Epidermolysis bullosa hereditaria (overview) Q81.-

Group of rare hereditary skin diseases (genodermatoses) characterized by mutation-related disturbance of the structural and functional integrity of intraepidermal adhesion or dermoepidermal anchorage by skin fragility and blistering of skin and mucosa. The disorders occur after minor mechanical or thermal trauma. Extracutaneous manifestations and their complications in other epithelium-bearing organs make the hereditary bullous epidermolyses multisystem diseases with sometimes dramatic morbidity.

Classification is based on genetic, clinical, electron microscopic, immunohistologic (immunomapping), and molecular biologic criteria. According to the position of the blister formation in relation to the dermoepidermal basement membrane, epidermolyses are divided into 4 groups:

Epidermolytic blistering:

• suprabasal and
• basal cleft formation

Cytolysis of keratinocytes(epidermolysis bullosa simplex group).

Junctiolytic bl istering: loss of continuity in the lamina lucida area of the basement membrane(epidermolysis bullosa junctionalis group).

Dermolytic bl istering: cleavage formation below the basement membrane(epidermolysis bullosa dystrophica group).

Variable blistering: cleavage intraepidermal/junctional/dermal (Kindler syndrome ).

While the first two forms do not lead to scarring, the blisters in the latter forms heal with scarring.

Epidermolysis bullosa simplex group

Epidermolysis bullosasimplex Weber-Cockayne (localized) (EBS-WC)

Epidermolysis bullosasimplex Köbner (generalized) (EBS-K)

Epidermolysis bullosasimplex Dowling Meara (herpetiform type) (EBS-DM)

Rare subtypes of the EB simplex group

• Epidermolysis bullosasimplex with muscular dystrophy (EBS-MD)
• Epidermolysis bullosa simplex with pyloric atresia
• Epidermolysis bullosa simplex Ogna
• Epidermolysis bullosa simplexwith patchy hyperpigmentation (EBS-MP)
• Epidermolysis bullosasimplex, autosomal recessive with Bp230 deficiency (EBS3)
• Epidermolysis bullosa simplex with mutations in KLHL24
• Superficial epidermolysis bullosa simplex (SEBS)
• Acral peeling skin syndrome, with circumscribed keratolysis
• Hypotrichosis and recurrent skin vesicles (HYPTSV/OMIM: 613102), mutation in DSC3 gene (see there)

Epidermolysis bullosa junctionalis group (EBJ)

Epidermolysis bullosa junctionalis generalized severe (historically:type Herlitz )(JEB-H)

Epidermolysis bullosa junctionalis generalized, intermediate (historically: JEB-non-Herlitz (JEB nH)

Epidermolysis bullosa junctionalis localized (historically: JEB nH)

• Epidermolysis bullosa junctionalis localized, acral type
• Epidermolysis bullosa junctionalis localized, inverse type
• Laryngo-onychocutaneous syndrome (LOC syndrome)

Other rare subtypes of junctional EB

• Epidermolysis bullosajunctionalis with pyloric atresia (JEB-PA)
• Epidermolysis bullosa junctionalis with hypacusis
• Epidermolysis bullosa junctionalis with lung and kidney involvement

Epidermolysis bullosa dystrophica group (EBD)

• Epidermolysis bullosadystrophica dominans (DEBD); syn.: dominant EBD
• Epidermolysis bullosa dystrophicarecessive, generalized severe (historically: Hallopeau-Siemens type)
• Epidermolysis bullosa dystrophica recessive, generalized intermediate

Rare subtypes of dystrophic EB

• Epidermolysis bullosadystrophica inversa (REBD-I)
• Epidermolysis bullosa dystrophicapraetibialis (DEBD-Pt)
• Epidermolysis bullosa dystrophicaalbopapuloidea (formerly Pasini type)
• Transient bullous dermolysis of the newborn (TBDN-EBD)
• Dominant EBD with pruritus (DEBD-Pr)
• "Nails only"

Kindler syndrome

Incidence for the entire group of diseases: 2.0/100,000 live births/year. The hereditary epidermolyses belong to the rare(orphan diseases) diseases.

EB- exhibits a large molecular heterogeneity. Thus, >1500 mutations in 19 genes encoding components of the keratin filaments of the cytoskeleton, adherens junctions, desmosomes and hemidesmosomes have been described so far.

The "index genes" are also expressed in other organs (gastrointestinal, respiratory and urogenital tracts).

The leading symptom on all epithelia is moderate to extreme vulnerability with formation of blisters and sequelae such as erosions, crusts, scars and their sequelae. Since the corresponding structural proteins are expressed in the skin as well as in mucous membranes or in other organs (muscles, lungs, kidneys), extracutaneous manifestations occur depending on the genotype.

Since epidermolyses are mostly polygenic and not monogenic diseases, it is evident that the "disease-causing" mutations alone cannot explain the full clinical picture, but that the phenotype is caused by the interaction of several genes as well as by environmental influences. Furthermore, even mutations in a single gene show great variability in phenotype.

The primary, structural-functional defects also influence secondary epigenetic phenomena (induction of inflammatory cascades, influence of the microenvironment) and thus in turn the individual phenotype.

Epidermolysis bullosa simplex group (EBS); most common EB type (75% of cases). The common features of the EBS subtypes are:

• Genetics: Mostly autosomal dominant inheritance. Missense mutations in the genes coding for keratin 5 or 14 (KRT5; KRT14) and those coding for desmoplakin and plakoplakin, respectively. The significance of the recently discovered mutation in the KLH24 gene remains to be seen (HeY 2016).
• Histology: Intraepidermal blistering by cytolysis of basal/suprabasal keratinocytes (epidermolytic blistering).
• Antigen mapping: Intraepidermal cleft formation with hemidesmosome markers at the blister base.
• Electron microscopy: Intracellular cytolysis above the hemidesmosomes in the basal keratinocytes.
• Clinic: Healing of blister formation without scars. The pruritus occurring in this group seems to be triggered by the releasing cytokine"Thymic Stromal Lymphopoietin", which also has a pathogenetic significance in atopic eczema.

Epidermolysis bullosa junctionalis (EBJ) group. The common features of the EBJ subtypes are:

• Genetics: Autosomal recessive inheritance; heterogeneous genetic background; at least 6 index genes (genes encoding laminin, integrin, and type VII collagen).
• Histology: blisters in the lamina lucida of the basement membrane.
• Antigen mapping: Junctional, suprabasal blistering with hemidesmosome markers on the blister roof and lamina densa markers on the blister floor.
• Clinic: Very heterogeneous, late-onset localized forms and early lethal forms (Herlitz type). Healing without scarring (suprabasal blister); however, skin atrophy develops with prolonged course.
• Electron microscopy: Junctional blister, rudimentary or absent hemidesmosomes on blister roof and blister floor.

Epidermolysis bullosa dystrophica group (EBD). The common features of EBD subtypes are:

• Genetics: Autosomal dominant or recessive inheritance; mutations in the collagen VII gene (COL7A1).
• Histology: Dermolytic blistering.
• Antigen mapping: Lamina densa markers are found on the blister roof. Staining with collagen VII is reduced or negative.
• Clinic: Scarring, milia, nail loss.
• Electron microscopy: blistering below the lamina densa.

Poikilodermic Kindler syndrome . Autosomal recessive Kindler syndrome is listed as the 4th group of EB:

• The cleft formation of Kindler syndrome is called mixed. The defective protein Kindlin-1 plays a significant role in cell adhesion. Acral blistering, generalized poikiloderma as well as photosensitivity are the dominant clinical symptoms.

• Acquired diseases:
• Traumatic blistering
• Mastocytosis, bullous
• Infectious diseases:
• Herpes Infections
• contagious impetigo
• Staphylococcal Scalded Skin Syndrome
• Pustulous candidiasis.
• Bullous autoimmune diseases:
• Pemphigoid diseases
• Pemphigus diseases
• Dermatitis herpetiformis Duhring
• Dermatosis, IgA linear
• Epidermolysis bullosa acquisita.
• Hereditary and congenital diseases:
• Peeling skin syndrome
• Congenital Porphyria
• acrodermatitis enteropathica
• incontinentia pigmenti
• aplasia cutis congenita
• Ectodermal dysplasia with plakophilin deficiency
• Poikiloderma (see Kindler syndrome below).

Overall, treatment is unsatisfactory and predominantly symptomatic. Genetic counselling of affected families, if necessary use the possibilities of prenatal diagnostics.

In dystrophic forms, physiotherapeutic measures to prevent contractures are important and surgical interventions may be necessary, especially to improve the function of the hands.

Overall, the aggressiveness of treatment should correspond to the severity of the clinical picture. In the case of non-dystrophic epidermolyses, the prevention of secondary infections is of primary importance. In the case of dystrophic changes, the preservation of as high a quality of life as possible, i.e. the avoidance of secondary damage (e.g. scarring, scar contractures in the area of the eyes, mucous membranes and oesophagus, anaemia and vitamin deficiency due to restricted nutrition, skin carcinomas, secondary infections). Patients may have difficulty with food intake due to painful involvement of the mucosa, among other things. Therefore pay attention to nutrition with sufficient vitamins and minerals, if necessary passaged food, if necessary diet plan.

Further things to consider: Wear soft, non-abrasive clothing, avoid rough seams, if necessary wear the clothing inside out or resew the seams. Appropriately padded underlay, if necessary gel underlay or air cushion bed. Cleaning, if necessary disinfecting baths for erosions, sterile dressings. In case of extensive erosions, dressing with hydrogel (e.g. Intrasite) or hydrocolloid films (e.g. Varihesive E). For children, padded furniture and floors.

The main focus is to avoid mechanical irritation and irritation and to monitor and treat secondary infections. Drying and antiseptic solutions such as quinolinol solution(e.g., Chinosol 1:1000), R042 or potassium permanganate solution(light pink), polihexanide (Serasept, Prontoderm) if necessary. If necessary, wound treatment, see there. Sufficient fluid replacement. Sterile lancing and emptying of the blisters prevents their expansion and relieves pressure. The bladder roof should be left in place to protect against infection. External glucocorticoids such as 0.1% triamcinolone cream(e.g., Triamgalen) only in cases of eczematization and pruritus. General skin care (e.g., with Ungt. emulsif. aq. or 2% urea cream).

On 06/24/2022, the EMA Committee for Medicinal Products for Human Use (CHMP) granted marketing authorization to Filsuvez® birch bark extract for the treatment of superficial wounds associated with dystrophic and junctional epidermolysis bullosa.

Classification of hereditary bullous epidermolyses (EB) modified according to Schumann

Remember! Since 2003, an Epidermolysis bullosa Centre has been in existence at the University Dermatology Clinic Freiburg, supported by the BMBF and the DEBRA International Foundation. This includes the clinical care of patients with Epidermolysis bullosa as well as morphological and molecular diagnostics and the processing of scientific questions concerning hereditary skin diseases. Patients can be registered at the address below.

• EB Centre Freiburg
  • telephone: 0761-270-6614
  • Fax: 0761-270-6791
  • Email: [email protected]
  • Website: www.netzwerk-eb.de

The Centre also acts as the coordinating body of the national competence network Epidermolysis bullosa.

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