, i.e. transmitters of an unexpressed mutant gene that becomes expressed in subsequent generations.
In addition, there are two types of women - heterozygous carriers of the mutant gene:
a) daughters of male transmitters who do not have symptoms of the disease and in whom the fragile X chromosome is not detected;
b) granddaughters of normal male transmitters and sisters of affected males, who show clinical signs of the disease in 35% of cases.
Thus, the gene mutation in Martin-Bell syndrome exists in two forms, differing in their penetrance: the first form is a phenotypically silent premutation, which turns into a complete mutation (the second form) when passing through female meiosis. A clear dependence of the development of mental retardation on the position of the individual in the pedigree was discovered. At the same time, the phenomenon of anticipation is clearly visible - a more severe manifestation of the disease in subsequent generations.
The molecular mechanism of the mutation became clear in 1991, when the gene responsible for the development of this disease was characterized. The gene was named FMR1 (English - Fragile site Mental Retardation 1 - a fragile section of the chromosome associated with the development of type 1 mental retardation). It was found that the clinical manifestations and cytogenetic instability in the Xq27.3 locus are based on a multiple increase in the first exon of the FMR-1 gene of a simple trinucleotide repeat CGG.
In normal people, the number of these repeats in the X chromosome ranges from 5 to 52, and in patients their number is 200 or more. This phenomenon of a sharp, abrupt change in the number of CGG repeats in patients is called expansion of the number of trinucleotide repeats: It has been shown that the expansion of CGG repeats significantly depends on the sex of the descendant; it is noticeably increased when the mutation is transmitted from mother to son. It is important to note that nucleotide repeat expansion is a postzygotic event and occurs very early in embryogenesis.
