% vol = 14 number = 3 prevlink = 143 nextlink = 151 titolo = "PATIENTS SUFFERING FROM EPIDERMOLYSIS BULLOSA HEREDITARIA TREATED IN THE SIEM PIROGOV BURNS AND PLASTIC SURGERY CLINIC" volromano = "XIV" data_pubblicazione = "september 2001" header titolo %>
SUMMARY. Hereditary dermatoses of the epidermolysis bullosa (EB) group are the result of improper connection of the epidermis to the basal membrane and the dermis. According to Gedde-Dahls classification, the group consists of three major types divided into 23 subtypes. We discuss two clinical cases of EB treated in 1999 and 2000. The first case is that of a boy aged 10 months with EB-generalisata multilans (Hallopeau-Simens) (R-EBD-GM) who was treated conservatively and after the skin lesions closed. He was dismissed for further observation in a regional hospital. The second case is that of a 2-month-old boy showing signs of EB dystrophica (Type Cocayne Touraine (D-EBD-L) who died of pneumonia. EB treatment is difficult because there is no definite, specific treatment. This is limited to care for the patient in terms of personal hygiene, careful nutrition, and prevention of traumas and infections; this should be the main task of the hospital staff. Such patients have high protein and calorie needs owing to the large skin lesion surfaces. Local treatment should not involve pulling or tangential forces. In EB the skin can cope with compressive forces. The wound should be treated with careful water procedures and, after drying, standard medications containing 1% silver sulphadiazine lotion should be used. Dressings are changed every 1-3 days. The new methods of gene therapy are not yet available to patients. The skin lesions look like a IIA-degree burn and EB can be treated effectively in a burns unit.
The growing interest in hereditary diseases is due mainly to two reasons: their relative increase in the structure of childhood morbidity and the growing possibilities for their early diagnosis and treatment.
The epidermolysis bullosa hereditary disease group is a clinically, genetically, and biologically heterogeneous group of hereditary diseases that manifest themselves through blisters on the skin and mucosa that appear either spontaneously or as a result of tangential trauma caused by improper connection of the epidermis to the basal membrane and the dermis.
The boundary between the epidermis and the dermis is a place of complex immune-morphological and biochemical processes. These provide the epidermal metabolism and the skins defence function against the outside environment.
In the dermis-epidermis boundary zone the basal keratocytes connect to the basal membrane. It possesses a light part - lamina lucida - and a darker part - lamina densa - under the lamina lucida.
The connection of the basal keratocytes to the membrane is achieved with the help of hemidesmosomal complexes and anchoring filaments, which cross the lamina lucida and combine with the lamina densa.
The basal membrane, on the other hand, combines with dermal connecting tissue with the help of a net of anchoring filaments accompanied by interstitial collagen fibrils and other microfibril structures.1-8
Gedde-Dahl suggests a classification that provides the precise level of the lesion above, in, and under the dermis-epidermis boundary zone and the respective clinical evidence.1,9
Three clinical forms of the disease have been defined:
The whole subgroup of simplex bullous epidermolysis is characterized by the fact that the genetic defect is localized in the area of the basal epidermal layer. The blisters are interepidermal among the basal keratinocytes and heal without scars. There are recessive and dominant forms of the disease. The mutation takes place in the fourth and fourteenth genes of keratin. It is probable that the defects of the genes that encode the proteins responsible for the insertion of the keratin filaments in the hemidesmosomes also play some role, such as BP230 and HAI. However, there is as yet no proof of the existence of mutations there.
The defect in the case of epidermolysis bullosa junctionalis is localized in the lamina lucida area of the basal dermoepidermal zone. The epithelialization of the affected areas takes place without cicatrix formation, but is followed by mild skin atrophy.
All six subtypes are inherited recessively.
In dystrophic bullous epidermolysis the lesion affects the lower part of the dermis-epidermis zone (lamina densa) and heals with the formation of cicatrices.1,9
There are two dominantly and four recessively inherited subtypes.
Objects of observation were two cases of EB hereditaria, treated in our burns and plastic surgery clinic in 1999-2000.
The first case was that of a boy aged 10 months (reg. num. 11373/26 V. 1999, a second child, weight 2900 g, height 47 cm). Immediately after birth the limbs and corpus were covered with massive bullous alterations, de-epithelialized in places, which grew every day. The child had been treated in a regional hospital. Some of the wounds epithelialized with cicatrization but new de-epithelialized sections continued to appear, which either healed or formed granulating wounds. When 10 months old the child was sent to our burns and plastic surgery clinic for further treatment.
When admitted to the hospital the child was in bad overall condition without pathological signs from the internal organs. Locally, there were blisters, de-epithelialization, and granulating wounds over the corpus, limbs, and head in different stages of development. The left knee joint presented a cicatricial contra-structure of 90°. The scar was atrophic. The child had complete intergrowth of the toes of the left foot, invisible on the outside. The right foot had intergrowth of the toes in flexion, and the thumb had only a dystrophic nail. The mouth cavity had mucous erosions and sparse dystrophic teeth. The child had an anaemic syndrome (Hb, 64 g/l; Hct, 0.18) and slight hypoproteinaemia (total albumin, 58 g/l; leukocytes, 12300). The immune test revealed suppressed phagocytosis, positive nitroblauterose test, strongly suppressed T-cell immunity, reduced CD3 lymphocytes and CD4 (helpers), and CD3/CD-4 ratio below 1. Monocyte-macrophage markers were strongly activated. The serum immunoglobulins were within normal values. Highly positive C-reactive protein. Weight of child when hospitalized, 6800 g (average weight for this age, 9500 g). X-ray revealed spina bifida from C3 to Th-2. The physical tests did not reveal pathological changes in the internal organs. The microbiological test did not reveal bacterial growth in the skin lesions although the immune tests showed the presence of bacterial infection.
The treatment initiated was general and local, and the anaemic syndrome was compensated. The child remained on nasogastric tube feeding because of the mouth erosions. The local treatment consisted of antiseptic bandages. Until the end of the treatment no bacterial contaminants were isolated from the wound surfaces.
No new skin lesions appeared. The old lesions closed and the child was dismissed from hospital and directed once again to the regional hospital.
Clinically, the form of the skin and non-skin lesions and the cicatrization suggest EB-generalisata multilans (Hallopeau-Simens) (R-EBD-GM).
The second case was that of a boy aged 2 months (reg. num. 240/15.02.2000, a first child, normal birth, young parents, weight at birth 3400 g, height 50 cm).
Immediately after birth, while the child was still in the regional hospital, some dystrophic changes appeared on the nails of the upper limbs and bullae of 1 to 2 cm on the buttocks and forearms. On the third day a febrile state was observed, alternating with hypothermia. The skin lesions increased. Consultations with the dermatologist and geneticist suggested that this was a case of genetic dermatosis of the type EB dystrophica (Type Cocayne Touraine (D-EBD-L).
Serum tests for inborn infection (lues, herpes simplex) were negative. The skin secretions did not isolate any primary bacterial contaminant. The skin lesions increased and axillarily pervaded the chest, navel zone, and all nails of the limbs. On 11 February 2000 there was excessive secretion from the bronchial tree, plus tachypnoea for up to 60 min. Auscultation did not suggest changes in the lung. X-ray did not reveal inflammations in the lung. The haemoculture was without growth. Skin lesions were observed (Candida albicans and Pseudomonas aeruginosa). The C-reactive protein was higher than normal. Treatment was initiated with third-generation cephalosporin and after the fourth day aminoglycoside and Flagyl were added.
The bandages over the skin lesions contained a 1% lotion of silver sulphadiazine. In spite of these, the de-epithelialized areas kept growing and the child was hospitalized in our burns and plastic surgery clinic.
When hospitalized on 15 February 2000 the child was in a bad overall condition, non-febrile, somnolent, and weakly reactive to pain. Auscultation of the lungs revealed harsh vesicular breathing without dyspnoea. There was no rale (breathing rate, 45-50 per min). Cardiovascular system - tachycardia. Abdomen - soft. The liver was palpated 3 cm under the rib arch. The spleen could not be palpated. There was no non-skin evidence of the disease, i.e. affected mucosa and keratitis. Locally, de-epithelialized areas spread over the corpus, limbs, and face. The nails of the hands and feet were missing. The total de-epithelialized area was 7% TBSA.
Laboratory tests revealed ed anaemic and hypoproteinaemic syndromes (Hb, 72 g/l, total albumin 49 g/l).
The treatment we initiated included infusion therapy with bioproducts, crystalline solutions, and vitamins. In the next few days there was no change in the childs overall condition. He was afebrile to subfebrile. The skin lesions partially epithelialized but others appeared, especially after tangential pressure. On 20 February 2000 there was X-ray evidence of a bronchopneumonic process in the right side, without any clinical signs. On 26 February 26 the condition aggravated. There was tachydyspnoea for up to 60 min and the skin and visible mucosa became cyanotic. O2 therapy was started. The childs condition continued to get progressively worse - his temperature rose to 39.6 °C in spite of damp cold wrappings. Breathing was disturbed by snoring (rate, up to 80 per min). The pulse was filoform and the child died on 27 February 2000 with a picture of cardiac weakness. Pathologically, interstitial pneumonia and large subpleural atelectatic zones were discovered, which were the immediate cause of death.
Genetic dermatoses of the epidermolysis bullosa hereditaria group are a result of a genobiochemical defect in the way the basal keratinocytes connect with the basal membrane and the derma.
The basal keratinocytes connect to the basal membrane by hemidesmosome complexes and anchoring filaments.
The upper ends of the anchoring fibrils connect to the lamina densa and the lower ends connect to the anchoring plaque. The plaque is an electronically dense amorphous structure submerged in the connective tissue of the dermis. Some of the fibrils make loops and go back to the lamina densa. The anchoring fibrils are made up almost entirely of anti-parallel dimer associations of collagen VII and NCI or of collagen fibrils (type IV) of the lamina densa. They wrap around various structures of the extracellular matrix of the papillary dermis, thus ensuring tight fixation of the dermis to the lamina densa.1-8
The differences in the EB types are in the type of defect that affects this connection.1,9 The severity of the manifestations in the whole group varies from mild vesiculation to severe and widespread skin lesion formation.
The disease is rare. The total density in Finland is 27/10 mill. births, in Denmark 25/10 mill., and in the USA 20/10 mill. In our country, only 55 cases have been described.1,10
The various forms of the disease affect ectodermal, endodermal, and mesodermal tissues. For this reason - apart from the skin changes - EB is accompanied by various systemic damage.
EB has various symptoms other than skin symptoms. The lesions affect the mucosa of the digestive tract as well as the mucosa of the urethra, the gallbladder, the trachea, bronchia, the urinary bladder, the ureters, and the lungs.
Severe anaemia and dystrophy of the teeth accompany some types of EB. The nails are lost in the first years of life. When the skin lesions heal hypotrophic scars and contractures appear.
The various forms affect the mucosa and teeth, and there are also corneal erosions. In the R-EBD-J type, oesophageal strictures appear as a result of erosions in the digestive tract and their healing.1,9,11-15 In the first of our study cases of EBD we found C3-Th2 spina bifida. Despite a thorough search we could not find any other such cases described in order to relate this case to symptomatic evidence other than skin evidence, although the two diseases could be united as a non-skin case of EBD.
Diagnosing the disease according to its external evidence is not easy. The definition of the EB type and its form is accompanied by various immune, biochemical, and electron-microscope tests - even prenatally.16-18
Differential diagnosis of EB, especially in the neonatal period, should be considered with a number of genetic anomalies - poikiloderma congenita, aplasia cutis congenita, and ichthyosis lamellaris. All of these are accompanied by the appearance of bullae and erosions even at birth, but the ultrastructural morphology is different from that of EB.1
Infections of the newly born child - e.g. lues, congenital herpes simplex, and exfoliate Staphylococcus skin syndrome), candidiasis, and neonatal impetigo can be identified by microbiological tests.
Other auto-immune bullous dermatoses can be identified by electron-microscope investigation or by direct immune-fluorescence.
EB treatment is difficult because there is no definite and specific treatment. Treatment consists of care of the patient in terms of personal hygiene, careful nutrition, and prevention of traumas and infections - this is the hospital staffs main task. These patients have high protein and calorie needs owing to the large skin lesion surfaces. They are also subject to bacterial infections due to the loss of the skins barrier function.
Local treatment should avoid pulling or tangential forces since these lead to the appearance of bullae and de-epithelialization. In cases of EB the skin can cope with compressive forces. This is characteristic of EB, as a result of the damaged, tight bondage in the dermis-epidermis zone.
The wound should be treated with careful water procedures and, after drying, medications containing 1% silver sulphadiazine lotion (Flamazin) should be used. Epithelio-tonic lotions should also be used, e.g. B-patent, Solcoseryl, Actovegin, etc. In cases of Staphylococcus infection Bactroban should be used and, in some cases, Braunovidon - but not often.
The bandage should be soft and it should be changed every 2-5 days.1
We prefer to change the bandage every 1 to 3 days. Bandages with Flamazin should be changed every day, while with other medication they should be changed up to the third day, depending on the quantity of wound exudation. Skin plastic surgery is used in patients suffering from R-EBD-GM and has partial results. Very often new surgery is required.19 Tissue samples from the keratinocytes are used to cover the erosions in cases of EB.
Recently, many of the encoding gene sequences of the EB-affected genes have been discovered, and gene therapy is now held in high esteem; however, at present, the only possible change of genes is the ex vivo type. This method consists of a biopsy, the keratinocytes being multiplied in the sample. In the cultivated cells the correct DNA is inserted and this encodes the defective gene. After gene transfer the cells are grafted. Gene therapy is still in the research phase and is not available to patients.1
RESUME. Les dermatoses héréditaires du groupe épidermolyse bulleuse (EB) sont le résultat de la connexion erronée de lépiderme avec la membrane basale et le derme. Selon la classification de Gedde-Dahl, le groupe est composé de trois groupes principaux divisés en 23 sous-types. Les Auteurs considèrent deux cas cliniques de EB traités en 1999 et 2000. Le premier cas était un garçon de 10 mois, atteint de EB-generalisata multilans (Hallopeau-Simens) (R-EBD-GM), traité en manière conservatrice. Après la guérison des lésions cutanées il a été renvoyé de lhôpital pour être observé dans un hôpital régional. Le deuxième cas était un garçon de 2 mois qui présentait des signes de dystrophica EB (Type Cocayne Touraine (P-EBDL) qui est mort de pneumonie. Le traitement de EB est difficile parce que il nexiste pas aucun traitement déterminé ou specifique, et se limite aux soins hygiéniques personnels, à lalimentation soignée, et à la prévention des traumatismes et des infections, ce qui représente la tâche principale du personnel hospitalier. Ce type de patient a un besoin élevé de protéines et de calories à cause de la grande extension des surfaces brûlées. Le traitement local doit éviter les forces de traction ou tangentielles. Dans les cas de EB la peau est capable daffronter les forces compressives. La lésion doit être traitée avec des procédures attentives avec de leau, et après lessuyage il faut utiliser des pansements qui contiennent une lotion (1%) de sulphadiazine argentée. Les nouvelles méthodes de la thérapie des gènes nest pas ancore disponible pour ces patients. Les lésions cutanées ressemblent à une brûlure de degré IIA, et le EB peut être traité efficacement dans une unité des brûlures.