Epidermolysis bullosa is a group of hereditary diseases characterized by mild skin vulnerability, hence the second name of these pathologies – “mechanobullous disease”. The main symptom is the development of bubbles with serous contents on the surface of the skin, after which long-lasting erosions occur in their place. Diagnosis of various types of epidermolysis bullosa is carried out using immunohistological and genetic techniques, as well as based on the patient’s examination data and the study of his hereditary history. There is no specific treatment, but proper and complex symptomatic therapy can in some cases significantly improve the patient’s condition.
Q81 Epidermolysis bullosa
Epidermolysis bullosa is a heterogeneous group of hereditary skin diseases characterized by the formation of blisters and erosions in response to minor mechanical impact. For the first time this term was used in 1886 by the German dermatologist Heinrich Kebner, further studies have shown that there are many varieties of this pathology. Genetic studies of epidermolysis bullosa have shown that it can be inherited both autosomal recessive and autosomal dominant, mutations of more than 10 genes are associated with it. There are significant differences in the clinical course of different types of this disease, the occurrence ranges from 1:30000-1:1000000.
The pathogenesis of disorders in epidermolysis bullosa has remained poorly understood for a long time. A breakthrough in this direction occurred with the introduction of electron microscopy into medical practice, which helped to visualize the ultrastructure of the affected skin tissues. The next important step in the study of epidermolysis bullosa was made with the discovery of immunohistological studies (immunofluorescence). Currently, it is these techniques that play a crucial role in the diagnosis of these diseases, second only to genetic analysis in accuracy. Due to the fact that the methods of studying epidermolysis bullosa have been constantly improved, the classification of forms of this group of diseases has also undergone changes.
The etiology of epidermolysis bullosa varies in different types of the disease, which in some cases greatly complicates the diagnosis. Simple epidermolysis bullosa is caused by mutations of the KRT5 and KRT14 genes, however, according to geneticists, only 75% of cases of this type of disease are explained by a violation of the structure of these genes. At the same time, the equilibrium in the “enzyme-inhibitor” system is presumably disturbed in the skin, and some proteins become the object of attack. With simple epidermolysis bullosa, these may be proteins of the basement membrane (alpha6-beta4-integrin) and proteins of the desmosomes of the basal layer of the epidermis – desmoplakin, plakophylline-1. As a result, under mechanical action, enzymes are released that destroy these proteins, thereby provoking cytolysis and destruction of the structure of the epidermis, leading to the formation of bubbles.
The cause of the development of another form of pathology – borderline epidermolysis bullosa – are mutations in the genes LAMB3, LAMA3 and some others. Most of these mutations are inherited by an autosomal recessive mechanism, and proteins such as type 17 collagen and laminin-332 become the object of attack by an unbalanced enzyme system. These proteins are involved in maintaining the normal structure of the lower layers of the epidermis, so their damage leads to the characteristic clinical symptoms of borderline epidermolysis bullosa. In addition to the easy formation of blisters and erosions, it is also characterized by increased fragility of the skin and a more severe course.
The dystrophic type of epidermolysis bullosa is caused by mutations in the COL7A1 gene, which can be inherited by both autosomal dominant and autosomal recessive mechanisms. The target protein is type 7 collagen, which is responsible for the stability of the structure of other connective tissue fibers of the skin. A decrease in the amount of this protein in the tissues of the skin leads to the easy development of rashes, erosions and blisters, and is also often accompanied by disorders of other organs. In particular, dystrophic epidermolysis bullosa often leads to the development of joint contracture, the lesion captures the mucous membranes of the respiratory and digestive systems. On the scars that remain after the healing of erosions, malignant tumors often occur.
In general, the general pathogenesis of epidermolysis bullosa can be reduced to a violation of the activity of certain enzymes in the skin tissues. As a result, certain key structural proteins of the epidermis, dermis or basement membrane are destroyed, which disrupts the connections between cells and leads to the formation of bubbles under mechanical action of even insignificant force. The types of epidermolysis bullosa differ from each other by the localization of vesicles, the type of mutation that led to this disease, and the type of protein that became the object of enzyme attack.
Currently, there are dozens of varieties of epidermolysis bullosa, which are quite difficult to classify into certain groups. The problem is further complicated by the fact that for almost a century and a half of studying this pathology, repeated attempts were made to divide it into certain types using the most up-to-date data at that time. In the end, this led to some confusion, even in the scientific literature, you can find a wide variety of options for dividing epidermolysis bullosa into varieties. The most modern classification of this condition in dermatology includes four types of the disease, which, in turn, are divided into a number of subtypes:
- Simple epidermolysis bullosa – has 12 subtypes, the most common of which are Weber-Kokkane, Kebner, Dowling-Meara syndromes. It can be inherited both autosomally dominant and recessive, the occurrence is 1:100000. Simple epidermolysis bullosa is characterized by the formation of intraepidermal or, less often, subepidermal blisters, since in this disease the proteins of the epidermis are affected.
- Borderline epidermolysis bullosa is divided into 2 subtypes, one of which has 6 more independent clinical forms. The most severe form of this disease is the Herlitz subtype, which has an extremely high mortality rate. The occurrence of borderline epidermolysis bullosa is about 1:500,000, the formation of bubbles with it occurs at the level of the light plate, which gave it the name “borderline”.
- Dystrophic epidermolysis bullosa – has two subtypes, which are divided according to the mechanism of inheritance of this pathology (dominant and recessive subtypes). At the same time, the occurrence of the dominant variant is slightly higher (3:1,000,000 versus 1:500,000 in the recessive form of dystrophic epidermolysis bullosa). The recessive variety also has several clinical forms, the most severe of which is the Allopo-Siemens subtype. In this variant of the disease, patients have deep erosions that leave scars, joint contractures, and damage to the mucous membranes are possible. The formation of blisters occurs in the papillary layer of the dermis, which causes the appearance of scars and prolonged healing of erosions.
- Kindler syndrome, or mixed epidermolysis bullosa, is one of the most rare and poorly studied forms of this pathology. The feature that made it possible to distinguish this form into a separate type is the formation of bubbles in all layers of the skin – the epidermis, the light plate, and the dermis. At the moment, only the protein acting as the target of enzymes in mixed epidermolysis bullosa – kindlin-1 – has been identified.
This type of separation of all clinical forms of epidermolysis bullosa is currently generally accepted. But even within the same type, there is a wide variety of clinical symptoms of the disease, which complicates diagnosis and often affects the prognosis of pathology. Therefore, to date, the search for a more structured and acceptable classification of epidermolysis bullosa has not stopped.
Manifestations of epidermolysis bullosa of different types are united by one thing – the development of blisters and erosions in response to mechanical action on the skin. The only difference is the degree of severity of these changes, localization, time of existence and the results of healing. In the localized form of simple epidermolysis bullosa (Weber-Kokkein subtype), lesions are located only on a certain area of the body (arms, feet). In infancy, a wider area of the appearance of bubbles is possible, but with age their severity decreases. On the contrary, the generalized Dowling-Meara subtype is characterized by the development of small vesicular eruptions over a significant area of the body. This type of epidermolysis bullosa occurs from early childhood and can cause the death of a child, the result of the resolution of bubbles can be hyperkeratosis, skin pigmentation disorders, sometimes there is a lesion of the mucous membranes.
The borderline form of epidermolysis bullosa is much more severe, especially the so-called lethal subtype of Herlitz. At the same time, there is an increased fragility of the skin, the formation of a large number of bubbles, erosions, symmetrical granulations often occur on the face and back. The mucous membranes of the mouth are also affected, enamel hypoplasia and severe caries caused by it are detected. Such a severe course of borderline epidermolysis bullosa often causes death in the first years of life. In surviving patients, joint contractures, kidney damage, and nail loss form in adulthood. The milder atrophic form of borderline epidermolysis bullosa is also characterized by extensive rashes, after resolution of which atrophic areas and scars form. It also often leads to nail dystrophy and scar alopecia.
Dystrophic epidermolysis bullosa is almost always generalized and affects large areas of the body. The dominant variant of the disease is generally characterized by a more benign course, the formation of blisters and their resolution occurs slowly, but most patients eventually lose their fingernails. After the erosion heals, noticeable scars form on the surface of the skin. The recessive variant of dystrophic epidermolysis bullosa, especially its severe generalized subtype, is much more severe: in addition to rashes, pseudosyndactyly, extensive scars, and nail loss are often recorded in patients. There is a lesion of the bones of the skeleton, in place of healed scars, squamous cell carcinoma may develop over the years. The problem is also the high resistance of the Allopo-Siemens subtype to therapeutic measures.
Complications of any type of epidermolysis bullosa are reduced to the risk of shock (with extensive lesions), secondary infection and sepsis provoked by it, dehydration of patients. In most cases, therapeutic procedures are performed only in order to prevent these conditions. The probability of complications is higher, the larger the area of the body is occupied by pathological foci and the more destructive their nature (tense blisters, erosions, ulcers).
Currently, the diagnosis of epidermolysis bullosa is carried out by examining the patient’s skin, using immunohistological studies and genetic analyses, in some cases, a hereditary history is studied. When examining the skin, a specialist can also perform diagnostic tests – mechanically affect the patient’s skin and evaluate the results after a while. The development of blisters or erosions characteristic of epidermolysis bullosa in this area speaks in favor of the presence of this disease. At the next stages of diagnosis, a more accurate determination of the form of pathology is made.
Immunofluorescence analysis in epidermolysis bullosa is carried out using mono- and polyclonal antibodies having affinity for the main proteins of the epidermis, the light plate and the upper layers of the dermis. This allows you to estimate the amount of a particular protein, which, in turn, indicates the enzyme activity of tissues. A decrease in the amount of a particular protein indicates its low release or accelerated destruction. A decrease in the concentration of key proteins in certain areas allows you to determine the level of development of blisters at the earliest stage, which already helps to determine the type of epidermolysis bullosa with a high degree of probability. The point in the diagnosis of this condition is put by genetic analysis by direct sequencing of genes that are associated with a particular type of disease. This multi-stage approach to the diagnosis of epidermolysis bullosa provides high accuracy.
Significantly simplify the diagnosis of this disease allows the study of the hereditary history of the patient, according to which it is possible to identify his blood relatives with the same problem. In addition, if one of the relatives has epidermolysis bullosa, it makes sense to make a prenatal genetic diagnosis, which will reveal the presence of this pathology in the early stages of fetal development. Differential diagnosis is carried out with true pemphigus, some forms of bullous pemphigoid, acquired epidermolysis bullosa (which is not hereditary, but an autoimmune disease).
There is no specific treatment for this disease, all therapeutic procedures are reduced to preventing the development of complications and reducing the severity of bubbles and erosions. In the case of severe forms of epidermolysis bullosa, prednisone is prescribed. From external therapeutic manipulations, aseptic opening of the bubbles is performed, their caps are treated with antiseptics, and heliomycin ointment is applied. The application of bandages should be done very carefully, since the pressure of bandages can provoke the appearance of new bubbles. In the presence of complications (shock, sepsis), symptomatic treatment with antishock drugs and antibiotics is carried out. For preventive purposes, it is possible to irradiate the skin with ultraviolet rays.
Modern genetics and a number of other fields of medicine continue extensive studies of epidermolysis bullosa in order to find more effective treatment methods. Among the main technologies and methods, methods using stem cells, protein and gene therapy are considered the most promising. However, so far none of the methods has gone beyond animal experiments, so epidermolysis bullosa is currently an incurable disease.
The prognosis of epidermolysis bullosa is often uncertain, as it depends on many factors and circumstances – the type of disease, the presence or absence of concomitant disorders in the patient, his lifestyle. For example, the local subtype of simple epidermolysis most often has a benign course and rarely poses a threat to the patient’s life. Whereas the Allopo-Siemens subtype has a very high mortality rate – both from skin manifestations and due to long-term complications, such as kidney and gastrointestinal lesions, as well as the development of squamous cell skin cancer. Patients with such a problem should take care of their skin, do not forget about the antiseptic treatment of erosions and other lesions, avoid engaging in traumatic sports and other activities of this kind.