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, vascular fragility with the development of hemorrhages, hematomas with the slightest trauma.

This syndrome includes 10 types of the disease, differing in inheritance, genetic defect and clinical picture: I - classic severe; II - mild; III - benign hypermobile; IV - ecchymotic (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 periodontosis; IX - excluded from the classification of Chernogubov-Ehlers-Danlos syndrome, designated as X-linked variant of flaccid skin; X - dysfibronectinemic; XI - familial joint instability. In some forms of the disease, a primary biochemical defect is suspected or identified: in type I - decreased fibroblast activity, increased synthesis of proteoglycans by them, possible absence of enzymes that control normal collagen synthesis; in type IV - insufficient production of type III collagen; in type VI - lysyl hydroxylase deficiency; in type VII - pathological change in the conversion of type I procollagen to collagen; in type IX - lysyl hydroxylase deficiency due to impaired copper metabolism; in type X - pathological function of plasma fibronectin. Possible disturbance of the hyaluronic acid/proteoglycan ratio with a significant increase in the hyaluronic acid content. Increased bleeding is explained by changes in the collagen of the vascular system and impaired functional state of platelets.

Pathomorphology. The histological picture of all types of Chernogubov-Ehlers-Danlos syndrome is similar. The main histological sign is thinning of the dermis. At the same time, collagen fibers look normal and 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 widened, with fibroblast and histiocyte clusters around them.

Type I syndrome - classical severe - is the most common, accounting for up to 43% of all cases. All the above-mentioned signs of the disease are well expressed, but especially hyperelasticity of the skin. Skin extensibility is increased by 100-150% compared to the norm. The type of inheritance is autosomal dominant, although cases of recessive inheritance have also been described. Increased joint mobility is generalized, musculoskeletal deformities often develop, scarring is characteristic at the site of injury, especially noticeable on the forehead, elbows, knees and ankles. Severe skin vulnerability with a tendency to bleeding, poor wound healing are noted. Subcutaneous tumor-like elements are encountered, mainly in the shin area, molluscum-like pseudotumors and varicose veins. In pregnant women with this disease, premature birth is common as a result of rupture of the membranes.

Pathomorphology. Thinning of the dermis is pronounced (approximately by half). The sizes of collagen fiber bundles are uneven, their orientation is disrupted due to the loose arrangement of fibers in the bundles, their refraction in transmitted light is reduced. Scanning electron microscopy revealed a disruption of their orientation, felt-like interweaving, loss of compactness of the structure, thickening. Transmission microscopy revealed an increase in the average diameter of collagen fibers, unevenness of the size and shape of fibrils in cross sections, the presence of individual giant fibrils, sometimes split into individual microfibrils. The fibers are often twisted along the axis, but normal periodicity is preserved. Dystrophic changes in fibroblasts are noted in the form of a decrease in their size, the number of cytoplasmic outgrowths, poor development of the endoplasmic reticulum and vacuolization of the cytoplasm. Such changes in collagen fibers cause excessive extensibility of the skin. It is believed that the disruption of the structure of fibrils occurs at the stage of their aggregation and formation of cross-links, which may be due to both a disruption of the enzymatic regulation of fibrin synthesis and changes in the composition of the components of the main substance of the dermis that modulate synthesis.

Type II syndrome - the so-called mild type, is characterized by the same signs as the severe type, but significantly less pronounced. Skin extensibility is increased by only 30% compared to the norm. Increased mobility can be noted only in the joints of the hands and feet, scar formation and tendency to bleeding are weakly expressed.

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

Type III syndrome - benign hypermobility, also inherited autosomal dominantly. The main clinical feature is increased joint mobility, which is generalized ("snake man"), due to which orthopedic complications and skeletal deformities are frequent. Skin hyperelasticity is weakly expressed, scar formation, as well as increased vascular fragility, are expressed minimally.

Pathomorphology. The histological picture of the skin is close to normal, electron microscopy revealed changes similar to those in types I and II of the syndrome, but expressed to a lesser degree - giant collagen fibers are absent and fibril changes are rarely found.

The presented data indicate the similarity of the clinical and morphological parameters of the first three types of Chernogubov-Ehlers-Danlos syndrome, which allows us to agree with the opinion about their common nature.

Type IV syndrome is ecchymotic, the rarest and most severe. It has been established that this type is genetically heterogeneous, both dominantly and recessively inherited variants have been described. Skin manifestations are similar in all variants. Skin hyperelasticity may be minimal. The patient's appearance is characteristic: fine facial features, large eyes, thin nose, early formation of wrinkles on the face and limbs (acrogeria). The skin is thin and pale with translucent subcutaneous vessels, soft and velvety to the touch, noticeably atrophic on the hands. Thin, pigmented scars are visible in the area of bone protrusions, distinguishing this type of syndrome from others. Excessive joint mobility is limited to the fingers. The main clinical sign of this type is a tendency to bleeding. Patients easily develop ecchymoses, often extensive with the slightest injury, and hematomas spontaneously form, especially on the limbs and in the internal organs. In some cases, ruptures of large vessels, including the aorta, are observed. Sometimes patients are found to have hernias of the digestive tract, prolapse of the rectum, spontaneous ruptures of hollow organs.

A complicated course is more typical for the recessive variant of the syndrome, the dominant one is less severe. Due to the possibility of complications such as ruptures of the aorta and hollow organs, which usually occur in the third decade of life and lead to death, timely genetic consultation and antenatal diagnostics of this disease are necessary.

Pathomorphology. The thickness of the skin in type IV of this syndrome is reduced by 2/3. Electron microscopic examination revealed that the bundles of collagen fibers are smaller than normal and fragmented. The thickness of collagen fibrils is uneven, often smaller than normal, with a large number of fibrils with a diameter of 60 nm. In the main substance of the dermis, there are clusters of fine-grained and fibrous substances, proteoglycans. The sharply expanded endoplasmic reticulum of fibroblasts contains fine-grained substances. When studying by electrophoretic and peptide analysis methods using collagen cleavage with bromine cyanide, it was found that the skin of patients with type III collagen contains significantly smaller amounts compared to the norm. Skin and joint damage is associated mainly with a decrease in the content of type I collagen, which is normally predominant in them. The peculiarity of type IV Chernogubov-Ehlers-Danlos syndrome is associated with a defect in type III collagen, the content of which, in relation to type I collagen, in the vessels and organs of the digestive tract is significantly higher than in the skin.

Type V syndrome - X-linked recessive, characterized by more pronounced hyperelasticity of the skin compared to other types, while joint hypermobility is slight. The tendency to form ecchymosis and skin fragility are moderately expressed.

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

Type VI syndrome is ocular and is inherited in an autosomal recessive manner. This type is characterized by hyperelasticity of the skin, tendency to bleeding, joint mobility, and short stature of patients. Skeletal deformities such as clubfoot, severe kyphoscoliosis, and muscle weakness are usually present. A defect in the structure of the connective tissue of the eyes leads to myopia, keratoconus, microcornea, glaucoma, retinal detachment, fragility of the sclera and cornea with the possibility of their rupture. Insufficient production of hydroxylysine has been detected, and a defect or mutation of lysine hydroxylase, an enzyme that hydroxylates 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 types III and I has been described, which suggests heterogeneity of type VI syndrome.

Type VII syndrome - congenital multiple arthrochalasis, inherited in an autosomal recessive and autosomal dominant manner. The main clinical manifestation is hypermobility of joints with frequent habitual dislocations, which brings it closer to type III syndrome. Accumulation of procollagen is expressed in the dermis. A defect of procollagen peptidase was found - an enzyme that cleaves the terminal peptides of protofibrils secreted by fibroblasts during the formation of microfibrils.

Type VIII syndrome - with severe periodontosis, inherited autosomal dominantly, although there is also an indication of an autosomal recessive type of inheritance. The skin is fragile, moderate hypermobility of joints, mild hyperextensibility and increased bleeding of the skin, skin changes of the lipoid necrobiosis type, severe periodontosis with early tooth loss are noted.

Type X syndrome is inherited in an autosomal recessive manner. Clinically, there is moderate hyperelasticity and increased mobility of the joints, strip-like atrophy of the skin (stretch marks). A violation of platelet aggregation associated with a quantitative or qualitative defect in fibronectin, possibly its a-granules contained in platelets, has been revealed.

Type XI syndrome is inherited in an autosomal dominant manner, clinically characterized by recurrent joint dislocations, mainly shoulder dislocations, patellar dislocations are common, and congenital hip dislocation is observed less frequently. Skin symptoms are weakly expressed. The biochemical defect consists of a violation of the function of plasma fibronectin.

Histogenesis. The clinical manifestations of Chernogubov-Ehlers-Danlos syndrome are based on a disorder of the collagen fibril structure. 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 fiber bundles. Morphological disorders are manifested by the splitting of individual fibrils, unevenness of their diameter and changes in the density of fibrils in the fibers. A defect in the formation of cross-links is apparently present in all types of the syndrome. Their formation is the final stage of collagen biosynthesis, and a defect in any link in the biosynthesis can lead to the formation of defective fibers. Some defects are already known by now - lysine oxidase deficiency in type V, lysine hydroxylase - in VI, procollagen peptidase - in VII. Metabolic disorders are not always associated with defects in collagen biosynthesis enzymes; they can be caused by factors of the microenvironment, a certain composition of which ensures normal biosynthesis.

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