Karyotype analysis for the determination of Down, Klinefelter, Turner syndromes
Down, Klinefelter and Turner syndromes are the most common chromosomal abnormalities. Therefore, from a prophlactic point of view, it is important, through karyotyping, to diagnose these diseases as early as possible and, in some cases, to carry out prenatal diagnostics.
Down syndrome (trisomy 21) - one of the forms of genomic pathology, in which most often the karyotype is represented by 47 chromosomes instead of the normal 46, since the chromosomes of the 21st pair, instead of the normal two, are represented by three copies. There are two more forms of this syndrome: translocation of chromosome 21 to other chromosomes (more often by 15, less often by 14, even less often by 21, 22 and Y chromosomes) - 4% of cases, and a mosaic variant of the syndrome - 5%. Down's syndrome is not a rare condition - on average, there is one case in 700 births; at the moment, due to prenatal diagnosis, the frequency of births of children with Down syndrome has decreased to 1 in 1100. In boys and girls, the anomaly occurs with the same frequency. The likelihood of having children with Down syndrome increases with the age of the mother (after 35 years) and, to a lesser extent, with the age of the father. According to the literature, the frequency of nondisjunction of the 21st chromosome in spermatogenesis, as well as in oogenesis, increases with age. After the accident at the Chernobyl nuclear power plant, an increase in the number of congenital abnormalities was found in various regions of Belarus between 1986 and 1994, but it was approximately the same in both polluted and clean areas. no trend towards an increase in morbidity was observed.
Klinefelter's syndrome occurs in 1 in 500 boys. Patients with the classic variant of the syndrome have a 47, XXY karyotype. Other karyotypes are also possible, and in 10% of patients mosaicism 46, XY / 47, XXY is detected, there are also more rare karyotypes: 48, XXXY; 49, XXXXY; 48, XXYY; 49, XXXYY. The syndrome usually manifests itself in adolescence as a delay in puberty. The penis and testicles are reduced, the physique is eunuchoid, infertility, gynecomastia, moderate mental retardation and antisocial behavior are characteristic. Sometimes testicular hypoplasia is the only symptom of the disease in apparently healthy men. Patients are prone to diabetes mellitus, thyroid disease and breast cancer. The presence of at least two X chromosomes and one Y chromosome in a karyotype is the most common cause of primary hypogonadism in men. Treatments for infertility in Klinefelter's syndrome have not yet been developed. Testosterone replacement therapy is usually started at the age of 11-14; with androgen deficiency, it significantly accelerates the formation of secondary sexual characteristics. In adult patients, on the background of testosterone treatment, libido increases. Gynecomastia may require surgery. Psychotherapy contributes to the social adaptation of patients with Klinefelter's syndrome and patients with other sex chromosome abnormalities.
Shereshevsky-Turner syndrome or gonadal dysgenesis - This is a violation of the development of the gonads caused by an abnormality of the sex chromosomes. During the division of the sex cells of the parents, the divergence of the sex chromosomes is disrupted, as a result of which, instead of the normal number of X-romosomes (and normally a woman has two), the embryo receives only one X-chromosome. The set of chromosomes is incomplete. This syndrome occurs with a frequency of one in three thousand girls born. The development of the gonads is disrupted already in the early period of development of the embryo. During puberty, secondary sexual characteristics do not develop (the mammary glands are underdeveloped, hairiness on the pubis and in the armpits is not expressed). There is no menses. One third of patients have malformations of other organs, as well as diabetes mellitus, inflammatory diseases of the colon, goiter and thyroiditis, gastrointestinal bleeding.
X0 syndrome - Shereshevsky-Turner syndrome. Syndrome XXY - Klinefelter syndrome in neurology
X0 syndrome due to a lack of genetic material localized on the X chromosome. First described by N. A. Shereshevsky in 1925, and in 1938 - 1. Turner. It occurs with a frequency of 1: 2500-1: 3000 newborn girls.
Pathological studies indicate the underdevelopment of the gonads, which are either completely absent, or have the form of connective tissue cords with remnants of ovarian tissue and interstitial cells. Often, malformations of the cardiovascular system (coarctation of the aorta, stenosis of the pulmonary artery, defect of the interventricular septum, non-closure of the botalle duct), gastrointestinal tract, urinary system (cystic kidney, horseshoe-shaped kidneys) are found.
Diagnose the syndrome is possible already in the neonatal period. Children are born with a low weight and small stature, moderate swelling of the hands and feet can be observed for several months; low hair growth on the neck, short neck with pterygoid folds extending from the mastoid processes to the shoulders, or excessive mobility of the skin on the neck. Other developmental anomalies include epicant, fused eyebrows, ptosis, lagophthalmos or exophthalmos, hypertelorism, microphthalmos, eyelid colobomas, wide flat chest imitating wide-spaced nipples, vertebral fusion, clinodactyly, valgus curvature of the feet of the body and anomalies of bite , osteoporosis.
With ophthalmological examination cloudy opacities and decreased sensitivity of the cornea, pallor of the optic nerve, narrowing of the arteries in the fundus, microphthalmos, cataracts are detected.
In neurological status usually no abnormalities are observed, with the exception of general muscle hypotension. Mental development at an early age is normal or its pace is somewhat slowed down.
With dermatoglyphic research changes in the skin patterns of the fingers and palms are revealed. An increase in the frequency of ulnar loops on the thumb and forefinger is usually found. Distal axial triradius occurs in 50% of patients with Shereshevsky-Turner syndrome. More often than in healthy people, there is a transverse fold of the palm and a single fold on the V finger. Palmar patterns are very large distal loops or curls with a large ridge score.
The complex of these symptoms is an indication for the study of scrapings of the oral mucosa for sex chromatin. About 80% of patients with Shereshevsky-Turner syndrome are chromatin-negative, their karyotype is 45, XO. With deletions of Xq-, Xp-, as well as with the circular X chromosome, XO / XX mozapcism, the clinical signs are less pronounced than with the XO syndrome. In scrapings from the mucous membrane, small Barr bodies are determined in fewer numbers than in normal girls.
Diagnosis verified by examining the karyotype of peripheral blood lymphocytes.
In young years syndrome should be differentiated from hypotrophy of another etiology, hypothyroidism, congenital malformations of a non-chromosomal nature; with pronounced redundancy of the skin on the neck - from cutis laxa and Ehlers-Danlos syndrome.
Treatment of Shereshevsky-Turner syndrome symptomatic at an early age. In order to stimulate mental and motor development, Cerebrolysin, Aminolone, Acefen, Prephysone, B vitamins, massage, and physiotherapy exercises are used.
XXY Syndrome (Klinefelter Syndrome)
Syndrome due to trisomy of the sex chromosomes due to the presence of an additional X chromosome. It occurs with a frequency of 1: 400-500 newborn boys. Described in 1942 by A. Klinefelter et al.
Pathomorphologically characterized primary gonadal dysgenesis. Their histological examination reveals a narrowing or obliteration of the seminiferous tubules, hyaline sclerosis, proliferation of Leydig cells. Non-lyterated tubules are filled with degenerative sertolium cells.
A characteristic feature syndrome in early childhood, there is a decrease in the size of the testicles and a change in their consistency (denser or, conversely, softer). Already in the neonatal period, attention is drawn to the features of the physique of the child - disproportionately long legs and arms, a narrow chest. Mental development is usually normal. In a number of patients, eye changes are described in the form of retinal pigment degeneration and colobomas of the uveal tract.
Boys with Klinefelter syndrome chromatin-positive. On dermatoglyphs, there may be a displacement of the axial triradius, an increase in the angle atd, an increase in the frequency of arcs on the fingers, a tendency to a decrease in the ridge count.
Diagnosis verified by examining the karyotype in peripheral blood lymphocytes, in which, in most cases, 47 chromosomes are detected due to an additional X chromosome. However, the number of X chromosomes can be more than 2. In such patients, all the symptoms of the disease are more pronounced, mental retardation is necessarily noted, the deeper, the more X chromosomes in the karyotype, gigantism and acromegaly can be.
At an early age, the syndrome diagnosed only with a screening study of sex chromatin.
Treatment at an early age, they are carried out only in cases of mental retardation. Prescribe drugs that stimulate the function of the central nervous system (aminolone, cerebrolysin, vitamins of group B), conduct speech therapy and pedagogical classes, purposefully forming the higher cortical functions.
XYY syndrome. The 47, XYY karyotype occurs among newborn boys with a frequency of 1: 250-500 and is most often not accompanied by a pathological phenotype. At an early age, developmental features are not found. May be an accidental karyoloptic find.
Polysomy X syndrome. Most often it occurs in the form of trisomy X (47, XXX) and may not be accompanied by a pathological phenotype. When the number of X chromosomes is more than 3, mental retardation and dysgenesis of the gonads are characteristic, the more pronounced the more additional X chromosomes.
Karyotype - (from karyo, Greek káryon - nut, core and Greek týpos - sample, shape, type) a set of chromosomes, a set of chromosome features (number, size, shape) in the cells of the body of an organism of a particular species. The study is carried out during the metaphase of cell division. A common cause of genetic infertility / miscarriage is a change in the number of chromosomes or a change in their structure. Therefore, the study of the karyotype is indicated (for infertility) for both spouses. Chromosomes are DNA molecules that are packed together with proteins necessary for DNA to function. There are 46 chromosomes in the nucleus of all human somatic cells. Of the 46 chromosomes, 44 or 22 pairs are autosomal chromosomes, the last pair being sex chromosomes. In women, sex chromosomes are normally represented by two X chromosomes, in men - by two chromosomes X and Y. In all pairs of chromosomes, both autosomal and sex, one of the chromosomes is obtained from the father, and the other from the mother. In the reproductive cells - in the sperm and in the egg, there are 23 chromosomes (haploid set). Spermatozoa are divided into two types depending on whether they contain the X or Y chromosome.The eggs normally contain only the X chromosome. Chromosomes contain about 99% of the entire DNA of a cell, the rest of the DNA is located in other cellular organelles (for example, in mitochondria). DNA in eukaryotic chromosomes is in a complex with the main proteins - histones and non-histone proteins, which provide complex packaging of DNA in chromosomes and regulation of its ability to synthesize ribonucleic acids (RNA). Every year, a large number of descriptions of new genetically determined anomalies appear in the literature. According to one of the data, more than 2000 hereditary syndromes in humans are known. According to statistics, about 0.7% of children are born with multiple developmental defects. Violations of the karyotype are often accompanied by malformations that are incompatible with life, which ends in intrauterine fetal death and abortion. However, some defects in the karyotype allow the fetus to mature and the child is born with the inherent phenotypic and genotypic characteristics for a particular disease or syndrome. The main anomalies of the karyotype include: Down syndrome, Shereshevsky-Turner syndrome, Edwards syndrome, Klinefelter syndrome. Chromosomal abnormalities are detected in at least 10% of fertilized eggs and in 5-6% of fetuses. Spontaneous abortion with chromosomal defects is usually recorded at 8-11 weeks of pregnancy (later spontaneous abortions and stillbirths are possible). Based on the results of examinations of 65,000 newborns carried out in different laboratories, significant chromosomal aberrations or changes in the number of chromosomes are detected in about 0.5% of children. At least 1 in 700 children have trisomy on chromosome 21, 18, or 13; about 1 in 350 newborn boys have a 47, XXY or 47, XYY karyotype; one child for every several thousand newborns has monosomy on the X chromosome; one in 500 has chromosomal aberrations, most of which are genetically compensated. When examining adults, inherited compensated chromosomal aberrations are rarely detected, as well as a number of people with karyotypes 47, XXY, 47, XYY and 47, XXX. With mental retardation, chromosomal abnormalities are found in 10-15% of patients, and even more often with concomitant anatomical defects. Men with infertility or behavioral disorders often have an extra X or Y chromosome. In women with infertility and low fertility, aberrations of the X chromosome or monosomy on the X chromosome are often found. In primary amenorrhea, X-chromosome aberrations are found in about a quarter of women. Chromosomal aberrations are often found in infertility in both men and women. The most common chromosomal mutations are trisomies. Trisomy is the appearance of an additional chromosome in the karyotype. The most famous examples are Down's disease, which is also called chromosome 21 trisomy. Chromosome 13 trisomy is Patau's syndrome and chromosome 18 is Edwards syndrome. These trisomies are autosomal. Other trisomics are not viable in autosomes and die in utero. Individuals with additional sex chromosomes are viable. Trisomy on sex chromosomes can be of three types - 47, XXY; 47, XXX; 47, XYY (trisomy 47, XXY, known as Klinefelter syndrome). The clinical manifestations of additional X or Y chromosomes may be minor. Trisomies 47, XXY and 47, XYY occur with a frequency of 1: 1000 among women and men, respectively, are relatively minor phenotypic manifestations and are usually found as coincidental findings. Down syndrome (synonyms: trisomy on the 21st chromosome, G 1 -trisomy). Described by Down JLH in 1866. One of the most common congenital human diseases (1 in 660 newborns according to Penrose L.S., Smith G.F. 1966). Distinctive features - mental retardation, muscle hypotonia, flat face, Mongoloid eyes, small auricles. The likelihood of nondisjunction of chromosomes in female reproductive cells increases with the age of the mother. The frequency of birth of a sick child in women 15-29 years old is 1 in 1500 births, 30-34 years - 1 in 800, 35-39 years 1 in 270, 40-44 years 1 in 100, after 45 years 1 in 50. Down syndrome is caused by trisomy on all or most of chromosome 21. Based on the generalized research data, the relative frequency of chromosomal aberrations for this syndrome is as follows: 1. Complete trisomy on the 21st chromosome - 94%; 2. Mosaicism, combining trisomy with a normal set of chromosomes - 2.4%; 3. Translocation of the 21st chromosome or its greater part to chromosomes of group D or G (with approximately the same frequency) - 3.3%. Mosaicism causes less severe manifestations, mental development is delayed, or may not be disturbed, which cannot be predicted by appearance. Mosaicism is the existence in the body of two or more genetically different types of cells. Well-developed children with Down syndrome appearance are more likely to have mosaicism, which is sometimes not easy to confirm. The average IQ in sick adolescents and adults (according to some estimates) is 24. According to statistics, in 1983, patients with Down syndrome lived up to 25 years on average, and in 1997 already up to 49 years. The main cause of early death is congenital heart defects, as well as respiratory diseases, leukemia. Weakening of humoral and cellular immunity is observed. The most common comorbidities are rhinitis, conjunctivitis, and periodontitis, which are difficult to treat. Edwards syndrome (synonyms: trisomy on the 18th chromosome, E 1 - trisomy). First described by Edwards JH in 1960. The second most common syndrome of multiple malformations. It occurs with a frequency of 1 in 3000 newborns (3 times more sick girls are born than boys). More than 130 symptoms of this chromosomal abnormality have been described. Distinctive features - clenched fists with overlapping fingers, short sternum, skin pattern in the form of arcs on most of the fingers. Edwards syndrome is caused by trisomy on chromosome 18 or a large part of it. In most patients, complete trisomy is found, due to an abnormal separation of chromosomes in meiosis. The likelihood of such a discrepancy increases with the age of the mother. The mosaic form of trisomy on the 18th chromosome proceeds more easily than complete trisomy. The phenotype ranges from nearly normal to advanced disease. The partial form manifests itself in different ways - depending on which part of the chromosome is duplicated. Trisomy along the short shoulder is accompanied by a blurred clinical picture with normal mental development or mild mental retardation. Children with this syndrome are born weak, half of the children die in the first week of life, few live up to a year. the average life expectancy is 14.5 days, children who are going through a year (5-10%) suffer from profound mental retardation. There are isolated cases of survival of children over 10 years old. Patau syndrome (synonyms: trisomy on the 13th chromosome, D 1 - trisomy). First described by Patau K in 1960. It occurs with a frequency of 1 in 5000 newborns. Distinctive features - malformations of the eyes, nose and upper lip, proencephalic defects, polydactyly, long convex nails, focal aplasia of the scalp. The syndrome is caused by trisomy on the 13th chromosome or a large part of it. The mosaic form of trisomy proceeds, as a rule, easier with varying severity of symptoms and the degree of mental retardation. Life expectancy is higher. Trisomy along the short arm and the proximal part of the long arm of chromosome 13 is manifested by nonspecific features and usually severe mental retardation. Trisomy along the distal part of the chromosome is manifested by profound mental retardation and death in the early neonatal period. Half of babies die in the first week after birth, and only one in ten survive one year. Turner syndrome (synonyms: sexogenic dwarfism, CO syndrome, X-chromosome monosomy syndrome, Ullrich syndrome, Shereshevsky-Turner syndrome). Described in detail by Turner HH in 1938. First spotted by Rossle RI in 1922. It occurs with a frequency of 1 in 2500 newborn girls. Distinctive features - short stature, wide chest, nipple hypertelorism, congenital lymphatic edema of the hands and feet. The cause of the syndrome is the nondisjunction of chromosomes in meiosis with the formation of karyotype 45, XO. One of the two X chromosomes is missing completely or partially. More often the paternal chromosome is absent. The most common manifestations of the disease are short stature and dysgenesis of the gonads (underdevelopment or complete absence of follicles, ovarian atrophy). Since dysgenesis does not manifest itself until puberty, girls with stunted growth in the absence of symptoms that exclude Turner syndrome can be recommended for behavior by cytogenetic examination. Mosaic form of the disease - karyotype 46, XX / 45, XO or 46, XY / 45X and incomplete monosomy on the X chromosome (isochromosome X or deletion of part of the X chromosome) often occurs in a mild form. It is advisable to carry out a cytogenetic study for all girls who, by the age of 13, lack thelarche and adrenarche, and also have primary or secondary amenorrhea with an increased content of FSH. It has been shown that during the period of intrauterine development, the ovaries develop normally, however, primordial follicles, apparently, are not formed and the ovaries subsequently atrophy. Growth retardation in girls is sometimes noticeable at birth. Until the age of 3 years, the child grows normally, but with a delay in the maturation of bone tissue, and from 3 to 12 years, on the contrary, the bone tissue matures normally, but growth is slowed down. After 12 years, the growth and maturation of bones is slowed down, a tendency to be overweight appears. Growth without treatment is (on average) 143 cm. Due to the developing atrophy of the ovaries, such women are infertile. Adults with Turner syndrome have an increased incidence of aortic dissection. The incidence of arterial hypertension, diabetes mellitus, arterial hypertension, and stroke is increased. 6% of girls have a mosaic karyotype - 45, XO / 46, XY and they have a significantly increased risk of gonadoblastoma. Klinefelter syndrome (synonyms: XXY syndrome, 47, XXY syndrome, Klinefelter-Reyfenstein-Albright syndrome). Described by Klinefelter HF 1942. It occurs with a frequency of 1 in 500 newborn boys. Distinguishing features: hypogonadism, long legs, decreased intelligence, behavioral disorders. The manifestation of the syndrome is associated with the presence of an extra X chromosome in the male karyotype. The reason, in about half of the cases, is the nondisjunction of chromosomes in the 1st division of meiosis during spermatogenesis, the other half is a violation of oogenesis, and in a small number of cases, a violation of mitosis in fertilized cells. The older a man becomes, the more often sperm with both sex chromosomes are found in him, i.e. the risk of having a baby with Klinefelter syndrome should be higher. The syndrome is the most common cause of male hypogonadism and infertility. From childhood, such patients are characterized by a eunuchoid physique - tall, disproportionately long limbs, long legs. Speech development is delayed, mental infantilism, uncertainty, or vice versa, self-confidence, impaired judgment are manifested. The penis and testicles are relatively small since childhood, testosterone synthesis, with rare exceptions, is halved. Secondary signs are poorly developed, gynecomastia in a third of adolescents. Rare symptoms in Klinefelter's syndrome include: cryptorchidism, scoliosis, diabetes mellitus, chronic bronchitis, mild ataxia, trophic ulcers of the legs, varicose veins, deep vein thrombosis, osteoporosis, breast cancer (20 times more often), extragonadal tumors (more often in age 15-30), autoimmune diseases. In childhood, the symptoms are minimal, the clinical picture develops in the pubertal and post-pubertal period and reflects the degree of androgen deficiency. With the mosaic form of the syndrome (46, XY / 47, XXY), the disease is easier with less testicular impairment. A variant of Klinefelter's syndrome - XXYY syndrome is characterized by more severe mental retardation and severe behavioral disorders. Syndromes XXX and XXXX (synonyms: polysomies on the X chromosome, XXX syndrome - triplo-X syndrome, trisomy syndrome on the X chromosome, XXXX syndrome - tetrasomy syndrome on the X chromosome, tetra-X syndrome). XXX syndrome is described by Jacobs PA et al. in 1959. Karyotype 47, XXX occurs with a frequency of 1 per 1000 newborn girls. The manifestation of the syndrome is associated with the presence of an additional X chromosome (one or two) in the female karyotype. The cause of XXX syndrome is mainly chromosome nondisjunction during the 1st division of meiosis. In such patients, motor speech is often impaired, auditory memory is weakened, the acquisition of motor skills occurs with a delay, poor coordination of movements and clumsiness are typical. IQ reduced (80 -90). A third of adolescents have behavioral disorders - withdrawal, antisocial behavior, mild depression. Over time, these violations disappear. Puberty is normal. XXXX syndrome is described by Carr DH et al. in 1961. For this syndrome, mental retardation is characteristic of clinical manifestations. Height is normal or tall. Facial features resemble Down syndrome. IQ is reduced (55 on average). Delayed development of speech and behavior is characteristic. These patients have frequent menstrual irregularities and reduced fertility, but their children are usually healthy. XXXXX syndrome (synonyms: pentasomy syndrome on the X chromosome, penta-X syndrome). XXXXX syndrome was described by Kesaree N and Wooley PV in 1963. Distinctive features: Mongoloid eye incision, open arterial eye incision, small palms, clinodictalia of the fifth finger. The syndrome is caused by the presence of three additional X chromosomes in the karyotype of women. The extra chromosomes come from the mother. For this syndrome, clinical manifestations are characterized by mental retardation, growth retardation, short stature, microcephaly, slightly Mongoloid eye incision, sunken nose bridge, short neck, low hairline, malocclusion, congenital heart defects - open mitral defect, ventricular septal defect. IQ in the range of 20-75. Cat's eye syndrome (synonyms: iris colomba syndrome and atresia of the anus, Schmid-Frakkaro syndrome). Distinctive features: colombus of the iris, antimongoloid eye incision, atresia of the anus. In such patients, an extra chromosome is found, consisting of two identical sections of the 22nd chromosome, containing the entire short arm together with satellites, the centromere and the short part of the long arm. Those. this section is present in 4 copies. Sometimes the disease is caused by a doubling of the 22q11 segment. Colombus of the iris and atresia of the anus, as the main symptoms of the disease, are present simultaneously in only 9% of cases. The disease is characterized by: mild mental retardation, sometimes delayed emotional development with normal intelligence, slight hypertelorism of the eyes, inferior colombus of the iris or retina, antimongoloid eye incision, pre-auricular fossa, ear appendages, congenital heart defects in more than a third of patients (complete abnormal confluence of the pulmonary veins , atrial and ventricular septal defects), atresia of the anus in combination with rectal fistulas, hypospadias, hydronephrosis, renal agenesis, vesicoureteral reflux. Rare symptoms include: microcephaly, hearing loss, stenosis of the external auditory canal, atresia of the bile ducts, cleft palate, polycystic kidney disease, Meckel's diverticulum and others. Trisomy syndrome on the 8th chromosome. The first works on the description of the syndrome date back to 1963. The syndrome is caused by trisomy on the 8th chromosome, as a rule, it is a mosaic trisomy, complete trisomy, apparently, is rarely compatible with life. For this syndrome, clinical manifestations are characterized by: mental retardation of varying severity, a long narrow body, growth from low to high, anomalies of the shoulder blades and sternum, short neck, narrow pelvis, hip dysplasia, malformations of the heart, kidneys, ureters, poor coordination of movements , protruding forehead, deep-set eyes, wide nose bridge, wide nostrils, plump lips, everted lower lip, lower micrognathia, narrow high palate / cleft palate, large cup-shaped ears with a thick curl, camptodactyly of 2-5 fingers and toes, incomplete supination in elbow joint, deep palmar and plantar grooves, contractures of large joints, abnormal nails. Rare symptoms include: aplasia of the patella, bifurcated hair, conductive hearing loss, abnormal structure of the vertebrae (splitting of the vertebrae, accessory lumbar vertebra), scoliosis, cryptorchidism, doubling of the jejunum, agenesis of the corpus callosum, germ cell tumors, gastric leiomyosarcoma. The prognosis of the disease is determined by the severity of mental retardation.
The human genome is made up of 46 chromosomes arranged in 23 pairs. Of these, 44 are somatic, that is, they are responsible for the structure and characteristics of the entire human body. And only one pair of chromosomes carries information about his gender and determines the differences between men and women.
Both sex chromosomes of women are the same in structure and are designated in genetics by the letter X. And in men, this pair is represented by different chromosomes - X and Y.
Klinefelter's syndrome: karyotype
Klinefelter's syndrome is such a change in the chromosome set, in which one or more X chromosomes are added to the XY karyotype. Accordingly, only carriers of the Y chromosome, that is, men, suffer from this disease.
A person with Klinefelter's syndrome has a chromosome set that differs from the norm by only one pair of chromosomes - just the one that is responsible for sexual characteristics.
For clarity, we tried to depict the karyotype of a patient with Klinefelter's syndrome in the figure:
Variety of options
Klinefelter's syndrome can be represented by different cytogenetic variants, which also determine the difference in the severity of symptoms and tactics of patient management.
The origins of the disease
The causes of the appearance of Klinefelter's syndrome lie in the nondisjunction of chromosomes during cell division.
According to statistics, a third of patients receive an extra chromosome from the father's sperm, and the other two-thirds from the mother's egg.
Risk factors for the appearance of this disease are traditionally considered viral infections, disturbances in the functioning of the immune systems of the parents and the late age of the mother.
Establishing diagnosis
When the doctor can rely on the level of hormones in the blood test, the results of a spermogram, ultrasound of the scrotum and testicular biopsy. But the diagnosis can only be finally confirmed by the results of a blood test for the karyotype characteristic of Klinefelter's syndrome.
For this, leukocytes isolated from the blood are placed in a nutrient medium and then examined for the presence of a chromosomal abnormality in their DNA.
A modern blood test allows you to accurately differentiate any genetic disease and with a 100% probability to distinguish, for example, a syndrome from a syndrome even at the stage of pregnancy. For this, the cells of the embryo or amniotic fluid are taken.
In developed countries, many chromosomal abnormalities, including Klinefelter's syndrome, are detected even during pregnancy, since women planning motherhood at a later age try to eliminate the risk of having a sick baby as much as possible.
In the United States, in the presence of such an anomaly in the unborn child, about half of women prefer to terminate the pregnancy. In Russia, karyotyping analysis is not a widespread practice; it is carried out only if, according to the results of screening a pregnant woman, there are suspicions about the presence of genetic abnormalities in the fetus.
In many cases, the syndrome is detected much later.- when characteristic signs occur during growing up.
Despite the advances in modern medicine, about half of the cases of Klinefelter's syndrome remain generally unrecognized, although patients go to doctors with complaints of enlarged mammary glands, erectile dysfunction and infertility.
Clinical diagnosis of Down syndrome usually does not present any difficulties. However, karyotyping is necessary to confirm the diagnosis and provide a basis for genetic counseling. Although differences in the specific karyotype variants responsible for Down syndrome usually have little effect on the patient's phenotype, they are significant in determining the risk of recurrence.
Trisomy 21 with Down syndrome... About 95% of all patients with Down syndrome have chromosome 21 trisomy caused by meiotic nondisjunction of 21 pairs of chromosomes, as discussed in the previous chapter. It has already been noted that the risk of having a child with trisomy 21 increases with the age of the mother, especially after 30 years. The meiotic error responsible for trisomy usually occurs during maternal meiosis (about 90% of cases), predominantly in the first division, but about 10% of cases occur in paternal meiosis, usually in the second division.
Robertsonian translocation in Down syndrome... About 4% of patients with Down syndrome have 46 chromosomes, one of which is a Robertsonian translocation between chromosome 21q and the long arm of one of the other acrocentric chromosomes (usually chromosomes 14 or 22). The translocated chromosome replaces one of the normal acrocentric chromosomes, and the karyotype of a patient with a Robertsonian translocation between chromosomes 14 and 21 is 46, XX / XY, rob (14; 21) (ql0; ql0), + 21.
Such chromosome can also be defined as der (14; 21), in practice both nomenclatures are used. In fact, patients with a Robertsonian translocation involving chromosome 21 are trisomal for genes located in the long arm 21q.
Unlike standard trisomy 21, translocation Down syndrome does not show any connection with the age of the mother, but has a relatively high risk of recurrence in families if one of the parents, especially the mother, is a carrier of the translocation. For this reason, karyotyping of the parents and possibly other relatives is important for accurate genetic counseling.
Carriers Robertsonian translocation, including chromosomes 14 and 21, have only 45 chromosomes; one 14 and one 21 are missing and replaced by a translocated chromosome. Six types of gametes are theoretically possible, but three of them cannot lead to viable offspring. The three types of gametes are viable, normal, balanced and unbalanced, with both translocated and normal chromosome 21. Combined with a normal gamete, this can result in the conception of a child with translocation Down syndrome.
In theory, these three types gametes are produced in equal quantities, so the theoretical risk of a child with Down syndrome should be 1 in 3. However, extended population studies have shown that imbalanced chromosome sets appear in only 10-15% of the offspring of mothers and only a few percent of offspring of fathers carrying translocations involving chromosome 21.
Translocation 21q21q at... Chromosomal translocation 21q21q - chromosome formed from two long arms of chromosome 21; occurs in several percent of patients with Down syndrome. They are thought to appear as isochromosomes rather than Robertsonian translocations. Most of these cases occur postzigotically, so the risk of recurrence is low. However, it is especially important to make sure that the parent is not a carrier (possibly mosaic) of this translocation, since all the gametes of the carrier of such a chromosome must also contain the 21q21q chromosome, with a double dose of the genetic material from chromosome 21, or not have chromosome 21 at all.
Potential offspring therefore inevitably has either Down syndrome or nonviable monosomy 21. Mosaic carriers have an increased risk of recurrence, thus prenatal diagnosis is necessary in all subsequent pregnancies.
Mosaic Down Syndrome... About 2% of Down syndrome patients are mosaic, usually with populations of normal cells and with trisomy 21. The phenotype may be milder than typical trisomy 21. In general, there is wide variation in the phenotypes of mosaic patients, probably reflecting the different proportions of trisomal cells in the embryo on early stages of development. It is possible that patients with established mosaic Down syndrome only reflect clinically more severe cases, since mild cases are less likely to be karyotyped.
Partial trisomy 21 in Down syndrome... Very rarely, Down syndrome is diagnosed in patients with trisomy only on a part of the long arm of chromosome 21, and even less often, patients with Down syndrome are diagnosed without a cytogenetically visible chromosomal abnormality. Such cases are of some interest, since they can indicate which region of chromosome 21 is probably responsible for specific components of the Down syndrome phenotype and which regions can triple without causing phenotypic manifestations.
Though chromosome 21 contains only a few hundred genes, attempts to match a triple dose of specific genes with specific aspects of the Down syndrome phenotype have so far met with limited success. Most notable was the identification of an area critical for heart defects seen in about 40% of Down syndrome patients. The search for specific genes essential for the manifestation of the phenotype of Down syndrome, among those randomly adjacent to them on chromosome 21, is the main task of modern research, especially in mice as a model.
Potentially promising direction- study of genetically engineered mice with an additional dose of genes from human chromosome 21 (or even with a full copy of chromosome 21). Such mice can exhibit phenotypic abnormalities in behavior, brain function, and heart formation.
In 1971. at the Paris Conference, a special nomenclature for recording the karyotype of a person was approved.
Normal human karyotype:
46, XX - woman; 46, XY - man.
Polyploidy karyotype:
69, XXX; 69, XXY - triploidy;
92, XXXX; 92, XXXY - tetraploidy.
Monosomy carity:
45, XO is the only monosomy that is possible in living people (Shereshevsky-Turner syndrome).
Autosomal trisomy karyotype:
47, XX, + 21 or 47, XY, + 21 - trisomy on chromosome 21 (Down syndrome);
47, XX, + 13 or 47, XY. + 13 - trisomy on chromosome 13 (Patau syndrome);
47, XX. + 18 or 47, XY, + 18 - trisomy on chromosome 18 (Evards syndrome).
Sex chromosome trisomy karyotype:
47, XXX - trisomy X in a woman;
47, HUU - trisomy Y in a man.
47, XXY - Klinefelter's syndrome.
Sex chromosome tetrasomies and pentasomies:
48, XXXX - tetrasomy X;
49, XXXXX - X pentasomies;
48, XXXY; 49, XXXXY - variants of Klinefelter's syndrome;
48, HUUU; 49, HUUUU - variants of polysomy syndrome Y in a man.
Karyotype for chromosomal aberrations:
46, XX, del 5p - - deletion of the short arm of chromosome 5 (crying cat syndrome) in a woman;
46, XY, del 4p - - deletion of the short arm of chromosome 4 (Wolf-Hirschhorn syndrome) in a man;
46, X, i (Xq) - isochromosome X along the long arm in a woman;
46, XY, r (18) - radial 18 chromosome in a man;
45, XX, -D, -Y, + t (Dq, Yq) is a balanced Robertsonian translocation formed by joining the long arms of one D and one Y chromosome in a woman.
Mosaic karyotype:
45, X / 46, XX or 45, X / 46, XX - some cells have a normal karyotype (46, XX) and some with X monosomy (45, X). We are talking about the mosaic form of Shereshevsky-Turner syndrome;
47, XX, + 21/46, XX - mosaic form of Down syndrome.
Pathogenesis of chromosomal diseases.
In chromosomal diseases, as a rule, there is an imbalance in a large number of genes. The altered genotype manifests itself in the embryonic period of development. The earliest stages of zygote cleavage are controlled by substances accumulated in the egg. Then the zygote's own genes are turned on. In total, about 1000 genes work in the embryonic period, which are responsible for different stages of ontogenesis. They are scattered across all chromosomes. With genomic and chromosomal mutations, the balance in a large number of genes is disturbed, including genes that regulate embryonic development. This inevitably leads to disruption of histogenesis and organogenesis. Malformations are formed. More often violations are incompatible with life, which leads to intrauterine death of the embryo. Less often, a child is born with developmental defects.
From 35 to 50% (now they write up to 70%) of human embryos die at the blastocyst stage, i.e. before implantation. A large percentage of them have chromosomal rearrangements. After implantation, the total contribution of chromosomal abnormalities to intrauterine death in humans is 45%. The earlier a pregnancy is terminated, the more likely this is due to a chromosomal imbalance.
If abortion occurs in the first 2-4 weeks, then chromosomal imbalance is observed in 60-70% of abortions. In the 1st trimester, 50%, in the 2nd trimester, 30%, at 20-27 weeks, 7% and, finally, 6% of stillbirths are due to chromosomal abnormalities.
If violations of embryonic development are compatible with life, then a child is born with developmental defects.
U 1 % alive newborns are found to have certain chromosomal diseases.
Clinically, chromosomal diseases are manifested by syndromes of multiple congenital malformations. Almost all of them are formed by the time of birth. Exceptions are violations in the formation of sexual characteristics with an imbalance of sex chromosomes. Some of their symptoms appear in adolescence. Geneticists compare chromosomal diseases to the ashes after a fire. Fire is what happens in the embryonic period. By the time of birth, the final phenotype is formed (embers after a fire). It is no longer possible to fix anything. You can only carry out a cosmetic correction, operate on a patient with a developmental defect (if the syndrome is compatible with life).
Since the early stages of embryonic development are disrupted in chronic bronchitis, many organs and organ systems are simultaneously affected. This makes the clinical picture of many chromosomal diseases similar. The greater the chromosome imbalance, the more nonspecific the picture.
Any chromosomal disease is characterized by polymorphism, because the individual genotype of individuals affects gene expression.
CLINICAL AND CYTOGENETIC CHARACTERISTICS OF THE MOST COMMON CHROMOSOMAL DISEASES
