Destruction of connective tissue in the human body. Connective tissue and human diseases

Hereditary connective tissue diseases (connective tissue dysplasia - CTD) - a group of nosological forms that combine violations of structural proteins and enzyme systems related to the synthesis and metabolism of collagen. These diseases are characterized by a high frequency of occurrence in pediatric practice, multiple organ lesions, pronounced clinical polymorphism, and the complexity of diagnosis and treatment. The term "dysplasia" means a violation of the formation of organs and tissues in the embryonic and postnatal periods.

All hereditary or congenital connective tissue diseases are usually divided into differentiated connective tissue dysplasias that have a certain type of inheritance and a delineated manifest clinical picture (Marfan, Ehlers-Danlos syndromes, osteogenesis imperfecta, varieties of chondrodysplasia) and undifferentiated connective tissue dysplasia (NDCT), including many syndromes without clear symptoms.

While the population frequency of monogenic connective tissue defects is relatively low, UCTDs are extremely common, they can be not only genetically determined, but also develop due to various environmental influences. In addition to severe, clinically significant, there are benign forms. The cellular elements of the connective tissue are represented by fibroblasts and their varieties (osteoblasts, chondrocytes, odontoblasts, keratoblasts), macrophages (histiocytes) and mast cells (labrocytes). The extracellular matrix is ​​represented by 3 types of fibers: collagen, reticular and elastic. Connective tissue performs five functions: biomechanical (support-frame), trophic (metabolic), barrier (protective), plastic (reparative) and morphogenetic (structural-educational).

Since the connective tissue makes up about 50% of the body weight and is present in all organs and systems, CTD is more common in nature, less often local with a predominant lesion of any organs and systems. In hereditary connective tissue diseases caused by a defect in different genes, a similar clinical picture is noted,

structural changes caused by the loss of glycosaminoglycans and hydroxyproline, as a result, the tissue loses its strength and elasticity. The phenotypic and organ manifestations depend on which tissue is affected more - dense or loose. Genetically determined traits (perhaps controlled by a single gene) are called hair dryers. All clinical signs of CTD can be divided into 3 groups according to the primary laying of organs in embryogenesis: meso-, ecto- and endodermal anomalies. Mesodermal anomalies (damage to densely formed connective tissue) are manifested by skeletal changes and include asthenic physique, dolichostenomelia, arachnodactyly, deformity of the chest, spine and skull, flat feet, gothic palate, joint hypermobility. Variants with a predominant lesion of loose tissue are characterized by skin changes (thinning, hyperelasticity), hypoplasia of muscles and adipose tissue, pathology of the organs of vision, nervous, cardiovascular (heart defects, prolapses, an increase in the diameter of large vessels) and respiratory systems, kidneys. Connective tissue disorders accompany many chromosomal and monogenic diseases (Down syndrome, Aarskog-Scott syndrome, mucopolysaccharidoses, etc.).

DST is an anomaly of the tissue structure, manifested in a decrease in the content of certain types of collagen or a violation of their ratio, which leads to a decrease in the strength of the connective tissue of many organs and systems. Elongation (insertion), shortening (deletion) of the collagen chain and various point mutations cause disturbances in the formation of cross-links in the collagen molecule, a decrease in its thermal stability, a slowdown in scar formation, a change in post-granulation modifications, and an increase in intracellular degradation.

Hereditary connective tissue disorders (HHCT) or, as they are also called in Russia, connective tissue dysplasia, is one of the most controversial problems in clinical medicine. Until recently, in our country there was a terminological confusion and lack of a unified approach to assessing these conditions. This mainly concerned the so-called undifferentiated HNST, which included all variants of congenital "weakness" of the connective tissue, with the exception of the monogenic syndromes of Marfan, Ehlers-Danlos and a number of others. The lack of clear diagnostic criteria led to the fact that any cases of detection of any signs of dysembryogenesis were arbitrarily designated as HHCT. Such a broad and unreasonable interpretation led to overdiagnosis and created preconditions for psychogenic iatrogenies.

To overcome the existing contradictions in the definitions and criteria for diagnosing certain clinical variants of HNSCT, the expert committee of the All-Russian Scientific Society of Cardiology (VNOK) developed the first national recommendations adopted at the Russian National Congress of Cardiology in 2009 and revised in 2012. These efforts have made it possible to significantly bring approaches to the diagnosis of HNST in our country closer to international practice.

The term "HHST" combines a genetically and clinically heterogeneous group of diseases based on the commonality of disorders in the formation of connective tissue in the embryonic and postnatal periods. The genetic heterogeneity of HHCT implies a monogenic and multifactorial nature of the disease. The first is realized in the group of relatively rare monogenic Marfan and Ehlers-Danlos syndromes associated with mutations in the genes of extracellular matrix proteins. Both mutations of a large number of different genes and the impact of environmental factors are significant in the emergence of the most numerous group of HHSTs of a multifactorial nature. The clinical heterogeneity of HHCT is associated with the ubiquitous distribution of connective tissue in the body and the variety of manifestations of congenital "weakness" of its individual components.

Since there are no specific laboratory markers for most HNSTs, and molecular genetic studies remain inaccessible and significant only in relation to monogenic variants of the pathology, the priority in diagnosis remains with clinical signs. In the recommendations mentioned above, such signs are systematized, of which those that have the greatest diagnostic value are singled out and included in published foreign recommendations for the diagnosis of the most studied HHST (Ghent criteria for Marfan syndrome, Villefranche criteria for Ehlers-Danlos syndrome, Brighton criteria for joint hypermobility syndrome). It is essential that dysembryogenesis stigmas (small developmental anomalies) are clearly separated from these signs, which, although they are detected in HHCT more often than in the general population (which confirms the role of embryogenesis disorders in the formation of HHCT), are not actually markers of "weakness" of the connective tissue. The list of the main external and visceral markers of HHCT is given in Table. 1. The totality of the identified signs in a particular patient makes it possible to diagnose one or another variant of connective tissue pathology.

At present, in relation to HHST, it is recommended to abandon the obsolete terms “differentiated” and “undifferentiated” and it is proposed to talk about disorders classified (having agreed recommendations for diagnosis) and unclassified (or dysplastic phenotypes) - Table. 2. Agreed diagnostic recommendations have: from monogenic HHST - Marfan and Ehlers-Danlos syndromes, from multifactorial - MASS-phenotype, primary mitral valve prolapse, joint hypermobility syndrome.

Marfan syndrome is an autosomal dominant disorder caused by mutations in the fibrillin-1 (FBN1) gene. Fibrillin forms the basis of elastic fibers; it is especially abundant in the intercellular matrix of the vascular wall, heart, cartilage, lens, cornea and ligament of Zinn. Mutations of the FBN1 gene lead to the inferiority of fibrillin and disruption of the structure and function of the listed organs and tissues.

The diagnosis of Marfan syndrome is based on the Ghent criteria (1996, 2010). In the latest version of the Ghent criteria, the division into major and minor features was abolished, and a number of minor features were excluded. At the same time, two most specific signs were identified - dilatation and / or dissection of the aorta and ectopia of the lens, and a scoring of the remaining signs was proposed to calculate the degree of systemic involvement of connective tissue (CBCT) - Table. 3. In the absence of a family history, the diagnosis of Marfan's syndrome can be established in the presence of aortic root dilatation and lens ectopia, or when aortic dilatation is combined with an FBN1 gene mutation or with a combination of SIDS signs of 7 or more points. With a burdened family history, the diagnosis is legitimate if one of the specific signs is detected or if the SICT is 7 or more points.

Ehlers-Danlos syndrome is a heterogeneous group of collagenopathies with different types of inheritance and common clinical manifestations in the form of joint hypermobility and increased skin elasticity. The diagnosis of Ehlers-Danlos syndrome is based on the Villefranche criteria. Instead of the previously recognized ten types of the disease, six are now distinguished: classical, hypermobile, vascular, kyphoscoliotic, arthrochalasia, dermatosparaxis; for each of them, major and minor diagnostic criteria are defined. Clinical diagnosis requires the presence of at least one major criterion (Table 4).

MASS phenotype (or Marfan-like syndrome) is an acronym for mitral valve prolapse (Mitral valve prolapse), aortic dilatation (Aotic dilatation), changes in the skin (Skin) and bones of the skeleton (Skeleton). The MASS phenotype can be diagnosed with borderline aortic root dilatation, at least one skeletal manifestation, and SIVT signs of 5 or more points. As can be seen, in the absence of molecular genetic diagnostic data, it is difficult (if not impossible) to distinguish the MASS phenotype from Marfan syndrome with an incomplete set of features.

Mitral valve prolapse is diagnosed when systolic displacement of one or both leaflets of the mitral valve beyond the line of the valve ring in the parasternal longitudinal position by more than 2 mm. The morphological substrate of primary mitral valve prolapse as one of the HHST variants is leaflet myxomatosis, which reflects the disorganization of collagen fibrils and the accumulation of acidic glycosaminoglycans in them.

When evaluating mitral valve prolapse, it is recommended to pay attention to the depth of prolapse, the thickness of the leaflets and the degree of mitral regurgitation - these parameters are essential for predicting intracardiac and general hemodynamic disorders. With a high degree of mitral regurgitation and a leaflet thickness of more than 5 mm (a sign of its myxomatous degeneration), the likelihood of hemodynamic disorders increases significantly. Significance is also attached to the signs of SIVT as a weighty confirmation of the prolapse belonging to HNST (in addition to the primary one, there are also secondary mitral valve prolapses that are not associated with congenital "weakness" of the connective tissue, but develop with lesions of the left ventricular myocardium - myocarditis, myocardial dystrophy, coronary pathology). If the prolapse of the mitral valve leaflets is no more than 2 mm, they are not thickened, and mitral regurgitation is absent or minimal, there is no reason to state pathology. In this case, we can talk about a variant of the norm in persons with an asthenic constitution or a transient "physiological" prolapse in adolescents.

Primary mitral valve prolapse should be distinguished from mitral prolapse as belonging to a monogenic HHCT or MASS phenotype. Differential criteria (unfortunately, not absolute) are the diameter of the aorta and the number of signs of SIDS.

Joint hypermobility syndrome is based on mutations in the genes encoding collagen, elastin, fibrillin and tenascin X, leading to weakness of the articular ligaments. The syndrome is characterized by an excessive range of motion in the joints, accompanied by clinical symptoms (habitual dislocations, arthralgia). When diagnosing joint hypermobility, a nine-point P. Beighton scale is used, which assesses the ability to perform the following five movements: passive flexion of the V metacarpophalangeal joint by more than 90 °, passive adduction of the first finger to the forearm, passive overextension of the knee and elbow joints by more than 10 °, free touching the palms of the floor with straight legs. The first four movements are paired (assigned a point for the ability to perform a movement on each side), the last one is unpaired (the maximum possible joint score is 9 points). Joint hypermobility, which is at least 4 points, and arthralgia in at least four joints lasting from three months, are major diagnostic criteria for this pathology.

Since weakness of the ligamentous apparatus is a universal sign of connective tissue insufficiency, the syndrome of joint hypermobility is excluded in the presence of Marfan, Ehlers-Danlos syndromes and a number of other HHST similar in clinical manifestations.

Unclassified HHCTs that do not meet agreed diagnostic criteria are much more common in everyday practice. The variety of their clinical variants is systematized into the following variants: MASS-like phenotype, marfanoid appearance, Ehlers-like phenotype, benign joint hypermobility, unclassified phenotype. The first two of them phenotypically resemble Marfan's syndrome, the next two - Ehlers-Danlos syndrome, not fully meeting the criteria for the diagnosis of these conditions. The diagnosis of unclassified HHCTs is based on the same principles (a combination of external and visceral phenotypic manifestations) that are used to identify HHCTs that have agreed recommendations, but the diagnostic threshold is lower.

The MASS-like (Marfan-like) phenotype is characterized by borderline aortic root size in combination with myopia and/or mitral valve prolapse and the presence of signs of SIVT less than 5 points (in contrast to the MASS phenotype, in which it is 5 points or more).

Marfanoid appearance is characterized only by signs of involvement of the skeletal system (usually in asthenics) in the absence of visceral changes. In this case, less severe skeletal changes are allowed than those necessary for ascertaining Marfan's syndrome, however, the presence of dolichostenomelia and arachnodactyly is recognized as mandatory.

The main condition for classifying a patient as an Ehlers-like phenotype is the presence of at least two signs of skin involvement, excluding the major criteria for Ehlers-Danlos syndrome.

Benign joint hypermobility is diagnosed based on the detection of an excessive range of motion in the joints, but without clinical symptoms.

It is proposed to refer to the unclassified phenotype cases of detection of at least six small external and/or visceral signs of congenital "weakness" of the connective tissue that do not fall under the criteria of the other above-mentioned syndromes and phenotypes.

The nonspecificity of external and visceral markers of "weakness" of the connective tissue, the well-known conventionality of diagnostic criteria for dysplastic phenotypes (some of which differ not qualitatively, but quantitatively in the number of identified signs) make it difficult to recognize individual HNSTs. In the process of diagnosis, one should be guided by a peculiar hierarchy of HHST, which constitutes a continuous phenotypic continuum: from monogenic syndromes through dysplastic phenotypes to an unclassified phenotype and the norm. According to this approach, the presence of features of Marfan or Ehlers-Danlos syndrome rules out the diagnosis of unclassifiable HHCT. The presence of criteria for the MASS phenotype (including mitral valve prolapse and skeletal changes) does not give grounds to speak of primary mitral valve prolapse or marfanoid appearance. Similarly, the diagnosis of primary mitral valve prolapse rejects the conclusion of any of the dysplastic phenotypes. The lowest clinical and diagnostic weight has an unclassified phenotype.

Literature

1. Zemtsovsky E.V. Undifferentiated connective tissue dysplasia. An attempt at a new understanding of the concept // Bulletin of Medicine of the North Caucasus. 2008; 2:8-14.
2. Hereditary disorders of connective tissue in cardiology. Diagnosis and treatment. Russian recommendations (I revision) // Russian Journal of Cardiology. 2013; 1 (App. 1): 1-32.
3. Loeys B. L., Dietz H. C., Braverman A. C. et al. The Revised Ghent Nosology for the Marfan Syndrome // J. Med. genetics. 2010; 4:476-485.
4. Beighton P., De Paepe A., Steinmann B. et al. Ehlers-Danlos syndromes: Revised nosology, Villefranche, 1997 // Am. J. Med. genetics. 1998; 1:31-37.
5. Grahame R., Bird H. A., Child A. The revised (Brighton, 1998) criteria for the diagnosis of benign joint hypermobility syndrome // J. Rheumatology. 2000; 7: 1777-1779.

A. V. Klemenov 1 Doctor of Medical Sciences
A. S. Suslov

GBUZ NO GKB No. 30, Nizhny Novgorod

abstract. The article is dedicated to modern concepts of terminology and nomenclature of hereditary disorders of connective tissues. The authors add diagnostic criteria of particular clinical variants of this pathology.

Mixed connective tissue disease (MCTD), also called Sharpe's syndrome, is an autoimmune connective tissue disease manifested by a combination of individual symptoms of systemic pathologies such as SJS, SLE, DM, SS, RA. As usual, two or three symptoms of the above diseases are combined. The incidence of CTD is approximately three cases per one hundred thousand of the population, mainly women of mature age suffer: there are ten sick women for one sick man. SCTD has a slowly progressive character. In the absence of adequate therapy, death occurs from infectious complications.

Despite the fact that the causes of the disease are not completely clear, the autoimmune nature of the disease is considered an established fact. This is confirmed by the presence in the blood of patients with MCTD of a large number of autoantibodies to the polypeptide associated with ribonucleoprotein (RNP) U1. They are considered to be a marker of this disease. MCTD has a hereditary determination: in almost all patients, the presence of the HLA antigen B27 is determined. With timely treatment, the course of the disease is favorable. Occasionally, CTD is complicated by the development of hypertension of the pulmonary circulation and renal failure.

Diagnosis of mixed connective tissue disease

It presents certain difficulties, since CTD does not have specific clinical symptoms, having similar features with many other autoimmune diseases. General clinical laboratory data are also nonspecific. However, SCTA is characterized by:

• KLA: moderate hypochromic anemia, leukopenia, accelerated ESR.
• OAM: hematuria, proteinuria, cylindruria.
• Blood biochemistry: hyper-γ-globulinemia, the appearance of RF.
• Serological examination: an increase in the titer of ANF with a mottled type of immunofluorescence.
• Capillaroscopy: sclerodermatous-altered nail folds, cessation of capillary circulation in the fingers.
• X-ray of the chest: lung tissue infiltration, hydrothorax.
• Echocardiography: exudative pericarditis, valvular pathology.
• Pulmonary function tests: pulmonary hypertension.

An unconditional sign of CTD is the presence of anti-U1-RNP antibodies in the blood serum in a titer of 1:600 ​​or more and 4 clinical signs.

Treatment of mixed connective tissue disease

The goal of treatment is to control the symptoms of CTD, maintain the function of target organs, and prevent complications. Patients are advised to lead an active lifestyle and follow dietary restrictions. In most cases, treatment is carried out on an outpatient basis. Of the drugs most commonly used are NSAIDs, corticosteroid hormones, antimalarial and cytostatic drugs, calcium antagonists, prostaglandins, proton pump inhibitors. The absence of complications with adequate maintenance therapy makes the prognosis of the disease favorable.

Essential drugs

There are contraindications. Specialist consultation is required.

1. (synthetic glucocorticoid drug). Dosage regimen: in the treatment of CTD, the starting dose of prednisone is 1 mg/kg/day. until the effect is achieved, then a slow (no more than 5 mg / week) dose reduction to 20 mg / day. Further dose reduction by 2.5 mg every 2-3 weeks. up to a maintenance dose of 5-10 mg (for an indefinitely long time).
2. Imuran) is an immunosuppressive drug, cytostatic. Dosage regimen: with SCTD, it is used orally at the rate of 1 mg / kg / day. The course of treatment is long.
3. Diclofenac sodium (, Diklonat P) is a non-steroidal anti-inflammatory drug with an analgesic effect. Dosage regimen: the average daily dose of diclofenac in the treatment of CTD is 150 mg, after achieving a therapeutic effect, it is recommended to reduce it to the minimum effective (50-100 mg / day).
4. Hydroxychloroquine ( , ) is an antimalarial drug, an immunosuppressant. Dosage regimen: for adults (including the elderly), the drug is prescribed in the minimum effective dose. The dose should not exceed 6.5 mg/kg of body weight per day (calculated from ideal, not actual body weight) and may be either 200 mg or 400 mg/day. In patients able to take 400 mg daily, the initial dose is 400 mg daily in divided doses. When an obvious improvement in the condition is achieved, the dose can be reduced to 200 mg. With a decrease in efficiency, the maintenance dose may be increased to 400 mg. The drug is taken in the evening after meals.

Dear colleagues!

The problem of diagnosing hereditary disorders (dysplasia) of the structure and function of the connective tissue (HHCT)

recognition of which today is already agreed upon by experts. In addition, the authors summarized the experience of diagnosing and treating the most common syndromes and phenotypes. It is quite understandable that all aspects of this complex problem, which is interdisciplinary in nature, could not find a place within the framework of the proposed recommendations. Obviously, in the future, it will be necessary to develop recommendations for doctors of various medical specialties, which will reflect modern ideas about the features of the diagnosis and treatment of dysplastic syndromes and phenotypes in cardiology, pulmonology, hematology, surgery, orthopedics, and many others. other fields of medicine. Nevertheless, today we have the first document that brings us closer to solving this extremely important task for a practical doctor. Let me express my conviction that the developed recommendations will help the practitioner to understand this complex problem.

President of VNOK Academician of the Russian Academy of Medical Sciences R. G. Oganov

I Introduction

II. Definition of concepts and causes of HHST

III. Principles of diagnosis of HHST

1. General principles for the diagnosis of hereditary connective tissue disorders

2. External and visceral signs of hereditary connective tissue disorders

And associated with them violations of the structure and function of various organs and systems

 Bone

 Dermal

 Muscular

 Articular

 Eye

 Cardiovascular system

 Bronchopulmonary system

3. Small anomalies of development

1. Marfan syndrome

2. Ehlers-Danlo Syndrome

3. Osteogenesis imperfecta

5. Algorithm for diagnosing NNST

v. Syndromes and phenotypes grouped based on similarity in appearance and/or visceral manifestations (connective tissue dysplasia)

1. Algorithms for diagnosing dysplastic syndromes and phenotypes

 Mitral valve prolapse

 Marfanoid appearance

 Marfan-like phenotype

 Ehlers-like phenotype

 Joint hypermobility syndrome

 Mixed phenotype

 Unclassifiable phenotype

 Non-diagnostic findings on connective tissue disorders

2. Differential diagnosis of dysplastic syndromes and phenotypes

3. Age aspects of the diagnosis of HNST

4. NNST in ICD-X

VI. Tactics of management and treatment of patients with HHCT

1. General approaches to the treatment of HHCT

2. vascular syndrome. Dissection and rupture of the aorta

 Management tactics, prevention and treatment

3. valvular syndrome. mitral valve prolapse

 Diagnostic principles

 Features of the course and risk stratification in MVP

 Lifestyle

 Features of managing patients with MVP

 Treatment

4. Syndrome of autonomic dysfunction

5. Arrhythmic syndrome and sudden death

6. Phlebeurysm

VII. Conclusion

VIII. Applications

List of abbreviations

AD - autosomal dominant

AR - autosomal recessive

AT - abnormal trabecula

EPF - hypermobile Ehlers-like phenotype

HMS - joint hypermobility

DST - connective tissue dysplasia

LV - left ventricle

LH - false chord

LP - left atrium

MAC - minor anomalies of the heart

MASS-phenotype (acronym: Mitral valve, Aorta, Skeleton, Skin)

MD - myxomatous degeneration of the mitral valve leaflets

MPF - Marfan-like phenotype

MR - mitral regurgitation

HHCT - hereditary connective tissue disorders

UCTD - unclassified connective tissue dysplasia

PDS - increased dysplastic stigmatization

PDSv - increased, predominantly visceral, dysplastic stigmatization

RV - right ventricle

MVP - mitral valve prolapse

PTC - tricuspid valve prolapse

SHMS - joint hypermobility syndrome

SM - Marfan syndrome

EDS - Ehlers-Danlos syndrome

EPF - Ehlers-like phenotype

Introduction

Hereditary disorders of the structure and function of the connective tissue (HHCT) are extremely common and knowledge of the basic principles of their diagnosis is necessary for physicians of various specialties. However, the social significance of the cardiological aspects of this problem is especially high, which served as the basis for the initiative of the section of the VNOK "Dysplasia of the connective tissue of the heart" to prepare national recommendations. An expert committee and a working group have been established to draft these recommendations. Draft recommendations were circulated to the experts on NNST issues. Subsequently, the working group, taking into account the comments and suggestions, prepared a document for approval at the Russian National Congress of Cardiology. Russian recommendations on the problem of NNST have been prepared for the first time.

1. Berlin nosology of hereditary connective tissue disorders (Beighton P. et al., 1988).

(Villefranche criteria, Beighton P. et al., 1998)

5. Guidelines for the treatment of patients with valvular heart disease//Bonow R.O. et al. ACC/AHA 2006 Guideline

for the Management of Patient with Valvular Heart Disease//Circulation. - August 1, 2006. - P.148

6. Analytical review “Dysplastic syndromes and phenotypes. Dysplastic heart. - E. V. Zemtsovsky. - St. Petersburg. - 2007. - 80s.

These recommendations do not aim to present all aspects of one of the most difficult problems of modern medicine, which is the problem of hereditary connective tissue pathology. There are no data on dozens of syndromes that are dealt with by doctors of various specialties - from orthopedists and surgeons to hematologists and dentists. The first national recommendations are intended to help physicians of various specialties in recognizing HHST, to unify approaches to diagnosing the most common dysplastic syndromes and phenotypes, and to make the data obtained by different researchers comparable. It is expected that the recommendations will be improved as scientific knowledge and practical experience accumulate.

1. Definition of concepts and causes of hereditary connective tissue disorders

An extremely important condition for conducting coordinated research on the problem of HHST is the coordination of the conceptual apparatus used in the process of diagnosing pathology. The following terms and definitions should be used.

Hereditary connective tissue disorders (HHCT) - heterogeneous group of monogenic diseases,

caused by genetic defects in the synthesis and / or breakdown of extracellular matrix proteins, or by a violation of connective tissue morphogenesis. (Definition of Perekalskaya).

Connective tissue dysplasia (CTD) - hereditary connective tissue disorders combined into syndromes and phenotypes based on the commonality of external and / or visceral signs and characterized by genetic heterogeneity and a variety of clinical manifestations from benign subclinical forms to the development of multiple organ and multisystem pathology with a progressive course.

Minor developmental anomalies (MAP) - hereditary or congenital deviations of organs from the normal anatomical structure, not accompanied by clinically significant dysfunction. Part of the MAP disappears with age, while the other part, under certain conditions, can cause the development of pathology.

A malformation is a deviation of an organ from the normal anatomical structure, leading to clinically significant violations of its function.

The development of HHCT is based on mutations in the genes responsible for the synthesis or breakdown of the components of the extracellular matrix of the connective tissue. Today, a large group of monogenic HHCTs associated with mutations in the genes of extracellular matrix proteins (collagen of various types, fibrillin, tenaskin), growth factor receptor genes, in particular TGF-β (transforming growth factor-β), and matrix metalloproteinases (MMPs) are known.

Mutations of these genes lead to the development of many HNSTs, the number of which today exceeded 250 (Kadurina T.I., Gorbunova V.N., 2007). Most of these syndromes are very rare. We are talking about Marfan syndrome (SM), Ehlers-Danlos syndrome (EDS), osteogenesis imperfecta (OI) and many others. others They are based on well-known

monogenic defects of the extracellular matrix, inherited by autosomal dominant (AD) or autosomal recessive types (AR).

Diagnosis of most dysplastic syndromes and phenotypes is fraught with difficulties that arise due to the similarity of their symptoms and clinical manifestations (overlap connective tissue disorder). For example, signs of joint hypermobility are common to such various classified hereditary diseases as Marfan syndrome (SM), Ehlers-Danlos syndrome (EDS) and osteogenesis imperfecta (Malfait F. et al., 2006). Similarly, mitral valve prolapse (MVP) can occur in all of the listed hereditary syndromes, but is even more often an independent hereditary disease.

On the contrary, there is an extremely large number of HHST grouped into syndromes and phenotypes similar in external and/or visceral signs, which are often not possible to identify due to the difficulties of molecular genetic studies. It is these NNST that can be called "connective tissue dysplasia" (CTD).

For the diagnosis of the most studied HNSTs, agreed criteria are used, which is one of the objectives of these recommendations to familiarize a wide range of the Russian medical community with. Another of its tasks is to systematize the signs (markers) underlying the diagnosis of any HNST, and to bring the algorithms for diagnosing individual syndromes and phenotypes adopted in Russia into line with generally accepted ones.

Since a detailed study of all signs of HHCT is extremely laborious, and the use of their complete list is unsuitable for practical use, priority is given to those that have the greatest diagnostic significance and are used in published recommendations for the diagnosis of the most studied HHCT.

Principles for diagnosing HHST

2.1. General principles for the diagnosis of hereditary connective tissue disorders

General approaches to the diagnosis of HNST should be based on a comprehensive analysis of the results of clinical, genealogical, laboratory instrumental and molecular genetic studies.

Clinical examination should include clarification of the patient's complaints, collection of hereditary and family history, phenotypic and physical examination. An extremely important part of a comprehensive examination of the patient is a family examination, which allows confirming the hereditary nature of the identified pathology.

Laboratory research provide important information for assessing connective tissue metabolism. The most accessible for practical use is the biochemical assessment of the level of hydroxyproline (HOP) in biological fluids (blood, urine, gastric juice, synovial fluid, etc.) according to the method of H. Stegmann (1958) modified by P. N. Sharaev (1990).

The level of free HOP is a marker of collagen destruction processes, and peptide-bound HOP reflects both the processes of degradation and biosynthesis of collagen. To analyze the processes of collagen biosynthesis, the coefficient free / peptide-bound GOP is used; Glycosaminoglycans (GAGs) are a marker of proteoglycan breakdown processes. It is customary to evaluate the concentration of proteoglycans - proteins associated with GAGs in biological fluids (P.N. Sharaev et al., 1987); The metabolism of glycoproteins is judged by the level of fucose, a marker of glycoprotein metabolism (L.A. Muravyova, E.E. Volkova, 1989). However, it must be emphasized that these studies are not specific. For the diagnosis of individual hereditary syndromes, it is necessary to use special methods, such as determining the deficiency of collagen hydroxylase and fibronectin activity in EDS, assessing collagen production by a culture of skin fibroblasts in OI, determining the tenascin X concentration in blood serum in HMS, and a number of others.

Among instrumental methods The most important study is Doppler echocardiography (ECH), which is mandatory for suspected HHCT, since cardiovascular complications are the main cause of death in such patients. No less important is the ultrasound examination of the abdominal organs and kidneys, which allows to identify ptosis of the internal organs, small anomalies in the development of the gallbladder,

spleen and kidneys. Beam methods		diagnostics	(Rg-examination of the hip joints,
spine)	must be included in the mandatory		complex of instrumental examination of patients
suspected of Marfan's syndrome.
Modern	immunohistochemical	and molecular genetic research in most

are available to the practitioner, so knowledge of the clinical and phenotypic features of HHCT is particularly important.

Certain combinations of external features make it possible to assume one or another hereditary syndrome or phenotype with a high probability. It should be noted that the signs of joint hypermobility have the least diagnostic sensitivity among the external signs of HHST. The latter are often detected in a wide variety of dysplastic syndromes and phenotypes.

Namely, based on the results of a phenotypic, clinical and family examination, it is necessary to refer the patient for a consultation with specialists, perform instrumental studies, molecular genetic, immunohistochemical or other special studies to clarify the diagnosis.

2.2 External and visceral signs of hereditary disorders of the connective tissue and associated disorders of the structure and function of various organs and systems

and, associated with various forms of HNST, changes from various organs and systems.

2.2.1 Bone

1. 1 Carinatal deformity of the chest

2. Funnel chest deformity

3. Dolichostenomelia is diagnosed by measuring the length of the trunk segments

1. 3.1 The ratio of the upper segment of the body (to the symphysis) to the lower is less than 0.86

2. 3.2 Arm span/height ≥ 1.05

3. 3.3 Foot length ratio: growth over 15%

4. 3.4 Hand length ratio: growth over 11%

4. Arachnodactyly *

1. 4.1 Wrist symptom

2. 4.2 Thumb symptom

5. Scoliotic deformity of the spine or spondylolisthesis

6. Kyphosis and kyphoscoliosis

8. Limiting elbow extension to 170º or less

9. Protrusion of the acetabulum of any degree

10. High arched sky

11. Growth failure and crowding of teeth

12. Broken bones

13. Skull deformities

14. Dolichocephaly*

o Hypoplasia of the zygomatic bones o Retrognathia*

2.2.2 Dermal

1. Increased (more than 3 cm) skin extensibility

2. Thin, easily damaged skin

3. Velvety skin due to the abundance of vellus hair of different lengths

4. Atrophic juvenile striae (not caused by obesity or pregnancy)

5. Wide atrophic scars in the form of tissue paper

6. Keloid scars

7. Molluscoid pseudotumors and spheroid masses in the elbows and knees

2.2.3 Muscular

1. 1Muscular hypotonia and/or malnutrition

2. Organ hernias and prolapses and/or incisional hernias

2.2.4 Articular

1. Joint hypermobility (according to P. Beighton) (see Table 3)

2. Spondylosis

3. Spondylolisthesis

4. Dislocations, subluxations in more than 1 joint, or recurring but in one joint

5. Medial displacement of the medial malleolus

6. Flat feet, longitudinal and/or transverse

2.2.5 Ophthalmic

1. Blue sclera

2. Subluxation of the lens

3. Abnormally flat cornea (according to keratometry)

4. Increase in the long axis of the eyeball (according to ultrasound)

5. Myopia

6. Hypoplastic iris or hypoplastic ciliated muscle causing miosis

7. Epicanthus

8. Enophthalmos

9. Oblique palpebral fissures (anti-Mongoloid incision of the eyes)

2.2.6 Cardiovascular system

1. Expansion of the ascending aorta (see Appendix 1)

2. Aortic regurgitation (due to a bicuspid aorta or severe asymmetry of the tricuspid aortic valve)

3. Mitral valve prolapse

4. Other minor anomalies of the heart: tricuspid and aortic valve prolapses, small atrial septal aneurysm (SAIA), tricuspid aortic valve asymmetry (ATAV), diagonal, transverse, and multiple false chordae (LVCH), and anomalous trabeculae (ATLV) of the left ventricle.

5. Pulmonary artery dilatation in the absence of valvular or peripheral pulmonary stenosis or any other obvious cause, before the age of 40 years

6. Calcification of the mitral ring before the age of 40 years

7. Expansion or dissection of the wall of the thoracic or abdominal aorta before the age of 50 years

8. Varicose veins that developed in adolescence

9. Varicocele

10. Easy bruising with minor impacts

2.2.7. Bronchopulmonary system

1. Tracheobronchial dyskinesia (expiratory collapse of the trachea and large bronchi)

2. Tracheobronchomalacia and tracheobronchomegaly

3. Pulmonary hypertension

4. Polycystic lung

5. Apical bullae, radiographically confirmed

6. Spontaneous pneumothorax

2.2.8 Abdominal, pelvic and kidney organs

1. Ptosis of the abdominal organs and kidneys

2. Diaphragmatic hernia

3. Failure of the cardia of the stomach

4. Diverticula of the esophagus and various parts of the intestine

5. Anomalies in the shape and location of the stomach, duodenum and gallbladder

6. Dolichosigma

7. Insufficiency of the bauginian damper

8. Genital prolapse in women

9. Doubling of the pelvicalyceal system, polycystic kidney disease

It is important to understand that almost all of the listed external and visceral signs can in one case act as an independent isolated defect of the connective tissue, and in the other, as a manifestation

In addition to changes in the structure and function of the listed organs and systems, HHCTs are often accompanied by disorders of the central and autonomic nervous systems (Gordon I.B. et al., 1984, Gazit Y et al., 2003), hemorrhagic and thrombotic disorders in the hemostasis system (Barkagan Z.S., and Sukhanova G.A., 2004), disorders of the immune defense system. There is evidence of a high frequency of detection of secondary immunodeficiency syndromes, autoimmune and allergic syndromes in CTD (Yakovlev V.M. et al., 2005, Eremin M.V. et al., 2008)

2.3 Minor developmental anomalies

Minor developmental anomalies (MAD) are changes in the structure of various organs and tissues that are not accompanied by clinically significant impairments to their function. MAP, as well as signs of HHCT, should be divided into external and visceral. External include abnormalities in the development of the skin and bones of the skull of the hand and foot (hyperpigmentation and depigmentation of the skin, protruding ears, absence of an earlobe, syndactyly, sandal gap, etc.). To visceral - changes in the structure of internal organs (doubling of the PLA of the kidneys, an additional lobule of the spleen, etc.) as well as the above minor anomalies of the heart (MAC). The average number of MAPs in individuals with HHCT is significantly higher than in the population, which only confirms their diagnostic role in the recognition of HHCT.

MAPs are detected at birth or in early childhood, some of them are amenable to reverse development (open foramen ovale-OOO), enlarged Eustachian valve, etc.) Others persist throughout life, but with age they can acquire independent clinical significance, contributing to the development of pathology or becoming a risk factor for cardiac pathology (paradoxical embolism in PAO (Onishchenko E.F., 2006), aortic stenosis with asymmetry of the tricuspid aortic valve (Zemtsovskiy E.V. et al., 2006), thromboembolic complications in AMPP (Mattioli A.V. et al., 2001 ).

Based on the phenotypic examination, the results of the examination of the family, the analysis of external and visceral signs, the doctor should suspect one or another HNST. The foregoing makes it necessary for a wide range of doctors to be familiar with the current recommendations for the diagnosis of the most common monogenic HHCTs.

3.1 Marfan syndrome (SM)

Marfan's syndrome is an autosomal dominant, multisystemic, pleiotropic HHST characterized by high variability in clinical manifestations. The diagnosis of SM today is still based on the Ghent criteria (De Paepe A. et al., 1996), which are currently under revision (Ades L; 2007). The need to revise approaches to the diagnosis of SM is associated with the success of molecular genetics, which made it possible to study the nature of fibrillin macromolecules and identify its three types. It also became known about the possibility of developing SM and related syndromes due to mutations in one of the two genes (TGFBR1 and TGFBR2 ) that encode transforming growth factor-β-TGF-β receptors (Neptune E.R. et al. , 2003).

The algorithm for diagnosing SM is based on the selection of large and small criteria that characterize the severity of changes in the connective tissue in various organs and systems. Large criteria indicate the presence in the corresponding system pathologically significant changes. Small criteria, and in some cases - one large criterion, indicate the involvement of one or another system in the pathology of the connective tissue. The list of large and small criteria is given in Table. 1.

Table 1. Ghent criteria for the diagnosis of Marfan syndrome (De Paepe et al., 1996)

big signs

Small signs

Presence of 4 signs out of 8 of the following:

Moderate pectus excavatum

Keeled deformity of the chest

Joint hypermobility

Funnel chest deformity

Arched palate with crowded teeth

requiring surgery

Skull deformities (dolichocephaly*,

zygomatic hypoplasia

The ratio of the upper and lower body segments

bones, enophthalmos, oblique palpebral fissures, retrognathia)

<0,86 или отношение между размахом рук и

height ≥ 1.05

4. Positive wrist test and

thumb (Steinberg)

5. Scoliosis > 20° or spondylolisthesis

Elbow straightening

joint up to 170°

Medial displacement of the medial malleolus,

leading to flat feet

8. Protrusion of the acetabulum of any degree

(confirmed by x-ray)

Changes in the skeletal system correspond to major criterion - pathologically significant

changes if at least 4 of the above 8 major signs are detected.

The skeletal system is involved if:

At least 2 large signs, or one large and 2 small signs.

visual system

Subluxation of the lens

abnormal

cornea

(according to the results

keratometric measurements)

Elongation of the anterior-posterior axis of the eyeball (according to

ultrasound) with myopia

Hypoplastic iris and hypoplastic pupillary sphincter

The visual system is involved if two minor signs are identified

The cardiovascular system

Extension

ascending

aorta* with aortic

Mitral valve prolapse

with or without regurgitation and involvement of both

Expansion of the pulmonary artery in the absence of

minimum of the sinuses of Valsalva; or

valvular or peripheral pulmonary stenosis or

Ascending aortic dissection

any other obvious cause, under the age of 40;

* Estimation of the degree of expansion is carried out taking into account

Calcification of the mitral ring before the age of 40;

age and body surface area

Expansion or stratification

chest or abdominal wall

according to nomograms (see Appendix 1)

aorta under the age of 50

The cardiovascular system is involved if one major or one minor criterion is met

Pulmonary system

Missing

Spontaneous pneumothorax

Apical bullae confirmed by x-ray

chest

local mechanical action

Recurrent or incisional hernias

The skin is involved if one minor sign is found

Dura mater

lumbosacral dural ectasia,

Missing

identified by CT or MRI**

Burdened heredity

relatives,

Missing

satisfy

diagnostic

criteria;

mutations in FBN1,

famous

as

causes of Marfan's syndrome; or

the presence of DNA markers of Marfan syndrome

Involvement in the presence of one big sign

Requirements for the diagnosis of SM differ depending on the data of hereditary history.

For the examined patient:

If the family or hereditary history is not burdened, SM is established in the presence of large criteria in at least two different systems and the involvement of a third organ system.

In the case of establishing a mutation that is known to cause SM in others, one large criterion in one organ system and the involvement of a second organ system is sufficient.

For persons who are related to a patient diagnosed with Marfan syndrome, the presence of a large criterion in the family history, as well as one large criterion in one organ system and involvement of another organ system, is sufficient.

If the Ghent criteria for the diagnosis of SM are met, a molecular genetic study should be performed to search for mutations in the genes encoding fibrillin.

From the standpoint of formal logic, in the case when the subject lacks two major criteria in two systems and signs of involvement of the third system, the diagnosis of SM cannot be made. However, a recent international study of 1009 patients with a genetically confirmed fibrillin gene mutation showed that the risk of complications (aortic dissection and the need for surgical intervention) in persons with an incomplete set of Ghent criteria is practically the same as in the group of persons with a complete set of criteria (Faivre L et al., 2008).

It follows from the above that many patients who do not meet the Ghent criteria require no less attention and medical supervision. Obviously, such patients cannot be attributed to the group of healthy individuals and pronounced deviations in the structure and function of the connective tissue, identified during the examination in this category of patients, should be designated as marfan-like phenotype (MPF). In addition to SM, the authors of the Ghent criteria identify HHSTs that are similar in phenotypic manifestations.

Inherited disorders with overlapping phenotypes related to Marfan syndrome

Congenital contracture arachnodactyly (121050)

Familial aneurysm of the thoracic aorta (in the past, this condition was called Erdheim's cystic medionecrosis). (OMIM 607086)

Familial dissection of the aortic wall (132900)

Familial ectopic lens (129600)

Loeys-Dietz syndrome, (type 2B; LDS2B) 610380

MASS - Syndrome 604308

Hereditary mitral valve prolapse syndrome(OMIM 157700)

Stickler syndrome (hereditary arthro-ophthalmopathy) (108300)

Shprintzen-Goldberg Syndrome (182212)

Homocystinuria (OMIM 236200)

Ehlers-Danlos syndrome (kyphoscoliotic type) (kyphoscoliotic type, OMIM 225400; hypermobility type, OMIM 130020)

Joint Hypermobility Syndrome (OMIM 147900).