Examples of phenotypic manifestation of gene mutations. Hereditary human diseases

Malformations of the craniofacial region occupy 3rd place among other types of congenital anomalies. According to experts from the World Health Organization (1999), about 7% of live births have birth defects and deformities of the craniofacial region. Among congenital craniofacial deformities, about 30% are craniosynostoses. Of all the syndromic forms of craniosynostosis, the most common, according to the overwhelming majority of experts, is Apert syndrome. In the domestic literature, unfortunately, one can often find incomplete and sometimes contradictory information about this syndrome. D. Leibek and C. Olbrich indicate the following characteristics Apert syndrome: dysostosis of the skull bones, premature synostosis of the coronal suture (acrocephaly, high spire-like skull), sagittal suture (scaphocephaly) or other sutures; dysmorphia of the facial skull: ocular hypertelorism, wide root of the nose, slit-like nose, flat orbits, exophthalmos; cutaneous or bone syndactyly, usually bilateral; rarely - polydactyly. Previously, radioulnar synostosis, synostosis of large joints, especially the elbow, hallux varus, malformations of the vertebrae, aplasia of the acromioclavicular joints, high palate, cleft uvula, anal atresia, optic nerve atrophy, mental retardation, and short stature were considered optional signs.

L. O. Badalyan, in his work devoted to the description of the clinical manifestations of various syndromes, notes that Apert syndrome is manifested by a change in the shape of the head (acrocephaly) and polysyndactyly, the big toes are enlarged in size, there are additional big toes, mental development is not impaired.

Giving clinical characterization Apert syndrome, Kh. A. Kalmakarov, N. A. Rabukhina, V. M. Bezrukov note that Apert syndrome, which combines craniofacial dysostosis with acrocephaly and syndactyly, has much in common with Crouzon dysostosis. In contrast to Crouzon's dysostosis, with this type of dyscrania early synostosis of the cranial sutures is observed. This process involves all cranial sutures, with the exception of the coronal ones. Therefore, growth occurs predominantly in height, the skull takes on a tower shape and remains narrow in the anteroposterior and transverse directions. The forehead and back of the head are wide and flat. As with Crouzon's dysostosis, there is pronounced exophthalmos due to a decrease in the depth of the orbit and ocular hypertelorism due to an increase in the size of the ethmoid labyrinth. The upper jaw is underdeveloped, the relationships of the dentition are disturbed, but the teeth themselves develop normally. At Apert syndrome There is a characteristic deformation of the eyelids - they are slightly raised and form folds that support the eyeballs. Ptosis is also observed upper eyelids and strabismus, flattening of the nose. The mental development of patients with this syndrome is usually not impaired, but very sharp emotional excitability is noted. Fusion of several fingers of the upper or lower extremities is typical.

S.I. Kozlova and co-authors indicate that Apert syndrome characterized by changes in the skull - synostosis of varying severity, mainly of the coronal sutures, in combination with sphenoethmoidomaxillary hypoplasia of the skull base; facial changes - flat forehead, ocular hypertelorism, anti-Mongoloid eye shape; sunken bridge of the nose, prognathism, complete fusion of the 2nd-5th fingers and toes.

I.R. Lazovskis describes Apert syndrome as a complex of hereditary anomalies (autosomal dominant inheritance): cranial dysostosis - premature synostosis of the coronal suture (with the formation of acrocephaly), lambdoid suture (with scaphocephaly), often premature synostosis of all sutures; dysmorphia of the facial skull: ocular hypertelorism, dilated nasal root, flat orbits, bulging eyes (exophthalmos); cutaneous or bone syndactyly, usually bilateral, less often - polydactyly; synostosis of the radial and ulnar bones and large joints, ankylosis are occasionally observed elbow joint, spinal abnormalities, high sky, cleft uvula, ophthalmoplegia, decreased vision; atresia anus, mental retardation, dwarf stature.

All this conflicting information presented in domestic sources creates some confusion and complicates the choice of an adequate treatment method. Basically, data related to this topic is reflected in foreign sources.

Clinical manifestations of Apert syndrome

The main clinical manifestations of acrocephalosyndactyly syndrome, described by the French physician E. Apert in 1906 and named after him, were as follows: craniosynostosis, hypoplasia middle zone face, symmetrical syndactyly of the hands and feet involving the 2nd-4th fingers.

In the United States, the prevalence is estimated to be 1 in 65,000 (approximately 15.5 per 1,000,000) live births. Blank described the collected material from 54 patients born in the UK. He divided patients into two clinical categories: "typical" acrocephalosyndactelia, to which he applied the name "Aper's syndrome", and other forms mixed in general group as “atypical” acrocephalosyndactyly. The feature that distinguishes these types is the "middle finger", consisting of several fingers (usually the 2nd-4th), with a single common nail, observed when Apert syndrome and not found in another group. Of these 54 patients, 39 had Apert syndrome. Frequency Apert syndrome he estimated as 1 in 160,000 live births. Cohen et al examined the prevalence of births with Apert syndrome in Denmark, Italy, Spain and partly in the United States. The total number made it possible to derive the estimated frequency of births from Apert syndrome- approximately 15.5 per 1,000,0000 live births. This figure is approximately double the results of other studies. Czeizel et al reported on the incidence of births of patients with Apert syndrome in Hungary, it was 9.9 per 1,000,000 live births. Tolarova et al reported that the California Congenital Disease Monitoring Program identified 33 newborns with Apert syndrome. The data were supplemented by 22 cases reported at the Center for Craniofacial Malformations (San Francisco). The incidence determined from these data was 31 cases per 12.4 million live births. Patients with Apert syndrome account for 4.5% of all cases of craniosynostosis. Most cases are sporadic and are the result of new mutations, however, in the literature there is a description of familial cases with full penetrance. Weech described mother and daughter, Van den Bosch, according to Blank, observed a typical picture in mother and son. Rollnick described an affected father and daughter, providing the first example of paternal transmission of the disease. These facts suggest an autosomal dominant type of inheritance.

Asians have the highest prevalence of the syndrome - 22.3 per 1 million live births, Spaniards, on the contrary, have the lowest - 7.6 per 1 million live births. No connection with gender was identified by any of the researchers.

Apert syndrome usually diagnosed at an early age due to postnatal findings of craniosynostosis and syndactyly. The syndrome is characterized by the presence of primary changes in the skull already at birth, but the final formation of the pathological form occurs during the first three years of life. Many patients have difficulty in nasal breathing due to a reduction in the size of the nasopharynx and choanae, and there may also be difficulty passing air through the trachea due to congenital anomaly tracheal cartilage, which can lead to early death. Headache and vomiting are possible - signs of increased intracranial pressure, especially in cases where several seams are involved in the process. Genealogical history does not seem to be so important, since most cases of births of children with this syndrome are sporadic.

Phenotypic signs of Apert syndrome

Craniofacial region. The most common is coronary craniosynostosis, leading to acrocephaly, brachycephaly, and turribrachycephaly. The sagittal, lambdoid, and frontal-basic sutures are also subject to synostosis. The rare trefoil-shaped skull anomaly is found in approximately 4% of infants. The base of the skull is reduced in size and often asymmetrical, the anterior cranial fossa is very short. The anterior and posterior fontanelles are increased in size and not closed. The midline of the calvarium may have a gaping defect extending from the glabella area through the metopic suture area to the anterior fontanel, through the sagittal suture area to the posterior fontanelle. Marked: ocular hypertelorism, exorbitism, small orbits, overhanging brow ridges. On the part of the eyes, the following are observed: exophthalmos, “broken eyebrows,” palpebral fissures, strabismus, amblyopia, optic nerve atrophy, and (rarely) dislocation of the eyeball, decreased pigment, congenital glaucoma, reversible vision loss. The bridge of the nose is often sunken. The nose is short with a flattened dorsum and a wide tip with choanal stenosis or atresia, deep nasolabial folds, deviation of the nasal septum is possible. There is hypoplasia of the midface - the upper jaw is hypoplastic, the zygomatic arches are short, the zygomatic bones are small. In this regard, relative mandibular prognathism is noted. The mouth at rest is trapezoidal in shape. A high arched palate, cleft of the soft palate and uvula are observed in 30% of cases. The hard palate is shorter than normal soft palate- longer and thicker, the maxillary dental arch has a V-shape. There may be protruding upper teeth, scoop-shaped incisors, supernumerary teeth, and prominent alveolar ridges. Patients have low-set ears and a high probability of hearing loss in the future (Fig. 1, 2).

Limbs and skeleton. One of the main manifestations of the syndrome is syndactyly of the hands and feet involving the 2nd, 3rd and 4th fingers. Less commonly, the 1st and 5th fingers are involved in the process (Fig. 3). Proximal phalanges thumbs the hands and feet are shortened, the distal ones have a trapezoidal shape. When studying Apert syndrome Wilkie et al modified Upton's (1991) classification of syndactyly. At Apert syndrome the central three fingers are always subject to syndactyly. Type 1 - the thumb and part of the 5th finger are separated from the fused fingers; in type 2, only the thumb is separated from the “middle finger”; in type 3, all fingers are fused. Similarly, syndactyly of the toes may involve the three lateral toes (type 1), or the 2nd to 5th toes with a separate big toe (type 2), or may be continuous (type 3). Cohen and Kreiborg studied 44 pairs of arms and 37 pairs of legs of patients with Apert syndrome using clinical, radiographic and dermatoglyphics methods, and also examined histological specimens upper limbs stillborn fetus at 31 weeks' gestation. They suggested that the distinction between acrocephalosyndactyly and acrocephalopolysyndactyly is false and that the use of these terms should be abandoned. The researchers also pointed out that when Apert syndrome The pathology of the upper extremities is always more pronounced than the lower ones. The fusion of the carpal bones with the distal phalanges does not have its counterpart on the foot. Other pathological changes in the limbs are also possible: radial deviation of short and wide thumbs, due to an altered proximal phalanx - brachydactyly; limited mobility in the shoulder joint, limited mobility of the elbow joint with difficulty in pronation and supination, limited mobility in knee joint, aplasia or ankylosis of the shoulder, elbow and hip joints. One of the relatively common skeletal anomalies in Apert syndrome is a congenital fusion of the vertebrae. Kleiborg et al found that cervical vertebral fusion was observed in 68% of patients with Apert syndrome: single fusions in 37% and multiple fusions in 31%. The most typical fusion was C5-C6. In contrast, cervical fusion occurs in only 25% of patients with Crouzon syndrome and is most commonly affected at C2-C3. Kleiborg et al concluded that C5-C6 fusion is more common in Apert syndrome, and C2-C3 for Crouzon syndrome, which helps differentiate these two diseases. X-ray examination of the cervical spine is mandatory before anesthesia for these patients. Schauerte and St-Aubin showed that progressive synostosis is observed not only in the cranial sutures, but also in the bones of the legs, arms, wrists, and cervical spine and proposed the term “progressive synostosis with syndactyly” as the most adequately reflecting the clinical picture.

Leather. According to some reports, for Apert syndrome elements of oculocutaneous albinism are characteristic (blond hair and pale coloring skin). Cohen and Kreiborg described skin manifestations in 136 cases of the syndrome. They found hyperhidrosis in all patients. They also described acneiform elements that were especially common on the face, chest, back, and arms. In addition, manifestations of hypopigmentation and hyperkeratosis of the palms, retraction of the skin over the large joints of the limbs are possible. Some patients have excess skin in the forehead folds.

Central nervous system (CNS). Various degrees of mental deficit are associated with the syndrome, but there are also reports of patients with normal intelligence. Damage to the central nervous system in most cases can be the cause of mental retardation. It is possible that early craniectomy promotes normal mental development. Patton et al conducted a long-term study of 29 patients, of whom 14 had normal or borderline IQ, 9 had mild mental retardation (intelligence quotient (IQ) 50–70), 4 were moderately retarded (IQ 35–49), and 2 were severely retarded. retarded (IQ less than 35). Early craniectomy did not appear to improve intellectual status. Six of the 7 patients who graduated from school were employed or were undergoing further training. Contrary to these conclusions, Park and Powers, Cohen and Kreiborg argue that many of the patients are mentally retarded. They collected information on 30 patients with pathology of the corpus callosum or limbal structures, or both. These patients also had various other disorders. The authors suggested that these abnormalities may be a cause of mental retardation. Progressive hydrocephalus was rare and often could not be differentiated from non-progressive ventriculomegaly. Cinalli et al found that only 4 of 65 patients with Apert syndrome were shunted due to progressive hydrocephalus. Renier et al found an IQ of 70 or greater in 50% of children who had cranial decompression before 1 year of age, versus 7.1% of those who had surgical treatment V late age. Pathology of the corpus callosum (corpus callosum) and the size of the ventricles of the brain did not correlate with the final indicator of intelligence, in contrast to pathology of the septum pellucidum (transparent septum). Environmental quality and family environment also determine intellectual development. Only 12.5% ​​of children with this syndrome have normal indicators intelligence, compared with 39.3% of children with a normal family background.

Internal organs and systems. For Apert syndrome characterized by minor changes in internal organs. Pathology of the cardiovascular system (defect interventricular septum, nonunion of the duct of Batallus, stenosis pulmonary artery, coarctation of the aorta, dextracardia, tetralogy of Fallot, endrocardial fibroelastosis) is observed in 10-20% of patients. Anomalies of the genitourinary system (polycystic kidney disease, additional renal pelvis, hydronephrosis, bladder neck stenosis, bicornuate uterus, vaginal atresia, enlarged labia majora, clitoromegaly, cryptorchidism) were identified in 9.6%. Anomalies of the digestive system (pyloric stenosis, esophageal atresia, ectopia anus, partial atresia or underdevelopment of the gallbladder) were found in 1.5%. Pelz et al described an 18-month-old girl who had distal esophageal syndrome in addition to typical manifestations Apert syndrome. Pathological changes are also mentioned in the literature respiratory system- abnormal tracheal cartilage, tracheoesophageal fistula, pulmonary aplasia, absence of the middle lobe of the lung, absent interlobar grooves.

Etiology of Apert syndrome

With rare exceptions Apert syndrome is caused by one of two missense mutations in the FGFR2 gene, involving two adjacent amino acids: S252W and P253R, in 63% and 37% of patients, respectively, according to Wilkie et al. Park et al examined phenotype/genotype correlations in 36 patients with Apert syndrome. Almost all but one patient had S252W or P253R mutations in the FGFR2 gene; the frequency was 71 and 26%, respectively. The fact that one patient did not have a mutation in this region suggests the presence of genetic heterogeneity Apert syndrome. A study of 29 different clinical presentations demonstrated statistically insignificant differences between the two subgroups of patients who had two major mutations. Moloney et al provided information regarding the spectrum of mutations and the hereditary nature of mutations in Apert syndrome. Their analysis of 118 patients showed that the mutational spectrum Apert syndrome narrow The S252W mutation was observed in 74 and the P253R mutation in 44 patients. Slaney et al found differences between the clinical manifestations of syndactyly and cleft palatine with two main mutations of the FGFR2 gene in Apert syndrome. Among 70 patients with Apert syndrome, 45 had the S252W mutation and 25 had the P253R mutation. Syndactyly of the hands and feet was more severe in patients with the P253R mutation. In contrast, cleft palate was more common in patients with the S252W mutation. No differences were found in the manifestation of other pathologies associated with Apert syndrome. Lajeunie et al conducted a screening study of 36 patients with Apert syndrome in order to detect mutations in the FGFR2 gene. Mutations were found in all cases. The ser252trp mutation was detected in 23 patients (64%). The pro253arg mutation was identified in 12 patients (33%). Oldridge et al reviewed the medical records of 260 unrelated patients with Apert syndrome and found that 258 had a missense mutation in exon 7 of the FGFR2 gene that affected a protein in the linker region between the second and third immunoglobulin-like domains. Therefore, the genetic cause Apert syndrome quite accurately defined. The authors found that 2 patients had Alu element insertions in or near exon 9. A study of fibroblasts showed ectopic expression of the KGFR region of FGFR2, which was associated with the severity of limb pathologies. This correlation provided the first genetic evidence that abnormal KGFR expression is the cause of syndactyly in Apert syndrome. Major missense mutations in exon 7 (ser252trp and ser252phe) were identified in 258 and 172 patients, respectively. Von Gernet et al conducted studies regarding post-surgical manifestations in the craniofacial region in patients with varying degrees of syndactyly. In the 21 patients with Apert syndrome who underwent craniofacial surgery, those with the P253R mutation performed better, although they had a more severe form of syndactyly. The P253R mutation was identified in 6 and S252W in 15 patients.

Diagnosis and treatment

It was possible to prove that more than 98% of cases are caused by certain missense mutations involving adjacent amino acids (Ser252Trp, Ser252Phe or Pro253Arg) in exon 7 of the FGFR2 gene, and therefore the possibility of molecular genetic diagnosis of Apert syndrome became possible. While this method has not become widespread, the main diagnostic method is to carry out computed tomography(CT) of the skull. CT scan reveals such characteristic pathological changes in the bones of the skull as coronary synostosis, hypoplasia upper jaw, small orbits, changes in the base of the skull, etc. The most visual data is obtained from a CT scan in 3D format. Magnetic resonance imaging (MRI) helps evaluate changes in the soft tissues of the skull associated with bone pathology. Also to clarify the clinical manifestations Apert syndrome X-ray examinations of the bones of the upper and lower extremities are carried out, the purpose of which is to detect various forms of bone syndactyly and changes in the bones of the feet and hands. In addition to the above studies, in diagnosing the severity of phenotypic manifestations of Apert syndrome and for prognosis of the development of the disease, data from psychometric assessment, hearing research, and condition are important. respiratory tract, and in addition, the opinions of such specialists as a pediatrician, clinical geneticist, neurosurgeon, orthodontist, otolaryngologist, ophthalmologist, neurologist, psychologist, speech therapist.

Surgical treatment includes early craniectomy of the coronal suture and fronto-orbital reposition to reduce the manifestations of dysmorphism and pathological changes in the shape of the skull. Operations regarding Apert syndrome often consist of several stages, the last one taking place during adolescence. The first stage is often performed as early as 3 months.

IN lately A new technique of craniofacial distraction with gradual bone traction has become widely used. This method leads to good cosmetic results and eliminates the need for bone grafting in patients aged 6-11 years. In addition to surgical treatment of pathology of the skull bones, patients with syndactyly of the hands and feet undergo surgical treatment of the fingers. To form a physiological bite for children with Apert syndrome orthodontic treatment is prescribed.

Advances in molecular genetics and the steady development of cell biology make it possible to understand the mechanisms of developmental defects in humans and their prenatal diagnosis. Determining the phenotype and genotype and their correlation is very important for the doctor. Knowledge of all clinical manifestations of a particular syndrome allows the surgeon to choose the correct tactics for managing patients in the pre- and postoperative period; helps determine the range of specialists and studies needed to examine patients. Practice shows that the problem of treating patients with syndromic craniosynostosis cannot be solved with the help of isolated work of craniofacial surgeons. As can be seen in the example Apert syndrome, syndromic craniosynostosis is accompanied not only by deformation of the skull bones, but also pathological changes both the entire complex of organs and tissues of the head, and the bones of the skeleton and internal organs. For adequate treatment of patients with syndromic forms of craniosynostosis, it is necessary to involve neurosurgeons, pediatric surgeons, pediatricians, psychologists, neurologists, ophthalmologists, radiologists, otolaryngologists, speech therapists and geneticists. Best results are achieved by combining the efforts of doctors of all these specialties.

Literature

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D. E. Koltunov, candidate medical sciences Scientific and Practical Center for medical care for children with developmental defects of the craniofacial region and congenital diseases nervous system, Moscow

The genotype is the totality of all the genes of an organism, which are its hereditary basis.

Phenotype is the totality of all signs and properties of an organism that are revealed in the process individual development under these conditions and are the result of the interaction of the genotype with a complex of internal and external environmental factors.

Phenotype in general case- this is what can be seen (cat color), heard, felt (smell), as well as the behavior of the animal. Let's agree that we will consider the phenotype only from the point of view of color.

As for the genotype, they most often talk about it, meaning a certain small group of genes. For now, let's assume that our genotype consists of just one gene W(in the following paragraphs we will sequentially add other genes to it).

In a homozygous animal, the genotype coincides with the phenotype, but in a heterozygous animal, it does not.

Indeed, in the case of genotype WW, both alleles are responsible for white color, and the cat will be white. Likewise ww- both alleles are responsible for non-white color, and the cat will not be white.

But in the case of genotype Ww the cat will be externally (phenotypically) white, but in its genotype it will carry a recessive allele of a non-white color w .

Every biological species has a phenotype unique to it. It is formed in accordance with the hereditary information contained in the genes. However, depending on changes in the external environment, the state of traits varies from organism to organism, resulting in individual differences - variability.

Based on the variability of organisms, genetic diversity of forms appears. A distinction is made between modificational, or phenotypic, and genetic, or mutational variability.

Modifying variability does not cause changes in the genotype; it is associated with the reaction of a given, one and the same genotype to changes in the external environment: under optimal conditions, the maximum capabilities inherent in a given genotype are revealed. Modification variability manifests itself in quantitative and qualitative deviations from the original norm, which are not inherited, but are only adaptive in nature, for example, increased pigmentation of human skin under the influence of ultraviolet rays or development muscular system under the influence of physical exercise, etc.

The degree of variation of a trait in an organism, that is, the limits of modification variability, is called the reaction norm. Thus, the phenotype is formed as a result of the interaction of the genotype and environmental factors. Phenotypic characteristics are not transmitted from parents to offspring, only the reaction norm is inherited, that is, the nature of the response to changes in environmental conditions.
Genetic variability can be combinative and mutational.

Combinative variability arises as a result of the exchange of homologous regions of homologous chromosomes during the process of meiosis, which leads to the formation of new gene associations in the genotype. Occurs as a result of three processes:

1) independent chromosome segregation during meiosis;
2) their accidental combination during fertilization;
3) exchange of sections of homologous chromosomes or conjugation.

Mutational variability. Mutations are abrupt and stable changes in units of heredity - genes, entailing changes in hereditary characteristics. They necessarily cause changes in the genotype, which are inherited by the offspring and are not associated with crossing and recombination of genes.
There are chromosomal and gene mutations. Chromosomal mutations are associated with changes in the structure of chromosomes. This may be a change in the number of chromosomes that is a multiple or not a multiple of the haploid set (in plants - polyploidy, in humans - heteroploidy). An example of heteroploidy in humans can be Down syndrome (one extra chromosome and 47 chromosomes in the karyotype), Shereshevsky-Turner syndrome (one X chromosome is missing, 45). Such deviations in a person’s karyotype are accompanied by health disorders, mental and physical disorders, decreased vitality, etc.

Gene mutations affect the structure of the gene itself and entail changes in the properties of the body (hemophilia, color blindness, albinism, etc.). Gene mutations occur in both somatic and germ cells.
Mutations that occur in germ cells are inherited. They are called generative mutations. Changes in somatic cells cause somatic mutations that spread to that part of the body that develops from the changed cell. For species that reproduce sexually, they are not essential; for vegetative propagation of plants they are important.

Hereditary human diseases

1. The role of heredity and environment in the formation of human phenotype.
2. Chromosomal diseases.
3. Gene diseases.
4. Diseases with a hereditary predisposition.

The human phenotype, which is formed at various stages of its ontogenesis, just like the phenotype of any living organism, is primarily a product of the implementation of a hereditary program. The degree of dependence of the results of this process on the conditions in which it occurs in a person is determined by his social nature. By determining the formation of an organism's phenotype during its ontogenesis, heredity and environment can be the cause or play a certain role in the development of a defect or disease. However, the contribution of genetic and environmental factors varies among different conditions. From this point of view, forms of deviations from normal development are usually divided into three main groups.

Hereditary diseases. The development of these diseases is entirely due to a defective hereditary program, and the role of the environment is only to modify the phenotypic manifestations of the disease. This group of pathological conditions includes chromosomal diseases, which are based on chromosomal and genomic mutations, and monogenically inherited diseases, caused by gene mutations.

Hereditary diseases are always associated with a mutation, however, the phenotypic manifestation of the latter and the severity of pathological symptoms may vary among different individuals. In some cases, these differences are due to the dose of the mutant allele in the genotype. In others, the severity of symptoms depends on environmental factors, including the presence of specific conditions for the manifestation of the corresponding mutation. Multifactorial diseases, or diseases with hereditary predisposition. These include a large group of common diseases, especially diseases of mature and old age, such as hypertension, coronary heart disease, peptic ulcer stomach and duodenum etc. Causal factors Their development is influenced by unfavorable environmental influences, but the implementation of these influences depends on the genetic constitution, which determines the predisposition of the organism. The relative role of heredity and environment in the development of various diseases with a hereditary predisposition is not the same.

Only a few forms of pathology are caused by solely influenced by environmental factors. As a rule, these are exceptional impacts - trauma, burns, frostbite, especially dangerous infections. But even in these forms of pathology, the course and outcome of the disease are largely determined by genetic factors.

Based on the level of damage to the hereditary material that causes the development of diseases, there are: chromosomal And genetic diseases.

Chromosomal diseases . This group of diseases is caused by changes in the structure of individual chromosomes or their number in the karyotype. As a rule, with such mutations there is an imbalance of hereditary material, which leads to disruption of the development of the body. Genomic mutations of the following types have been described in humans: polyploidy, which are rarely observed in live births, but are mainly found in aborted embryos and fetuses and in stillborns. The main part of chromosomal diseases are aneuploidy, and autosomal monosomies in live births are extremely rare. Most of them concern the 21st and 22nd chromosomes and are more often found in mosaics that have both cells with a normal and mutant karyotype. Monosomy on the X chromosome is also found quite rarely (Shereshevsky-Turner syndrome).

Unlike monosomies, trisomies are described by a large number of autosomes: 8, 9, 13, 14, 18, 21, 22 and the X chromosome, which can be present in the karyotype in 4-5 copies, which is quite compatible with life.

Structural rearrangements of chromosomes are also accompanied by an imbalance of genetic material (deletions, duplications). The degree of reduction in viability due to chromosomal aberrations depends on the amount of missing or excess hereditary material and on the type of altered chromosome.

Chromosomal changes leading to developmental defects are most often introduced into the zygote with the gamete of one of the parents during fertilization. In this case, all the cells of the new organism will contain an abnormal chromosome set, and to diagnose such a disease it is enough to analyze the karyotype of the cells of some tissue.

The most common chromosomal disorder in humans is Down Syndrome, caused by trisomy on chromosome 21, occurring with a frequency of 1-2 per 1000. Trisomy 21 often causes fetal death, but sometimes people with Down syndrome live to a considerable age, although in general their life expectancy is shortened. Trisomy 21 may result from random nondisjunction of homologous chromosomes during meiosis. Along with this, cases of regular trisomy are known. associated with the translocation of the 21st chromosome to another -21, 22, 13, 14 or 15th chromosome.

Among other autosomal trisomies, trisomy on chromosome 13 is known - Patau syndrome, as well as on the 18th chromosome - Edwards syndrome), in which the viability of newborns is sharply reduced. They die in the first months of life due to multiple developmental defects. Among aneuploid sex chromosome syndromes, it often occurs trisomy X And Klinefelter syndrome(ХХУ,ХХХУ, ХУУ).

Of the syndromes associated with structural abnormalities of chromosomes, the following has been described: translocation Down syndrome, in which the number of chromosomes in the karyotype is not formally changed and is equal to 46, since the additional 21st chromosome is transposed to one of the acrocentric chromosomes. When the long arm of chromosome 22 is translocated to chromosome 9, it develops chronic myeloid leukemia. When the short arm of chromosome 5 is deleted, cry cat syndrome, in which there is a general developmental delay, low birth weight, a moon-shaped face with wide-set eyes, and a characteristic baby cry reminiscent of a cat's meow, which is caused by underdevelopment of the larynx.

Some carriers pericentric inversions Anomalies in the form of mental retardation of varying degrees and developmental defects are often observed. Quite often, such rearrangements are observed in the 9th human chromosome, but they do not significantly affect the development of the organism.

Specificity of manifestation chromosomal disease is determined by changes in the content of certain structural genes encoding the synthesis of specific proteins. Thus, in Down disease, a 1.5-fold increase in the activity of the enzyme superoxide dismutase I was found, the gene of which is located on chromosome 21 and is present in patients in a three-fold dose. The “gene dosage” effect was found for more than 30 genes localized on different human chromosomes.

Semi-specific symptoms of chromosomal diseases are largely associated with an imbalance of genes, represented by many copies, which control key processes in cell life and encode, for example, the structure of rRNA, tRNA, histones, ribosomal proteins, actin, tubulin.

Nonspecific manifestations in chromosomal diseases are associated with changes in the content of heterochromatin in cells, which affects the normal course of cell division and growth, and the formation in ontogenesis of quantitative characteristics determined by polygenes.

Gene diseases. Among gene diseases, there are both monogenically caused pathological conditions inherited in accordance with Mendelian laws and polygenic diseases. The latter primarily include diseases with a hereditary predisposition, complex inheritance and called multifactorial.

Depending on functional significance primary products of the corresponding genes, gene diseases are divided into:

· hereditary disorders enzyme systems (enzymopathies),

defects in blood proteins (hemoglobinopathies),

· defects in structural proteins (collagen diseases)

· gene diseases with an unclear primary biochemical defect.

Enzymopathies. Enzymopathies are based on either changes in enzyme activity or a decrease in the intensity of its synthesis. In heterozygous carriers of the mutant gene, the presence of the normal allele ensures the preservation of about 50% of the enzyme activity compared to the normal state. Therefore, hereditary enzyme defects are clinically manifested in homozygotes, and in heterozygotes, insufficient enzyme activity is revealed by special studies.

Depending on the nature of the metabolic disorder in cells, enzymopathies are distinguished following forms:

1. Hereditary defects in carbohydrate metabolism (galactosemia -
metabolic disorder milk sugar lactose; mucopolis-
charidoses - a violation of the breakdown of polysaccharides).

2. Hereditary defects in lipid and lipoprotein metabolism
(sphingolipidoses - impaired breakdown of structural lipids
Dov; disorders of blood plasma lipid metabolism, accompanied by
increase or decrease in blood cholesterol, lecithin).

3. Hereditary defects in amino acid metabolism (phenylketo-
Nuria - a disorder of phenylalanine metabolism; tyrosinosis - disorder
tyrosine metabolism; albinism - a disorder of pigment synthesis
melanin from tyrosine, etc.).

4. Hereditary defects in vitamin metabolism (homocystinuria -
develops as a result of a genetic defect in the coenzyme vitamin
mines B6 and B12, inherited in an autosomal recessive manner).

5. Hereditary defects in purine and pyrimidine metabolism
of nitrogenous bases (Lesch-Nayan syndrome associated with
deficiency of the enzyme that catalyzes the conversion
free purine bases into nucleotides, is inherited by
X-linked recessive type).

6. Hereditary defects in hormone biosynthesis (adrenogenic
tal syndrome associated with gene mutations that control
lyse the synthesis of androgens; testicular feminization, which
swarm does not form androgen receptors).

7. Hereditary defects in erythrocyte enzymes (some
hemolytic nonspherocytic anemia, characterized by
normal structure of hemoglobin, but a violation of the enzyme
system involved in anaerobic (oxygen-free) digestion
glucose research. Inherited both autosomal recessively and
according to the X-linked recessive type).

Hemoglobinopathies. This is a group of hereditary diseases caused by a primary defect in the peptide chains of hemoglobin and the associated violation of its properties and functions. These include methemoglobinemia, erythrocytosis, sickle cell anemia, and thalassemia.

Collagen diseases. The occurrence of these diseases is based on genetic defects in the biosynthesis and breakdown of collagen - the most important structural component connective tissue. This group includes Ellers-Danlos disease, characterized by large genetic polymorphism and inherited in both an autosomal dominant and autosomal recessive manner, Marfan disease, inherited in an autosomal dominant pattern, and a number of other diseases.

Hereditary diseases with an unknown primary biochemical defect. This group includes the vast majority of monogenic hereditary diseases. The most common are the following:

1. Cystic fibrosis- occur with a frequency of 1:2500 newborns; are inherited in an autosomal dominant manner. The pathogenesis of the disease is based on hereditary damage to the exocrine glands and glandular cells of the body, their secretion of thick secretions that have changed in composition and the associated consequences.

2. Achondroplasia- a disease, in 80-95% of cases caused by a newly emerging mutation; inherited in an autosomal dominant manner; occurs with a frequency of approximately 1:100,000. This disease skeletal system, in which anomalies in the development of cartilage tissue are observed mainly in the epiphyses of tubular bones and bones of the base of the skull.

3. Muscular dystrophies (myopathies)- diseases associated with damage to striated and smooth muscles. Various shapes characterized by different types of inheritance. For example, progressive pseudohypertrophic Duchenne myopathy is inherited in an X-linked recessive manner and appears predominantly in boys at the beginning of the first decade of life.

Diseases with a hereditary predisposition. This group of diseases differs from gene diseases in that they require action to manifest themselves. environmental factors. Among them there are also monogenic, in which the hereditary predisposition is due to one pathologically altered gene, and polygenic. The latter are determined by many genes, which are in good condition, but with a certain interaction between themselves and with environmental factors they create a predisposition to the onset of the disease. Such diseases are called multifactorial diseases.

Monogenic diseases with a hereditary predisposition are relatively few in number. Considering the important role of the environment in their manifestation, they are considered as hereditarily determined pathological reactions to the action of various external factors(drugs, food additives, physical and biological agents), which are based on hereditary deficiency of certain enzymes.

Such reactions may include hereditary intolerance to sulfonamide drugs, manifested in hemolysis of red blood cells, and increased temperature when using general anesthetics.

Along with chemical agents, people have an inherited pathological reaction to physical factors (heat, cold, sunlight) and factors biological nature(viral, bacterial, fungal infections, vaccines). Sometimes there is hereditary resistance to the action of biological agents. For example, heterozygotes HbA, HbS are resistant to infection by the pathogen of tropical malaria.

Diseases with a hereditary predisposition due to many genetic and environmental factors include diabetes mellitus, psoriasis, schizophrenia. These diseases have a familial nature, and the participation of hereditary factors in their occurrence is beyond doubt.

Methods for studying human genetics

1. Features of humans as objects of genetic research
2. Methods of human genetics.

The basic patterns of heredity and variability of living organisms were discovered thanks to the development and application of the hybridological method genetic analysis, the founder of which is G. Mendel. The most convenient objects, widely used by geneticists for hybridization and subsequent analysis of progeny, have become peas, Drosophila, yeast, some bacteria and other species that easily interbreed artificial conditions. Distinctive feature These species have a sufficiently high fertility that allows the use of a statistical approach in the analysis of offspring. Short life cycle and the rapid change of generations allow researchers to observe the transmission of traits in a succession of many generations in relatively short periods of time. An important characteristic of species used in genetic experiments is also the small number of linkage groups in their genomes and moderate modification of traits under the influence of the environment.

From the point of view of the above characteristics of species that are convenient for using the hybridological method of genetic analysis, man as a species has a number of features that do not allow this method to be used to study his heredity and variability. Firstly, artificial directed crossbreeding cannot be carried out in humans in the interests of the researcher. Secondly, low fertility makes it impossible to use a statistical approach when assessing the few offspring of one pair of parents. Thirdly, a rare change of generations, occurring on average every 25 years, with a significant life expectancy, makes it possible for one researcher to observe no more than 3-4 consecutive generations. Finally, the study of human genetics is complicated by the presence of a large number of gene linkage groups in its genome (23 in women and 24 in men), as well as a high degree of phenotypic polymorphism associated with environmental influences.

All of the listed human characteristics make it impossible to use the classical hybridological method of genetic analysis to study his heredity and variability, with the help of which all the basic patterns of inheritance of traits were discovered and the laws of heredity were established. However, geneticists have developed techniques that make it possible to study the inheritance and variability of traits in humans, despite the limitations listed above.

Methods for studying human genetics. Methods widely used in the study of human genetics include genealogical, population-statistical, twin, dermatoglyphics, cytogenetic, biochemical, and methods of somatic cell genetics.

Genealogical method. This method is based on the compilation and analysis of pedigrees. Using the genealogical method, the hereditary nature of the trait under study can be established, as well as the type of its inheritance (autosomal dominant, autosomal recessive, X-linked dominant or recessive, Y-linked). When analyzing pedigrees based on several characteristics, the linked nature of their inheritance can be revealed, which is used in compiling chromosomal maps. This method allows you to study the intensity of the mutation process, assess the expressivity and penetrance of the allele. It is widely used in medical genetic counseling to predict offspring. However, it should be noted that genealogical analysis becomes significantly more complicated when families have few children.

Twin method. This method consists of studying the patterns of inheritance of traits in pairs of identical and fraternal twins. It was proposed in 1875 by Galton initially to assess the role of heredity and environment in development mental properties person. Currently, this method is widely used in the study of heredity and variability in humans to determine the relative role of heredity and environment in the formation of various traits, both normal and pathological. It allows you to identify the hereditary nature of a trait, determine the penetrance of the allele, and evaluate the effectiveness of certain external factors (medicines, training, education) on the body. The essence of the method is to compare the manifestation of a trait in different groups of twins, taking into account the similarities or differences of their genotypes. Monozygotic twins, developing from one fertilized egg are genetically identical, as they have 100% of the same genes.

Population statistical method. Using the population statistical method, hereditary traits are studied in large groups of the population, in one or several generations. An essential point when using this method is the statistical processing of the data obtained. Using this method, you can calculate the frequency of occurrence of various gene alleles and different genotypes for these alleles in a population, and find out the distribution of various hereditary traits, including diseases, in it. It allows you to study mutation process, the role of heredity and environment in the formation of human phenotypic polymorphism according to normal characteristics, as well as in the occurrence of diseases, especially with a hereditary predisposition. This method is also used to clarify the significance of genetic factors in anthropogenesis, in particular in race formation.

Dermatoglyphics and palmoscopy methods In 1892, F. Galton proposed a method for studying the skin ridge patterns of the fingers and palms, as well as the flexor palmar grooves, as one of the methods for studying humans. He established that these patterns are an individual characteristic of a person and do not change throughout his life. F. Galton clarified and supplemented the classification of the relief of skin patterns, the foundations of which were developed by J. Purkinje back in 1823. Later, Galton’s classification was improved by a number of scientists; it is still widely used in forensics and genetic research.

Currently, the hereditary nature of skin patterns has been established, although the nature of inheritance has not been fully clarified. This trait is probably inherited in a polygenic manner. The nature of the finger and palm patterns of the body is greatly influenced by the mother through the mechanism of cytoplasmic heredity.

Dermatoglyphic studies are important in identifying zygosity of twins. It is believed that if out of 10 pairs of homologous fingers at least 7 have similar patterns, this indicates identicalness. The similarity of the patterns of only 4-5 fingers indicates that the twins are heterogeneous.

Methods of somatic cell genetics. Using these methods, the heredity and variability of somatic cells are studied, which largely compensates for the impossibility of applying the method of hybridological analysis to humans.

Methods of genetics of somatic cells, based on the reproduction of these cells under artificial conditions, make it possible not only to analyze genetic processes in individual cells of the body, but, due to the usefulness of the hereditary material contained in them, to use them to study the genetic patterns of the whole organism.

Cultivation allows you to get sufficient quantity cellular material for cytogenetic, biochemical, immunological and other studies.

Cloning- obtaining descendants of one cell; makes it possible to carry out biochemical analysis of hereditarily determined processes in genetically identical cells.

Selection somatic cells using artificial media is used to select mutant cells with certain properties and other cells with characteristics of interest to the researcher.

Hybridization somatic cells is based on the fusion of co-cultured cells of different types, forming hybrid cells with the properties of both parental species.

Cytogenetic method. The cytogenetic method is based on the microscopic study of chromosomes in human cells. It began to be widely used in studies of human genetics since 1956, when Swedish scientists J. Tiyo and A. Levan, proposing a new method for studying chromosomes, established that the human karyotype contains 46, and not 48 chromosomes, as previously thought.

Modern stage in the application of the cytogenetic method is associated with the one developed in 1969 by T. Kasperson method of differential staining of chromosomes, which expanded the capabilities of cytogenetic analysis, making it possible to accurately identify chromosomes by the nature of the distribution of stained segments in them.

Biochemical method. These methods were first used to diagnose genetic diseases at the beginning of the 20th century. Over the past 30 years, they have been widely used in the search for new forms of mutant alleles. With their help, more than 1000 congenital metabolic diseases have been described. For many of them, a defect in the primary gene product was identified. The most common among such diseases are diseases associated with defects in enzymes, structural, transport or other proteins.

Phenotypic variability is very important process, which ensures the body's ability to survive. It is thanks to her that he is able to adapt to environmental conditions.

The modification variability of organisms was first noted in the studies of Charles Darwin. The scientist believed that this is exactly what happens in the wild.

Phenotypic variability and its main characteristics

It's no secret that in the process of evolution they constantly changed, adapting to survival in environmental conditions. The emergence of new species was ensured by several factors - a change in the structure of the hereditary material (genotypic variability), as well as the appearance of new properties that made the organism viable when environmental conditions changed.

Phenotypic variability has a number of features:

• Firstly, with this form only the phenotype is affected - the complex external characteristics and properties of a living organism. The genetic material does not change. For example, two populations of animals that live in different conditions have some external differences, despite the identical genotype.
• On the other hand, phenotypic variability is of a group nature. Changes in structure and properties occur in all organisms of a given population. For comparison, it is worth saying that genotype changes are single and spontaneous.
• reversible. If you remove the specific factors that caused the body’s reaction, then over time the distinctive features will disappear.
• Phenotypic changes are not inherited, unlike genetic modifications.

Phenotypic variability and reaction norm

As already mentioned, changes in phenotype are not the result of any genetic modifications. First of all, this is the reaction of the genotype to the influence. In this case, it is not the set of genes itself that changes, but the intensity of their manifestation.

Of course, such changes have their own limits, which are called reaction norms. The reaction norm is the spectrum of all possible changes, from which only those options are selected that will be suitable for living in certain conditions. This indicator depends solely on the genotype and has its own upper and lower limits.

Phenotypic variability and its classification

Of course, the typology of variability is very relative in nature, since all the processes and stages of the development of the organism have not yet been fully studied. However, modifications are usually divided into groups, depending on certain characteristics.

If we take into account the altered signs of the body, they can be divided into:

• Morphological (the appearance of the organism changes, for example, the thickness and color of the coat).
• Physiological (changes in metabolism and physiological properties of the body are observed; for example, in a person who climbs the mountains, the number of red blood cells sharply increases).

Modifications are classified according to duration:

• Non-heritable - changes are present only in that individual or population that has been directly influenced by the external environment.
• Long-term modifications - they are spoken of when the acquired adaptation is passed on to offspring and persists for another 1-3 generations.

There are also some forms of phenotypic variability that do not always have the same meaning:

• Modifications are changes that benefit the body, ensure adaptation and normal functioning in environmental conditions.
• Morphoses are those changes in phenotype that occur under the influence of aggressive, extreme environmental factors. Here the variability goes far beyond limits and can even lead to the death of the organism.

Genes and genotype (see Chapter 2);

Mechanisms of interaction between maternal and paternal genomes (see Chapter 4);

Environmental factors (see Chapters 4 and 5).

For a simplified consideration of the action of these factors in the formation of traits and phenotype in the middle of the 20th century. the basic equation is proposed: P = G + E, in which P is a trait (phenotype), G is a gene (genotype), E is an environmental factor(s).

Consequently, a trait (phenotype) is characterized as the result of the action of a gene (genotype), an environmental factor, or their joint influence (common effect).

In other words, P is the recorded result (internal and/or external) of the action (function) of genes and environmental factors, their phenotypic manifestation.

Thus, behind any trait (phenotype) there is a function of a specific gene (genotype) and/or the effect of environmental factor(s).

From the standpoint of proteomics, a trait (phenotype) - this is the result of gene expression, manifested in the form of a structural or regulatory protein (protein-enzyme) or their complexes.

Let us now formulate the basic concepts of proteomics.

Sign, normal sign, pathological sign

Sign- is a phenotypic manifestation or result of the action of a gene(s), environmental factor(s), or their combined action.

Another definition of a trait: it is a discrete unit that characterizes a specific level of an organism (molecular, biochemical, cellular, tissue, organ or systemic); it distinguishes one organism from another.

Different organisms (within the same biological species) have different characteristics (eye color, curly hair, body length and weight, etc.).

To the characteristics of a cell and an organism, manifested at the molecular (genetic and biochemical) level, or molecular characteristics, include the so-called building materials of cells and tissues, organs and systems, i.e. macromolecules and micromolecules of organic compounds with inorganic substances built into them. The main of these molecules are nucleic acids (polynucleotides and nucleotides), proteins (polypeptides, peptides and amino acids), polysaccharides and monosaccharides, lipids and their components.

TO supramolecular(supramolecular) signs, manifested at the cellular, tissue, organ and organismal levels, include: anthropometric, anatomical, morphological (histological), physiological (functional), neurological, endocrinological, immunological, mental, psychological and other phenotypic characteristics of the body.

Signs are divided into normal and pathological.

Normal sign- this is the phenotypic manifestation of a certain trait within the normal limits established for it, the result of the normal action of a gene, environmental factor or their combined influence.

For example, normal amount leukocytes in the child’s blood - 6-9 thousand.

Pathological sign - This is a phenotypic manifestation of a certain trait that goes beyond the normal boundaries established for it, or it is a manifestation of a previously unknown (new) trait.

For example, if a child has less than 6 thousand leukocytes in his blood, this is leukopenia, and more than 9 thousand is leukocytosis.

Pathological sign as symptom of illness- this is the result of the pathological action of a gene, an environmental factor, or their combined influence.

Phenotype, normal phenotype, pathological phenotype

Phenotype- this is the totality of all the characteristics of an organism, determined by the combined action of the genotype and environmental factors.

Normal phenotype - this is the totality of all normal signs of the body, caused by the normal action of the genotype and environmental factors (the result of their interaction).

Pathological phenotype- this is the presence of a number of pathological signs of the body, caused by the pathological effect of the genotype and environmental factors (the result of their interaction), against the background of other normal signs of the body.

Here it is necessary to clarify the meaning of the wording “...against the background of other normal signs.”

If a sick person has a specific pathological sign or phenotype (for example, ARVI symptoms), this does not mean that other (normal) signs have disappeared, for example, blue eye color, curly hair, etc.

Pathological phenotype as symptom complex of the disease- this is the result of the combined pathological action of the genotype and environmental factors.

Phenotypic polymorphism

Phenotypic polymorphism- this is a variety of normal and pathological signs and phenotypes detected at any level of discreteness of the organism: molecular, cellular, tissue, organ and organismal.

Closely related to phenotypic polymorphism are:

DNA sequence polymorphism or genetic polymorphism(see Chapter 2), which serves as the basis genetic uniqueness(individuality) of a person;

Protein polymorphism, or proteomic (biochemical) polymorphism (see above), which serves as the basis phenotypic uniqueness(individuality) of a person.

Clinical Proteomics Concepts

Clinical proteomics- these are pathological (clinical) signs and phenotypes that a doctor of any specialty deals with when examining patients.

Clinical signs and phenotypes include:

Symptom of disease (see “pathological sign”);

Symptom complex of the disease (see “pathological phenotype”);

Disease, pathokinesis and progression.

Disease- this is a pathological process that arose during ontogenesis, it is a temporary or permanent pathological phenotype (symptom complex of the disease), characterized by pathokinesis and progression.

The concepts of “pathokinesis” and “progredience” were first introduced by I.V. Davydovsky (1961).

Pathokinesis- this is movement pathological process, i.e. the disease moves from beginning to end, successively passing through the stages of prodrome (hidden or latent period), manifestation of the first signs, and course of the disease (the beginning coinciding with the manifestation, the middle of the course and the outcome). The outcome is recovery, transition of the disease to a chronic condition, or death.

Progressivity- this is the progression of the pathological process or the increase in the severity (expressiveness) of the disease as it progresses.

Hereditary disease

Hereditary disease is a permanent (constitutional) pathological phenotype that arises during ontogenesis with signs of pathokinesis and progression, transmitted from generation to generation.

Congenital disease

Congenital disease- this is a permanent pathological phenotype that has arisen in utero without signs of pathokinesis and progression, transmitted or not transmitted from generation to generation, which is associated with a genetic or non-genetic cause of the disease.

For example, if the diagnosis of Down syndrome is made at the birth of a child, then the phenotype of such a patient remains stable throughout his life, because it is caused by a chromosomal disorder.

Chromosomal syndrome

Chromosomal syndrome- this is an option congenital disease caused by a genetic cause (structural or genomic mutation), but usually not inherited, except in cases of balanced familial translocations (see Chapter 17).

Clinical syndrome

The concept " clinical syndrome"consonant with the concept" chromosomal syndrome", but does not at all coincide with it.

Clinical syndrome characterizes the most pronounced clinical features of an individual disease (group of diseases) or individual periods diseases. There are several dozen such syndromes. Examples include:

Respiratory neurodistress syndrome is a variant of the onset of glycogenosis of various types (see Chapter 21);

Respiratory failure syndrome - develops in a newborn due to incomplete differentiation of the alveolar epithelium and weak production of surfactant (see Chapter 14);

“Sudden death” syndrome (“death in the cradle”) is a variant of the outcomes of Pompe glycogenosis and adrenal crisis in the salt-wasting form of AHS (see Chapters 14, 17 and 21);

Malabsorption syndrome or impaired intestinal absorption is one of the characteristic features of many hereditary metabolic diseases (see Chapter 21);

Hormonal crisis syndrome (see Chapter 14);

Androgen insensitivity syndrome (see Chapter 16);

Thalidomide syndrome (see Chapter 23).

Syndrome as a concept of teratology

In teratology (dysmorphology), the concept of “syndrome” refers to a stable combination of two or more developmental defects detected in different systems of the body and pathogenetically related to each other (see Chapter 23). This syndrome is based on one reason, which can be caused by a gene mutation, chromosomal aberration, or the action of a teratogen.

Congenital malformation

Congenital malformation (CDM) or major developmental anomaly (MAD) - a stable pathological sign, registered as a morphological change in an organ (large area of ​​the body) that goes beyond variations in the boundaries of the structure (beyond the boundaries of the norm) and is accompanied by dysfunction, i.e. persistent morphofunctional disorder.

Depending on the etiological cause, congenital malformation (BD) is either transmitted from generation to generation or not. In the first case it is

Congenital malformations caused by dominantly and recessively inherited gene mutations, defects of a multifactorial nature, as well as familial translocations. In the second case, these are defects of exogenous origin.

Minor developmental anomaly

Minor anomaly (MDA)- this is, as a rule, a stable pathological sign or change in an organ (part of the body) at the final stage of morphogenesis (histogenesis stage), which does not go beyond variations in the boundaries of the structure and is not accompanied by dysfunction, i.e. persistent (in most cases) histological disorder.

Depending on the etiological cause, MARs may or may not be transmitted from generation to generation, and in some cases change with age until they disappear completely (see Chapter 23).

Clinical polymorphism, levels of its manifestation and signs

Clinical polymorphism as the concept of clinical proteomics implies differences in the clinical picture of the same disease in different patients, i.e. discrepancy between individual symptoms (symptom complexes).

It is known that in ancient times and especially in the Middle Ages, doctors were distinguished by their deep knowledge of anatomy at the tissue, organ and system levels of the body.

Doctors of the 18th-19th centuries. have already studied man cellular level; histology, biochemistry, physiology, pathological anatomy and physiology, microbiology. In the 20th century Virology, allergology, immunology, general and medical genetics, molecular biology and genetics, biophysics, physicochemical medicine; in the second half of the century, research began at the molecular level.

Modern molecular medicine is based on the knowledge of genomics, proteomics and bioinformatics. The transition to the atomic, subatomic (attomolar) levels, and nanolevel has begun (see Chapter 20).

Moreover, if earlier medicine progressed slowly, over centuries, then in modern conditions the emergence and implementation of new things occurs much faster - within several decades.

In parallel with the development of medicine, the problem of clinical polymorphism of pathological signs and phenotypes has become more complex. As stated above, clinical polymorphism is caused by the action of genes within the genotype of an organism (the interaction of maternal and paternal genomes) with or without the participation of environmental factors. Unlike genetic and biochemical polymorphisms determined at the molecular level, clinical polymorphism manifests itself at the tissue, organ and system levels, and therefore the doctor independently evaluates pathological signs and phenotypes during the examination of patients, using general clinical, clinical and instrumental methods available only to him and clinical and laboratory methods for examining patients with hereditary and non-hereditary pathologies (see Chapter 18).

In addition, if a doctor examines in a particular family, in addition to the patient himself, his relatives suffering from the same disease, then the next level of clinical polymorphism occurs - the level of intrafamily differences.

If a doctor examines different patients with the same disease in unrelated families, then there is another level of clinical polymorphism - the level of interfamily differences.

Thus, in total there are 5 levels of clinical manifestation of pathological signs and phenotypes: tissue, organ, organismal, intra- and interfamilial.

To the signs of clinical polymorphism, identified at all levels include: anthropometric, anatomical, morphological (histological), physiological (functional), neurological, endocrinological, immunological, mental, psychological and other characteristics of the body, recorded by the doctor himself during the examination (examination) of the patient.

Thus, the concept of “clinical polymorphism” in terms of the spectrum of signs and phenotypes is much narrower (pathology only) than the concept of “phenotypic polymorphism” (both normal and pathology). In turn, significantly fewer methods for studying the problem of clinical polymorphism are known (see Chapter 18) than methods for studying the problem of phenotypic polymorphism (see Chapter 19).

At the same time, in the conditions of modern molecular medicine, doctors should have no doubts about the future significant expansion of the range of molecular and submolecular methods for studying clinical polymorphism.