Epidermolysis bullosa hereditaria (overview) Q81.-

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 21.12.2020

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Synonym(s)

Bullous epidermolyses; EB; EB hereditary; epidermolysis bullosa; Epidermolysis bullosa diseases; Epidermolysis bullosa Group; Hereditary epidermolysis bullosa; Inherited epidermolysis bullosa; Shock Blister Addiction

Definition
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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 the skin and mucosa following minor mechanical or thermal trauma.

Extracutaneous manifestations and their complications in other epithelium-bearing organs make epidermolysis bullosa a multisystemic disease with sometimes dramatic morbidity.

The classification is based on genetic, clinical, electron microscopic, immunohistological (immunomapping) and molecular biological criteria. The epidermolyses are divided into 3 groups according to the position of blister formation in relation to the dermoepidermal basement membrane:

  • Epidermolytic blistering: Suprabasal cleavage due to cytolysis of the basal cells(Epidermolysis bullosa simplex group).
  • Junctiolytic blistering: loss of continuity in the lucid lamina of the basal membrane(Epidermolysis bullosa junctionalis group).
  • Dermolytic blistering: formation of gaps below the basement membrane(Epidermolysis bullosa dystrophica group).

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

Classification
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Epidermolysis bullosa group (EB) - Clinical entities

Epidermolysis bullosa simplex group

Epidermolysis bullosa junctionalis group (EBJ){{article-url::2941}}

Epidermolysis bullosa dystrophica group (EBD)

Occurrence/Epidemiology
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Incidence: 0.8/100,000 live births per year. It is one of the rare orphan diseases.

Etiopathogenesis
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Causative mutations have so far been described in 18 genes coding for components of the keratin filaments of the cytoskeleton, adherens junctions, desmosomes and hemidesmosomes. These "index genes" are also expressed in other organs (gastrointestinal, respiratory and urogenital tracts), which are also clinically implicated. 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. The primary, structural-functional defects also influence secondary epigenetic phenomena (induction of inflammatory cascades, influence on the microenvironment) and thus the individual highly variable 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 due to cytolysis of basal/suprabasal keratinocytes (epidermolytic blistering).
  • Antigen mapping: Intraepidermal cleavage with hemidesmosome markers at the base of the blister.
  • Electron microscopy: Intracellular cytolysis above the hemidesmosomes in the basal keratinocytes.
  • Clinical: Healing of the blisters 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.
  • Clinical: 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 the blister roof and blister floor.

Epidermolysis bullosa dystrophica group (EBD). The common features of the 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.
  • Clinical: Scarring, milia, nail loss.
  • Electron microscopy: blistering below the lamina densa.

Poikilodermic Kindler syndrome . Autosomal recessive Kindler syndrome may be referred to as the 4th group of EB:

  • The cleavage 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.

Differential diagnosis
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General therapy
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  • The treatment is generally unsatisfactory and predominantly symptomatic. Genetic counselling of diseased families, if necessary using possibilities for 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.
  • In general, the aggressiveness of the treatment should correspond to the severity of the clinical picture. In the case of non-dystrophic epidermolyses, the prevention of secondary infections is in the foreground, in the case of dystrophic changes, the preservation of the highest possible quality of life, i.e. avoidance of consequential damage (e.g. scarring, scar contractures in the area of the eyes, mucous membranes and esophagus, anemia and vitamin deficiency due to restricted nutrition, skin carcinomas, secondary infections). Patients may have difficulty in eating due to painful involvement of the mucosa, among other things. Therefore, pay attention to nutrition with sufficient vitamins and minerals, if necessary passed diet, if necessary diet plan.
  • Also to be observed: Wear soft, non-abrasive clothing, avoid rough seams, if necessary wear the clothes inside out or sew the seams over. Appropriately padded padding, gel pad or air cushion bed if necessary. Cleaning, possibly disinfecting baths in case of erosion, sterile dressings. In case of extensive erosions, bandage with hydrogel (e.g. Intrasite) or hydrocolloid foils (e.g. Varihesive E). For children upholstered furniture and floors.

External therapy
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The main focus is on the avoidance of mechanical stimuli and irritations as well as the monitoring and treatment of secondary infections. Drying and antiseptic solutions such as quinolinol solution(e.g. Chinosol 1:1000), R042 or potassium permanganate solution(light pink), possibly polihexanide (Serasept, Prontoderm). If necessary, wound treatment, see there. Sufficient fluid replacement. Sterile piercing 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 for eczematisation and itching. General skin care (e.g. with Ungt. emulsif. aq. or 2% urea cream).

Internal therapy
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See below the respective form. In case of secondary infections, broad-spectrum antibiotics as soon as possible after antibiogram.

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

Fissure formation

Clinical picture

Affected gene (protein)

epidermolytic (EBS group)

Epidermolysis bullosa simplex, generalized (Köbner)

KRT 5 (keratin 5); KRT 14 (keratin 14)

Epidermolysis bullosa simplex, localized (Weber-Cockayne)

KRT 5 (keratin 5); KRT 14 (keratin 14

Epidermolysis bullosa simplex, autosomal recessive

KRT 5 (keratin 5); KRT 14 (keratin 14)

Epidermolysis bullosa simplex, Dowling-Meara (EBS-DM)

KRT 5 (keratin 5); KRT 14 (keratin 14)

Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD)

ITGA6, ITGB4,PLECT1(alpha6beta4Integrin)

Epidermolysis bullosa simplex Ogna (Gedde-Dahl)

PLEC1 (Plectin 1)

Epidermolysis bullosa simplex with patchy hyperpigmentation

KTR 5 (Keratin 5)

junktiolytic (EBJ group)

Epidermolysis bullosa junctionalis, Herlitz (JEB-H)

LAMA3,LAMB3,LAMC2 (Laminin332)

Epidermolysis bullosa junctionalis non-Herlitz (JEB-nH) (generalized and localized forms)

Epidermolysis bullosa junctionalis JEB-nH generalized

LAMA3,LAMB3,LAMC2 (Laminin 332) COL17A1 (CollagenXVII)

COL17A1 (CollagenXVII)

Epidermolysis bullosa junctionalis JEB-nH localized

Epidermolysis bullosa junctionalis with pyloric atresia (JEB-PA)

ITGA6,ITGB4 (alpha6beta4Integrin)

dermolytic (EBD Group)

Epidermolysis bullosa dystrophica, generalized (DDEB generalized), previously: DDEB dominans

COL7A1 (collagen VII)

Epidermolysis bullosa dystrophica (RDEB severely generalized), previously: type Hallopeau-Siemens

COL7A1 (collagen VII)

(Recessive dystrophic) Epidermolysis bullosa dystrophica, generalized (RDEB, generalized), previously: RDEB non-Hallopeau-Siemens

COL7A1 (collagen VII)

Note(s)
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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.

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

Literature
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  1. Bauer JW et al (1999) Prenatal diagnosis of recessive hereditary dystrophic epidermolysis bullosa with haplotype analysis of the type VII collagen gene. dermatologist 50: 121-126
  2. Bauer JW et al (2001) Large melanocytic nevi in hereditary epidermolysis bullosa. J Am Acad Dermatol 44: 577-584
  3. Bruckner-Tuderman L (1995) Epidermolysis bullosa hereditaria. dermatologist 46: 61-72
  4. Jonkman MF et al (1999) Hereditary skin diseases of hemidesmosomes. J Dermatol Sci 20: 103-121
  5. He Y et al(2016) Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause SkinFragility
    . On J Hum Genet 99:1395-1404.
  6. Laimer M et al.(2015) Hereditary Epidermolyses JDDG 13: 1125-1134
  7. Schumann H (2009) Epidermolysis bullosa. dermatologist 60: 614-618
  8. Shimizu H, Suzumori K (1999) Prenatal diagnosis as a test for genodermatoses: its past, present and future. J Dermatol Sci 19: 1-8
  9. Woodley DT et al (2003) Normal and gene-corrected dystrophic epidermolysis bullosa fibroblasts alone can produce type VII collagen at the basement membrane zone. J Invest Dermatol 121: 1021-1028

Disclaimer

Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

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Last updated on: 21.12.2020