Epidermolysis bullosa: causes, symptoms, diagnosis, treatment

Congenital epidermolysis bullosa (syn. hereditary pemphigus) is a heterogeneous group of genetically determined diseases, among which there are both dominantly and recessively inherited forms. Thus, simple epidermolysis bullosa is inherited in an autosomal dominant manner, mutations in the genes encoding the expression of keratins 5 (12q) and 14 (17q) have been identified, an autosomal recessive type of transmission is possible; the dystrophic variant of Cockayne-Touraine is autosomal dominant, a mutation in the type VII collagen gene, chromosome 3p21; recessive dystrophic epidermolysis bullosa is inherited in an autosomal recessive manner, a mutation in the type VII collagen gene, chromosome 3p; borderline epidermolysis bullosa is inherited in an autosomal recessive manner, a mutation in one of the three genes encoding components of the laminin-5 protein is assumed; Congenital epidermolysis bullosa inversa is inherited in an augosomal recessive manner.

Common to all forms of the disease is the early onset of clinical manifestations (from birth or the first days of life) in the form of blisters at the site of the slightest mechanical injury (pressure and friction) of the skin. Based on such a clinical sign as the presence or absence of scars at the sites of blister resolution, congenital bullous epidermolysis is divided into two groups: simple and dystrophic, or, according to the proposal of R. Pearson (1962), into scarring and non-scarring bullous epidermolysis.

The pathomorphology of various disease groups is similar. There are subepidermal blisters, a slight inflammatory reaction in the dermis. Subepidermal location of blisters can be detected only in fresh (several hours) elements or in skin biopsies obtained after friction. In older elements, blisters are located intraepidermally due to epidermal regeneration, so histological diagnosis is difficult. Examination of biopsies under a light microscope with normal staining gives only an approximate diagnosis, an indication that this disease is bullous epidermolysis. The use of histochemical methods for staining the basement membrane of the epidermis allows us to determine more accurately the localization of the blister - above or below the basement membrane. Clinically, this division corresponds to simple bullous epidermolysis with a suprabasal location of the blister and dystrophic - with its subbasal localization. However, diagnostic errors are not uncommon even when using histochemical methods. Thus, in 8 cases of simple bullous epidermolysis described by LH Buchbinder et al. (1986), the histological picture corresponded to dystrophic bullous epidermolysis.

Only the introduction of electron microscopic examination into practice made it possible to clarify the mechanism and location of blisters formation, as well as to study in more detail the morphological disorders in various forms of the disease. According to electron microscopy data, this disease is divided into three groups: epidermolytic, if blisters form at the level of basal epithelial cells; borderline, if the blisters are at the level of the lamina lucidum of the basal membrane, and dermolytic, if the blisters form between the lamina densa of the basal membrane and the dermis. Taking into account the clinical picture and the type of inheritance, several more forms are distinguished in each group, which significantly expands the classification. Immunofluorescence methods used for the diagnosis of congenital bullous epidermolysis are based on the selective localization of the structural components of the basement membrane - bullous pemphigoid antigen (BPA) and laminin in the lamina lucidum, type IV collagen and KF-1 antigens in the lamina densa, AF-1 and AF-2 in the anchoring fibrils, LDA-1 antigen in the lamina densa of the basement membrane and the area beneath it. Thus, in direct immunofluorescence reaction in cases of simple bullous epidermolysis, when cleavage occurs above the basement membrane, all antigens are located at the base of the blister, in borderline forms cleavage occurs in the zone of the lamina lucidum of the basement membrane, therefore BPA is localized in the blister cap, laminin - at its base or cap, type IV collagen and LDA-1 - at the base of the blister, and in the dystrophic form of bullous epidermolysis all antigens are in the blister cap. Of the biochemical methods for diagnosing bullous epidermolysis, only collagenase determination is currently used, since it has been established that its amount is increased in the skin in borderline and recessive dystrophic forms and is unchanged in simple and dominant dystrophic bullous epidermolysis.

The epidermolytic (intraepidermal) group of bullous epidermolysis includes the most common form - simple bullous epidermolysis Koebner, inherited autosomal dominantly. Blisters on the skin appear from birth or in the first days of life in the most traumatized areas (hands, feet, knees, elbows), then spread to other areas. They are single-chambered and have different sizes. After opening the blisters, healing occurs quickly and without scars. Blisters often appear at elevated external temperatures, so exacerbation occurs in spring and summer, often accompanied by hyperhidrosis. Mucous membranes are often involved in the process. Improvement is sometimes observed during puberty. A combination with palmar-plantar keratoderma and its development after the resolution of the blisters have been described.

Electron microscopic examination reveals cytolysis of basal epithelial cells. Their tonofilaments in some cases form clusters in the form of lumps, more often around the nucleus or near hemidesmosomes, which leads to failure of the cell cytoskeleton and cytolysis with the slightest injury. The roof of the resulting bubble is represented by destroyed basal epithelial cells, and the base is represented by the remains of their cytoplasm. At the same time, hemidesmosomes, the basement membrane, the anchoring fibrils and collagen fibers under it remain intact. The tonofilament defect resembles that in bullous congenital ichthyosiform erythroderma, but differs in the location of the altered epithelial cells. The histogenesis of this form of bullous epidermolysis has not been sufficiently studied.

The mildest form of simple bullous epidermolysis is Weber-Cockayne syndrome, inherited in an autosomal dominant manner. In this form, blisters appear from birth or at an early age, but are localized on the hands and feet and appear mainly in the warm season, often combined with various ectodermal dysplasias: partial absence of teeth, diffuse alopecia, anomalies of the nail plates.

Examining the ultrastructure of the skin in the lesions, E. Haneke and I. Anton-Lamprecht (1982) found that cytolysis of basal epithelial cells occurs without changes in tonofilaments. Scaly epithelial cells are large, contain bundles of tonofilaments instead of keratin, and their appearance is possibly associated with damage to basal epithelial cells, which do not die but develop further. With repeated injuries, such cells undergo cytolysis.

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

Herpetiform simple bullous epidermolysis Dowling-Meara, inherited autosomal dominantly, is characterized by a severe course, appears from birth or from the first days of life. Clinically, it is characterized by the development of grouped generalized blisters of the herpetiform type with a pronounced inflammatory reaction. Healing of foci occurs from the center to the periphery, pigmentation and milia remain in their place. Often, lesions of the nails, mucous membranes of the mouth and esophagus, dental anomalies, palmar-plantar keratoses. In some patients, repeated formation of blisters leads to flexion contractures.

Histological examination of the skin in Dowling-Meara's simple bullous epidermolysis herpetiformis reveals a large number of eosinophilic granulocytes in the dermal infiltrate and the cavity of the blister, which makes this disease similar to herpetiform dermatitis. Immunomorphological and electron microscopic studies are of decisive importance in diagnostics. The electron microscopic data for this form of bullous epidermolysis differ little from those already described for simple bullous epidermolysis Koebner.

Cases of recessive inheritance of simple epidermolysis bullosa have been described. M.A.M. Salih et al. (1985) call recessive simple epidermolysis bullosa lethal due to its severe course, often with a fatal outcome. The clinical picture in the patients described by them differs little from that in simple epidermolysis bullosa of Koebner. The disease is complicated by anemia; a fatal outcome probably occurs from asphyxia of the separated mucous membrane from the affected areas 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 the rash, anodontia, anonychia, and muscular dystrophy were observed. In all cases of recessive inheritance of simple epidermolysis bullosa, cytolysis of basal epithelial cells was detected by electron microscopy.

The group of simple bullous epidermolysis also includes bullous epidermolysis of Ogne, in which, in addition to blistering rashes, multiple hemorrhages and onychogryphosis are noted, and bullous epidermolysis with mottled pigmentation. Pigmentation exists from birth, at the age of 2-3 years, focal palmar-plantar keratoderma and warty keratosis on the skin of the knees appear, in adults, all manifestations of keratosis are resolved, in places of which mild elastosis and atrophy of the skin remain.

The basis of the borderline group of congenital bullous epidermolysis is the most severe form - lethal generalized bullous epidermolysis of Herlitz, inherited in an autosomal recessive manner. The child is born with numerous blisters formed as a result of friction during passage through the birth canal. They can also appear in the first hours of the child's life. The favorite localization of lesions is the fingertips, trunk, shins, buttocks, mucous membrane of the oral cavity, where numerous erosions are observed. The intestines are often affected. Vesicular rashes spread quickly. Healing of erosions at the site of opened blisters occurs slowly, while scars do not develop, but superficial atrophy of the skin appears. Most patients die in the first months of life. The most common 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 in the nail plates, including onycholysis with periungual erosions covered with crusts, after healing of which anonychia develops. Changes in teeth are noted: an increase in their size, discoloration, early caries, enamel is often absent on permanent teeth. Lethal epidermolysis differs from dystrophic bullous epidermolysis by damage to the hands only in the area of the terminal phalanges, the absence of primary scar formation (excluding cases of secondary infection), ulcerative lesions existing from birth, finger fusion and the formation of synechiae, and the rarity of milia.

For histological examination, a biopsy of the edge of the blister should be taken, but exfoliated epidermis of fresh blisters can also be used, which is especially important when conducting a morphological study of the skin of newborns. In this case, the separation of the epidermis from the dermis occurs at the level of the lamina lucidum of the basal membrane of the epidermis, located between the basal epithelial cells and the dense plate of the basal membrane. At this site, the anchoring tonofilaments are damaged. The hemidesmosomes to which they are attached are absent in the blister zone. In other areas, their sparseness and hypoplasia are noted; the attachment disks in the cytoplasm of the basal epithelial cells are preserved, and the dense disks located extracellularly are absent. The lid of the blister is unchanged cell membranes of the basal epithelial cells, and the bottom is the dense plate of the basal membrane of the epidermis. In the dermis, edema and minor dystrophic changes in the collagen fibers of the papillary layer are noted. Desmosomal hypoplasia is a universal structural defect that develops not only in the area of blister formation, but also in unchanged skin, which makes antenatal diagnosis of this disease possible.

In the group of borderline bullous epidermolysis, benign generalized atrophic bullous epidermolysis, localized atrophic, inverse and progressive bullous epidermolysis are also distinguished, which differ from the lethal type in the nature of the course and the location of the rash. In all types of borderline bullous epidermolysis, histological changes are the same. Electron microscopic examination revealed that in non-lethal forms, dense discs of hemidesmosomes are partially preserved, hemidesmosomes are sparse.

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

Dystrophic epidermolysis bullosa Cockayne-Touraine is inherited in an autosomal dominant manner, blisters appear from birth or in early childhood, rarely later, localized mainly on the skin of the extremities and forehead. Atrophic scars and milia develop at the sites of blisters. Patients have lesions of the mucous membrane of the oral cavity, esophagus, pharynx, larynx, keratosis of the palms and soles, follicular keratosis, dystrophy of the teeth, nails (up to anokychia), thinning hair, generalized hypertrichosis are possible. It differs from the recessive form by less severe damage to internal organs, eyes and mainly the absence of coarse scars leading to mutilation.

Dystrophic white papuloid bullous epidermolysis of Pasini is also inherited in an autosomal dominant manner, characterized by the presence of small white papules, dense, ivory-colored, round or oval, slightly raised with a slightly corrugated surface, an emphasized follicular pattern, well demarcated from the surrounding tissue. Papules are localized more often on the trunk, in the lumbar region and on the shoulders, regardless of vesicular rashes, usually appear in adolescence.

Pathomorphology. In dystrophic bullous epidermolysis of Cockayne-Touraine, the blister is located under the epidermis, its cover is a slightly thinned epidermis with hyperkeratosis without any significant changes in the Malpighian layer. In the dermis in the area of the blister, small perivascular infiltrates of a lymphocytic nature with an admixture of histiocytes and eosinophilic granulocytes are noted. The absence of elastic fibers in the papillary and some areas of the reticular layer of the dermis is characteristic. Electron microscopic examination reveals in the area of the blisters and in the unchanged skin near the blisters in both forms of dominant bullous epidermolysis sparseness and changes in the structure of the anchoring fibrils, which is expressed in their thinning, shortening and loss of transverse striation (rudimentary forms). In Pasini's white papuloid epidermolysis, similar changes were found in clinically healthy skin, in areas where blisters had never appeared, and in Cockayne-Touraine's dystrophic bullous epidermolysis, the anchoring fibrils were normal or thinned in these areas, their number did not differ from the norm or was reduced. However, their absence was described in one case. In both forms, collagenolysis phenomena were not detected in the dermis.

Recessive forms of dystrophic bullous epidermolysis are among the most severe genodermatoses. They are characterized by extensive formation of blisters followed by the appearance of deep, poorly healing erosions and scarring in their place.

Dystrophic bullous epidermolysis of Hallopeau-Siemens is the most severe form in this group. The clinical picture manifests itself from birth, is characterized by generalized rashes of blisters, often with hemorrhagic contents, which can be located on any part of the skin, but most often in the area of the hands and feet, elbow and knee joints. Blisters occur with the slightest mechanical injury, and when they heal, milia and extensive scars are formed. Cicatricial changes can be observed in early childhood on the mucous membranes of the digestive and genitourinary tracts. In the fight against scarring, contractures, fusion of fingers, mutilation of the terminal phalanges with their complete fixation are formed. After their surgical correction, relapses often occur. Lesions of the oral mucosa are accompanied by the development of microstoma, shortening of the frenulum of the tongue, fusion of the mucous membrane of the tongue and cheeks. Esophageal lesions are complicated by strictures and stenoses, causing obstruction. A very serious complication is the development of cancerous tumors on scars, sometimes multiple. Bone lesions (acroosteolysis, osteoporosis, dystrophy of the bones of the hands and feet), and delayed cartilage development are also observed. Dental abnormalities, anonychia, baldness, eye lesions (keratitis, conjunctivitis, synblepharon, ectropion), growth retardation, anemia, and skin infections are often observed.

Pathomorphology. The main morphological signs of recessive dystrophic epidermolysis bullosa are changes in the anchoring fibrils and collagen fibers of the upper dermis. The basement membrane remains intact and forms the roof of the blister. The absence of anchoring fibrils in the lesion and in externally unchanged skin was noted by RA Briggaman and CE Wheeler (1975), their rudimentariness in unaffected skin - I. Hashimoto et al. (1976). Collagen fibers in the blister area have unclear contours or are absent (collagenolysis). Focal dissolution of collagen occurs during blister formation. At the same time, phagocytic activity in the dermis increases, phagocytosis of individual collagen fibers of large diameter, which are part of bundles among fibers of normal 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 process is based on a primary defect of the anchoring fibrils, the other - the development of collagenolysis is primary. The first assumption is supported by the presence of pathology of the anchoring fibrils in externally unchanged skin, where there is no collagenolysis. The second is supported by data on the occurrence of foci of collagenolysis with intact anchoring fibrils at the initial stage of blister formation during friction, as well as data on their preservation in a skin explant cultured with an extract of the dermis of a 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 collagenase activity, and then by data on excessive production of biochemically and immunologically altered collagenase by fibroblasts. 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 collagenolysis processes, but also with the action of other enzymes. Thus, the contents of the patient's blister induce the formation of subepidermal blisters in the normal skin of a healthy person. Apparently, the blister contains substances that lead to the separation of the epidermis from the dermis. The activity of collagenase and neutral protease is increased in the skin and blister fluid. Blister formation is also induced by fibroblastic factor secreted by modified fibroblasts.

The inverse form of recessive dystrophic bullous epidermolysis Hedde-Dyle is the second most common. Blisters begin to form in infancy. Unlike the previous form, the folds of the neck, lower abdomen and back are predominantly affected, atrophic scars are formed, and the condition improves with age. Scarring of blisters in the oral cavity leads to limited mobility of the tongue, and in the esophagus - to strictures. There are no changes in fingernails (toenails are usually dystrophic), tooth damage, milia, or finger fusion. Corneal erosions and recurrent traumatic keratitis often develop, which may be the only or main manifestation of the disease in early childhood. Eye damage is less severe than in dystrophic bullous epidermolysis Hallopeau-Siemens. The inverse form is similar in clinical picture to the borderline lethal bullous epidermolysis of Herlitz, but the results of electron microscopic examination correspond to those observed in recessive bullous epidermolysis of Hallopeau-Siemens.

In addition to the above forms, a less severe generalized form has been described, in which the clinical manifestations are similar to those in the Hallopeau-Siemens form, but are less pronounced, and a localized form, in which the rash is limited to the areas of greatest trauma (hands, feet, knees and elbows). Electron microscopy revealed a decrease in the number of anchoring 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 dystrophic white papuloid bullous epidermolysis of Pasini.

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

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

Acquired epidermolysis bullosa usually develops in adults. Bullous lesions appear suddenly on healthy skin or may be caused by minor trauma. The lesions are painful and lead to scarring. The palms and soles are often affected, leading to disability. Sometimes the mucous membranes of the eyes, mouth, or genitals may be affected, and the larynx and esophagus are also affected. A skin biopsy is necessary for diagnosis. The lesions are poorly responsive to glucocorticoids. Moderate forms of the disease can be treated with colchicine, but more severe forms require cyclosporine or immunoglobulin.

[ 1 ], [ 2 ]