Chernogubov-Ehlers-Danlos syndrome (hyperelastic skin): causes, symptoms, diagnosis, treatment

Chernogubov-Ehlers-Danlos Syndrome (syn. Hyperelastic skin) is a heterogeneous group of hereditary connective tissue diseases characterized by a number of common clinical signs and similar morphological changes. The main clinical manifestations are excessive skin plasticity, increased joint mobility, frequent subluxations, increased skin vulnerability, fragility of blood vessels with development of hemorrhages, hematomas with the slightest trauma.

This syndrome includes 10 types of the disease, which differ in inheritance, genetic defect and clinical picture: I - classical heavy; II - soft; III - benign hypermobile; IV - zikhimotic (gene locus 2q31); V - X-linked recessive; VI ocular (gene locus 1p36.3-p36.2); VII - congenital multiple arthrochalasis - gene locus 7q22.10; VIII - with periodontitis; IX - is excluded from the classification of Chernogubov-Ehlers-Danlos syndrome, is designated as an X-spangled variant of flaccid skin; X - dysfibronectinemic; XI - family instability of joints. In some forms of the disease, a primary biochemical defect is assumed or revealed: type I decreases the activity of fibroblasts, enhances the synthesis of proteoglycans by them, possibly the absence of enzymes that control the normal synthesis of collagen; at type IV - insufficiency of production III type of collagen; at type VI - insufficiency of lysyl hydroxylase; at VII type - a pathological change in the conversion of type I procollagen into collagen; at IX type - insufficiency of lysiloxylase due to impaired metabolism of copper; at X type - pathological function of plasma fibronectin. A violation of hyaluronic acid / proteoglycan ratio with a significant increase in hyaluronic acid content is possible. Increased bleeding is due to changes in the collagen of the vascular system and a violation of the functional state of thrombocytes.

Pathomorphology. The histological picture of all types of Chernogubov-Ehlers-Danlos syndrome is similar. The main histological sign is thinning of the dermis. In this case, the collagen fibers look normal, do not lose their tinctorial properties. The number of elastic fibers is relatively increased. The number of vessels is sometimes increased and their lumens are enlarged, around them are accumulations of fibroblasts and histiocytes.

I type of syndrome - classic heavy - occurs most often, it accounts for up to 43% of all cases. All the above signs of the disease are well pronounced, but especially the hyperelasticity of the skin. Skin stretch is increased by 100-150% compared to the norm. The type of inheritance is autosomal dominant, although cases and a recessive type of inheritance are described. Increased joint mobility is generalized, musculoskeletal deformations often develop, scarring at the site of injuries, especially visible on the forehead, elbows, knees and ankles. There is a strong vulnerability of the skin with a tendency to bleeding, poor healing of wounds. There are subcutaneous tumor-like elements, mainly in the region of the shins, mollusciform pseudotumors and varicose veins. Pregnant women with this disease often have premature births as a result of rupture of membranes.

Pathomorphology. The thinning of the dermis is expressed approximately (approximately half). The dimensions of the bundles of collagen fibers are not the same, their orientation is disturbed due to looseness of fiber arrangement in the bundles, their refraction in transmitted light is reduced. Scanning electron microscopy revealed a violation of their orientation, interlacing in the form of felt, loss of compactness of the structure, thickening. Transmissionmicroscopy revealed an increase in the average diameter of collagen fibers, irregularity in the size and shape of fibrils in transverse sections, the presence of individual giant fibrils, sometimes split into individual microfibrils. Fibers are often twisted along the axis, however the normal periodicity is preserved. There are dystrophic changes in fibroblasts in the form of a decrease in their size, the number of cytoplasmic outgrowths, weak development of the endoplasmic reticulum, and vacuolization of the cytoplasm. Similar changes in collagen fibers cause excessive stretchability of the skin. It is believed that the breakdown of the structure of fibrils occurs at the stage of their aggregation and the formation of cross-links, which can be due to both a violation of the enzymatic regulation of fibrin synthesis, and changes in the composition of the components of the basic dermis substance that modulate the synthesis.

II type of syndrome - the so-called mild type, is characterized by the same signs as heavy, but much less pronounced. Skin stretching is increased only by 30% compared to the norm. Increased mobility can be noted only in the joints of the hands and feet, the formation of scarring and the tendency to bleed are poorly expressed.

Pathomorphology. The thickness of the dermis is close to normal. Scanning electron microscopy revealed a decrease in the thickness of collagen fibers, and in the transmission electron microscopy, a significant amount of collagen fibers with broken ends, although their structure looks normal, single fibrils of large diameter are found.

III type of syndrome - benign hypermobile, is also inherited autosomal dominantly. The main clinical feature is increased mobility of joints, which is of generalized nature ("snake man"), which is why orthopedic complications and deformations of the skeleton are frequent. Hyperelasticity of the skin is poorly expressed, the formation of scars, as well as increased fragility of the vessels, are expressed minimally.

Pathomorphology. The histological picture of the skin is close to normal, electron microscopy shows changes similar to those of types I and II of the syndrome, but less pronounced - there are no giant collagen fibers and rarely find changes in fibrils.

The presented data testify to the proximity of the clinical and morphological parameters of the first three types of the Chernogubov-Ehlers-Danlo syndrome, which allows one to join the opinion of their common nature.

IV type of syndrome is an ecchymotic, the most rare and severe. It is established that this type is genetically heterogeneous, described both dominantly and recessively inherited variants. Skin manifestations are similar in all variants. Hyperelasticity of the skin can be minimal. Characteristic appearance of the patient: thin features, large eyes, thin nose, early formation of wrinkles on the face and extremities (acroheria). Skin thin and pale with translucent subcutaneous vessels, to the touch soft and velvety, brushes noticeably atrophic. In the area of the bony projections, thin, pigmented scars are visible, distinguishing this type of syndrome from the others. Excessive mobility of the joints is limited to the fingers. The main clinical sign of this type is the tendency to bleeding. Patients easily develop ecchymosis, often extensive with minor trauma, and spontaneously formed hematomas, especially on the limbs and internal organs. In some cases, there are ruptures of large vessels, including the aorta. Sometimes the patients show hernia of the digestive tract, prolapse of the rectum, spontaneous ruptures of the hollow organs.

The complicated course is more characteristic for the recessive variant of the syndrome, the dominant one proceeds less severely. Due to the possibility of complications such as aortic and hollow organ ruptures, which usually occur in the third decade of life and lead to death, it is necessary to have a timely genetic consultation and antenatal diagnosis of this disease.

Pathomorphology. The thickness of the skin with type IV of this syndrome is reduced by 2/3. With electron microscopic examination it was found that bundles of collagen fibers are smaller than normal, fragmented. The thickness of collagen fibrils is uneven, more often than normal, a large number of fibrils with a diameter of 60 nm are noted. In the main substance of the dermis, there are accumulations of fine granular and fibrous substances, proteoglycans. The sharply expanded endoplasmic fibroblast network contains fine granular substances. In studies using electrophoretic and peptide analysis using bromesium collagen splitting, it was found that in the skin of patients, type III of collagen is contained in significantly fewer amounts than in the norm. The defeat of the skin and joints is mainly due to a decrease in the content of type I collagen, which normally prevails in them. The peculiarity of the IV type of Chernogubov-Ehlers-Danlos syndrome is associated with a defect of type III collagen, whose content relative to type I collagen in the vessels and organs of the digestive tract is much higher than in the skin.

V type of syndrome - X-linked recessive, characterized by more pronounced hyperelasticity of the skin compared to other types, while hypermobility of the joints is small. The tendency to the formation of ecchymoses and the fragility of the skin are expressed moderately.

Pathomorphology. Electron microscopic examination of the skin revealed a similarity of changes with those of type I syndrome. Biochemically, in one case, a defect of lysinoxidase, an enzyme involved in the aggregation of collagen microfibrils and the formation of cross-links connecting microfibrils and collagen fibrils outside the cell, was detected. In other cases, this defect was not detected.

VI type of syndrome - ocular, is inherited by autosomal recessive type. With this type of hyperelasticity of the skin, a tendency to bleeding, mobility of the joints, there is a low growth of patients. Usually, there are deformations of the skeleton in the form of clubfoot, severe kyphoscoliosis, muscle weakness. A defect in the structure of the connective tissue of the eyes leads to myopia, keratoconus, microcorrhage, glaucoma, retinal detachment, fragility of the sclera and cornea with the possibility of their rupture. An inadequate production of hydroxylizine was found, and a defect or mutation of lysine hydroxylase, an enzyme that performs hydroxylation of lysine in the intracellular phase of collagen biosynthesis, during the formation of a triple helix from polypeptide pro-a chains is assumed. A simultaneous decrease in the ratio of collagen III and I types is described, which suggests heterogeneity of type VI syndrome.

VII type of syndrome - congenital multiple arthrochalasis, inherited by autosomal recessive type and autosomal dominant. The main clinical manifestation is the hyperplasticity of joints with frequent habitual dislocations, which brings it closer to type III syndrome. In the dermis, the accumulation of procollagen is expressed. Defect procollagen peptidase - an enzyme that cleaves end peptides of protofibrils secreted by fibroblasts during the formation of microfibrils.

VIII type of syndrome - with severe periodontitis, is inherited autosomal dominant, although there is an indication of an autosomal recessive type of inheritance. Skin is fragile, moderate hypermobility of the joints, mild hyperextension and increased bleeding of the skin, changes in skin as lipoid necrobiosis, severe periodontitis with early loss of teeth.

X type of syndrome is inherited autosomally-recessively. Clinically, there is moderate hyperelasticity and increased mobility of joints, banded atrophy of the skin (stretch striae). A violation of platelet aggregation was associated with a quantitative or qualitative defect in fibronectin, possibly its a-granules contained in platelets.

XI type of the syndrome is inherited autosomal dominant, it is clinically characterized by recurrent dislocations of the joints, mainly shoulder, dislocation of the patella, and congenital hip dislocation is less common. Skin symptoms are poorly expressed. A biochemical defect is a violation of the function of fibronectin of the blood plasma.

Histogenesis. At the heart of the clinical manifestations of the Chernogubov-Ehlers-Danlos syndrome lies the violation of the structure of collagen fibrils. The ability of fibers to stretch is associated with the formation of covalent cross-links between microfibrils, and also depends on the size and integrity of the fiber bundles. Morphological disorders are manifested by the cleavage of individual fibrils, unevenness of their diameter, and changes in the density of fibrils in the fibers. The defect of the formation of transverse bonds is, apparently, for all types of syndrome. Their formation is the final stage of collagen biosynthesis, and the defect of any biosynthetic link may lead to the formation of defective fibers. To date, some defects are already known - deficiency of lysinoxidase in type V, lysine hydroxylase - with VI, procollagenpeptidase - with VII. Metabolic disorders are not always associated with defects in collagen biosynthesis enzymes, they can be caused by microenvironment factors, a certain composition of which provides normal biosynthesis.

The manifestations of the syndrome are very diverse, and it is not always clinically possible to determine the type of the syndrome. Clinical variability appears to be related to the heterogeneity of collagen. Thus, in the IV type of syndrome, insufficient production of type III collagen was detected, with type IV morphological changes of type I collagen. Biochemical and morphological determination of other types of collagen (currently isolated 7 different types of it) in the Cherno-Gubov-Ehlers-Danlos syndrome were not performed.