Bullous epidermolysis: causes, symptoms, diagnosis, treatment

Congenital bullous epidermolysis (synovial pemphigus) is a heterogeneous troupe of genetically determined diseases, among which there are both dominant and recessively inherited forms. Thus, simple bullous epidermolysis is inherited autosomally dominant, mutations of genes encoding the expression of keratin 5 (12q) and 14 (17q) are revealed, autosomal recessive type of transmission is possible; dystrophic variant of Kokkein-Turen - autosomal dominant, mutation in the gene of type VII collagen, chromosome Sp21; Recessive dystrophic bullous epidermolysis is inherited autosomally recessively, a mutation in the gene of type VII collagen, chromosome Sp; border bullous epidermolysis - according to the autosomal recessive type, a mutation in one of the three genes encoding the components of the laminin-5 protein is assumed; Inverse congenital bullous epidermolysis is inherited by autosomal recessive.

Common to all forms of the disease is the early occurrence of clinical manifestations (from birth or early days of life) in the form of blisters on the site of the slightest mechanical trauma (pressure and friction) of the skin. On the basis of such a clinical sign as the presence or absence of scars in the field of resolution of blisters, congenital bullous epidermolysis is divided into two groups: simple and dystrophic, or, at the suggestion of R. Pearson (1962), to scarring and non-scaring bullous epidermolysis.

The pathomorphology of different disease groups is similar. There are subepidermal blisters, a small inflammatory reaction in the dermis. Subepidermal location of the blisters can be detected only in fresh (several hours) elements or in skin biopsy specimens obtained after friction. In older elements, blisters due to the regeneration of the epidermis are located intraepidermally, so histological diagnosis is difficult. Examination of biopsy specimens in a light microscope with normal coloration gives only an approximate diagnosis, an indication that the disease is bullous epidermolysis. The use of histochemical methods for the purpose of coloring the epidermal basement membrane makes it possible to determine more precisely the localization of the bladder - above the basal membrane or below it. Clinically, this division corresponds to simple bullous epidermolysis in the supra-basal arrangement of the bladder and dystrophic - with its sub-basal localization. However, when using histochemical methods, diagnostic errors are not uncommon. So, in 8 cases of simple bullous epidermolysis, described by LH Buchbinder et al. (1986), a histological pattern consistent with dystrophic bullous epidermolysis.

Only the introduction into practice of electron microscopy allowed to clarify the mechanism and place of the formation of blisters, as well as to study in more detail the morphological disorders in various forms of the disease. According to electron microscopy, this disease is divided into three groups: epidermolytic if the formation of blisters occurs at the level of basal epitheliocytes; border if the blisters are at the level of the light plate of the basal membrane, and dermolitic if the blisters are formed between the dense plate of the basal membrane and the dermis. Taking into account the clinical picture and the type of inheritance, in each group, several more forms are singled out, which significantly expands the classification. The immuno-fluorescent methods used to diagnose congenital bullous epidermolysis are based on the selective localization of the structural components of the basal membrane-the bullous pemphigoid (BPA) antigen and laminin in the light plate, type IV collagen and KF-1 antigens in a dense plate, AF-1 and AF -2 in the fixing fibrils, LDA-1 antigen in the dense plate of the basal membrane and the area beneath it. Thus, with the direct reaction of immunofluorescence in cases of simple bullous epidermolysis, when the cleavage occurs above the basal membrane, all antigens are located at the base of the bladder, with the boundary forms occurring in the region of the light plate of the basal membrane, therefore BPA is localized in the bladder cover, laminin at the base his or the cover, type IV collagen and LDA-1 - at the base of the bladder, and with the dystrophic form of bullous epidermolysis, all the antigens are in the blister cap. From the biochemical methods of diagnosing bullous epidermolysis, only the determination of collagenase is currently used, since it is established that its quantity is increased in the skin with borderline and recessive dystrophic forms and has not been altered with simple and dominant dystrophic bullous epidermolysis.

The epidermolithic (intraepidermal) group of bullous epidermolysis includes the most common form - a simple bullous epidermolysis of Kebner inherited by autosomal dominant. Bubbles on the skin appear from birth or in the first days of life in the most traumatized places (brushes, feet, knees, elbows), then spread to other areas. They are single-chambered and have a different value. After opening the blisters, the healing takes place quickly and without scarring. Bubbles often appear with increased external temperature, so exacerbation occurs in the spring and summer, often accompanied by hyperhidrosis. Often the mucous membranes are involved in the process. During puberty, there is sometimes an improvement. A combination with palmar-laden keratoderma is described and its development after the resolution of blisters.

Electron microscopic examination reveals cytolysis of basal epitheliocytes. Their tonofilaments in some cases form clumps in the form of clumps, more often around the nucleus or near the hemodesmosomes, which leads to insufficiency of the cytoskeleton of the cells and cytolysis in the slightest trauma. The lining of the resulting bladder is represented by destroyed basal epitheliocytes, and the base by the remnants of their cytoplasm. In this case, the hemidesmosomes, basal membrane, fixing fibrils and collagen fibers under it remain intact. The defect of tonofilamentes resembles that of bullous congenital ichthyosiform erythroderma, but differs in the location of altered epithelial cells. The histogenesis of this form of bullous epidermolysis has not been sufficiently studied.

The easiest form of simple bullous epidermolysis is Weber-Cockaine syndrome, inherited autosomal dominant. With this form, the blisters appear from birth or at an early age, but localize on hands and feet and appear mainly in the warm season, often combined with various ectodermal dysplasias: partial absence of teeth, diffuse baldness, abnormalities of the nail plates.

Examining the ultrastructure of the skin in lesions, E. Naneke and I. Anton-Lamprecht (I982) found that cytolysis of basal epithelial cells occurs without altering the tonofilament. Scale epitheliocytes are large, contain bundles of tonofilament instead of keratin, possibly, their appearance is associated with damage to basal epitheliocytes, which did not die, but develop further. With repeated injuries, these cells undergo cytolysis.

It is assumed that the cause of cytolysis is a genetically determined, temperature-dependent lability of the gel state of the cytosol, as well as cytolytic enzymes, although the lysosomes in the epithelial cells have a normal structure.

Herpetiform simple bullous epidermolysis of Dowling-Mehara inherited autosomally dominant, differs in severe course, appears from birth or from the first days of life. Clinically characterized by the development of grouped generalized blisters of the herpetiform type with a pronounced inflammatory response. Healing of foci occurs from the center to the periphery, in their place remain pigmentation and milium. Frequent lesions of nails, mucous membranes of the mouth and esophagus, anomalies of the teeth, palmar-plantar keratoses. In some patients, repeated blistering leads to flexion contractures.

In the histological examination of the skin in the herpetiform simple bullous epidermolysis of Dowling-Meare in the dermal infiltrate and the cavity of the bladder, a large number of eosinophilic granulocytes are found, which gives the disease a resemblance to herpetiform dermatitis. Critical in diagnosis are immunomorphological and electron microscopic studies. The electron microscopy data for this form of bullous epidermolysis differ little from those already described in the case of simple bullous epidermolysis of Kebner.

Cases of recessive inheritance of simple bullous epidermolysis are described. M.A.M. Salih et al. (1985) call recessive simple bullous epidermolysis lethal due to severe course, often fatal. The clinical picture of the patients described by them differs little from that of the simple bullous epidermolysis of Kebner. The disease is complicated by anemia; the lethal outcome comes, probably, from asphyxiation of the detached mucosa from the affected parts of the pharynx and esophagus and septicemia. In the case described by K.M. Niemi et al. (1988), atrophic scars appeared at the sites of rashes, anodontia, anonichia, muscular dystrophy were observed. In all cases of recessive inheritance of simple bullous epidermolysis, cytolysis of basal epitheliocytes was electron microscopically detected.

To the group of simple bullous epidermolysis also include bullous epidermolysis of Ogna, in which, in addition to blistering rashes, multiple hemorrhages and onychography, and bullous epidermolysis with mottled pigmentation are noted. Pigmentation exists from birth, at 2-3 years of age there are focal palmar-plantar keratoderma and warty keratosis on the skin of the knees, in adults the resolution of all manifestations of keratosis is noted, in places where the elastosis and skin atrophy are not clearly expressed.

The basis of the borderline group of congenital bullous epidermolysis is the most severe form - the lethal generalized bullous epidermolysis of Gerlitz, inherited in an autosomal recessive type. A child is born with numerous blisters formed as a result of friction during passage through the birth canal. They, in addition, may appear in the first hours of the child's life. The favorite localization of lesions is the tips of the fingers, the trunk, the lower leg, the buttocks, the mucous membrane of the oral cavity, where there are numerous erosions. Often the intestine is affected. Bubble rashes quickly spread. Healing of erosions in the place of the opened blisters occurs slowly, thus the scars do not develop, but there is a superficial atrophy of a skin. Most patients die in the first months of life. The most frequent cause of death is acute sepsis. Survivors have extensive lesions of the skin, mucous membranes of the oral cavity, digestive tract, granulation around the mouth, dystrophic changes of the nail plates, including onycholysis with peri-oedemal erosions, covered with crusts, after the healing of which the anonichia develops. There are changes in the teeth: an increase in their size, a discoloration, early caries, on permanent teeth often there is no enamel. From dystrophic bullous epidermolysis, lethal differs from lesions of the hands only in the region of terminal phalanges, absence of primary scar formation (excluding cases of secondary infection), ulcerative lesions existing from birth, fusion of fingers and formation of synechia, a rare milium.

For a histological examination, a biopsy of the edge of the bladder should be taken, but the peeled epidermis of fresh blisters can also be used, which is especially important when performing morphological examination of the skin of newborns. Separation of the epidermis from the dermis in this case occurs at the level of the light plate of the basal membrane of the epidermis located between the basal epitheliocytes and the dense plate of the basal membrane. At this point, the fixing tonofilaments are damaged, the half-desmosomes to which they attach are absent in the zone of the bladder. In other areas, their rarefaction and hypoplasia are noted; disks of attachment in the cytoplasm of basal epitheliocytes are preserved, and dense disks located extracellularly are absent. Bubble cover is the unaltered cell membrane of basal epitheliocytes, and the bottom is a dense plate of the basal membrane of the epidermis. In the dermis, there are edema and minor dystrophic changes in the collagen fibers of the papillary layer. Hypoplasia of desmosomes is a universal structural defect that develops not only in the bubble formation zone, but also in unchanged skin, which makes possible an antenatal diagnosis of this disease.

In the group of boundary bullous epidermolysis, benign generalized atrophic bullous epidermolysis, localized atrimic, inverse and progressive bullous epidermolysis, differing from the lethal nature of the course and the location of the rashes are also isolated. With all types of borderline bullous epidermolysis histological changes are the same. Electron microscopy revealed that in non-lethal forms, dense disks of hemidesmosomes were partially preserved, and half-desmosomes were rarefied.

The dermolytic group includes dominant and recessive varieties of dystrophic bullous epidermolysis.

Dystrophic bullous epidermolysis of Kokkein-Turena is inherited autosomally dominant, blisters appear from birth or in early childhood, rarely later, are localized primarily on the skin of the limbs and forehead. At the sites of the blisters develop atrophic scars, milium. In patients, the mucous membrane of the oral cavity, esophagus, pharynx, larynx is affected, keratosis of the palms and soles, follicular keratosis, dystrophy of the teeth, nails (up to the anoxia), hair thinning, generalized hypertrichosis. The recessive form is characterized by a less severe lesion of the internal organs, eyes and mainly the absence of gross scars leading to mutation.

Dystrophic white-populoid bullous epidermolysis Pazini is also inherited autosomal dominant, characterized by the presence of small white papules, dense, ivory, round or oval, slightly elevated with a slightly corrugated surface, underlined follicular pattern, well-delimited from the surrounding tissue. Papules are localized more often on the trunk, in the lumbar region and on the shoulders, regardless of the bubble rashes, appear usually in adolescence.

Pathomorphology. With dystrophic bullous epidermolysis of Coccayne-Turena, the bubble is located under the epidermis, its cover is a somewhat thinned epidermis with hyperkeratosis phenomena without special changes in the Malpighian layer. In the derma in the region of the bladder, small perivascular infiltrates of a lymphocytic character with an admixture of histiocytes and eosinophilic granulocytes are noted. Characteristic of the absence of elastic fibers in the papillate and some parts of the mesh layer of the dermis. In electron-microscopic examination, the rarefaction and changes in the structure of the fixing fibrils are revealed in the region of the blisters and in the unchanged skin near the blisters in both forms of dominant bullous epidermolysis, which is manifested in their thinning, shortening and loss of transverse striation (rudimentary forms). With Pasini's white epidemolipid epidermolysis, similar changes were found in clinically healthy skin, in areas where blisters never appeared, and in dystrophic bullous epidermolysis of Coccayne-Touraine, the fixing fibrils in these places were normal or thinned, their amount did not differ from the norm or was reduced. However, in one case, their absence is described. In both forms of phenomena, collagenolysis in the dermis was not detected.

Recessive forms of dystrophic bullous epidermolysis refer to the most severe genodermatosis. They are characterized by extensive formation of blisters with the subsequent appearance in their place of deep, poorly healing erosions and the formation of scars.

Allopo-Siemens dystrophic bullous epidermolysis is the most severe form in this group. The clinical picture is manifested from birth, characterized by generalized eruptions of blisters, often with hemorrhagic contents, which can be located in any area of the skin, but most often in the area of hands and feet, elbows and knee joints. Bubbles occur at the slightest mechanical trauma, with their healing, miliums and extensive scars are formed. Cicatricial changes can be observed in early childhood on the mucous membranes of the digestive and genito-urinary tracts. In the battle against scarring, contractures, fusion of fingers, mutation of terminal phalanges are formed with their full fixation. After their surgical correction, relapses often occur. The defeat of the mucous membrane of the oral cavity is accompanied by the development of the microstoma, the shortening of the frenum of the tongue, the fusion of the mucous membrane of the tongue and cheeks. The defeat of the esophagus is complicated by strictures and stenoses causing obstruction. A very serious complication is the development of cancerous tumors on the scars, sometimes multiple. There are bone lesions (acroosteolysis, osteoporosis, bone and hand bone dystrophy), delayed cartilage development. Often there are abnormalities of the teeth, anonichia, alopecia, eye damage (keratitis, conjunctivitis, synblepharon, ectropion), growth retardation, anemia, skin infections.

Pathomorphology. The main morphological features of recessive dystrophic bullous epidermolysis are changes in the fixing fibrils and collagen fibers of the upper dermis. The basal membrane remains intact and forms a bubble cap. The absence of fibrils in the lesion in the lesion and in the externally unchanged skin marked RA Briggaman and CE. Wheeler (1975), their rudimentary nature in unaffected skin - I. Hashimoto et al. (1976). Collagen fibers in the bladder zone have fuzzy contours or are absent (collagenolysis). When the bladder forms, focal dissolution of collagen occurs. At the same time, phagocytic activity increases in the dermis, phagocytosis of individual collagen fibers of large diameter, which are found in the bundles among fibers of ordinary diameter, is noted.

Histogenesis. There are two points of view on the histogenesis of changes in recessive bullous epidermolysis: according to one of them, the primary process of the fixing fibrils lies at the base of the process, the other is the development of collagenolysis primarily. In favor of the first assumption is the presence of the pathology of the fixing fibrils in the externally unchanged skin, where there is no collagenolysis. In favor of the second, there are data on the origin of collagenolysis foci with preserved fixing fibrils in the initial stage of the formation of the bladder in friction, as well as data on their preservation in the skin explant, cultured with the derma extract of the patient with recessive bullous epidermolysis. The assumption of R. Pearson (1962) on the presence of collagenolysis in this form of bullous epidermolysis was confirmed by the detection of increased activity of collagenase, and then by data on the excessive production of fibroblasts by biochemically and immunologically altered collagenase. Some authors believe that the increase in collagenase activity is secondary. It should be noted that the formation of blisters in recessive bullous epidermolysis is associated not only with the processes of collagenolysis, but also with the action of other enzymes. Thus, the contents of the patient's bladder induce the formation of subepidermal blisters in the normal skin of a healthy person. Obviously, the bubble contains substances that lead to the separation of the epidermis from the dermis. In the skin and the vesicle fluid, the activity of collagenase and neutral protease is increased. The formation of blisters is also induced by the fibroblastic factor released by the modified fibroblasts.

The inverse form of recessive dystrophic bullous epidermolysis of Gedd-Dail is the second in frequency. The formation of blisters begins in infancy. Unlike the previous form, the wrinkles of the neck, lower abdomen and back predominate, atrophic scars are formed, and the condition improves with age. Cicatrization of blisters in the oral cavity leads to a restriction of the mobility of the tongue, in the esophagus - to strictures. There are no changes in the nails on the hands (on the feet of the nails are usually dystrophic), tooth damage, milium, fusion of the fingers. Often develop corneal erosions, recurrent traumatic keratitis, which can in early childhood be the only or major manifestation of the disease. The lesion of the eyes is less severe than with the dystrophic bullous epidermolysis of Allopo-Siemens. The inverse shape in the clinical picture resembles the boundary lethal bullous epidermolysis of Gerlitz, but the results of the electron microscopic examination correspond to those observed in the recessive bullous epidermolysis of Allopo-Siemens.

In addition to the above forms, a less severe generalized form is described, in which the clinical manifestations are similar to those in the Allopo-Siemens form, but less pronounced, and a localized form in which the rashes are limited to the places of greatest trauma (brushes, feet, knees and elbows). Electron microscopy revealed a decrease in the number of fixing fibrils and a change in their structure in the lesions, as well as in various places of unchanged skin, which resembles the electron microscopic picture in the dystrophic white-populoid bullous epidermolysis of Pazini.

Thus, all forms of dystrophic bullous epidermolysis are histogenetically related.

Acquired bullous epidermolysis is an autoimmune disease of the skin and mucous membranes, which is characterized by the formation of blisters and leads to increased skin vulnerability.

Acquired bullous epidermolysis usually develops in adults. Bullous eruptions suddenly appear on healthy skin or may be caused by some minor trauma. Lesions are accompanied by pain and lead to the formation of scars. Often palms and feet are affected, which leads to disability. Sometimes mucous membranes of the eyes, mouth or genitals can be affected, the larynx and esophagus are also affected. For diagnosis, a skin biopsy is necessary. Eruptions are difficult to treat glucocorticoids. A moderate form of the disease can be treated with colchicine, but heavier forms require the use of cyclosporine or immunoglobulin.

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