Epidermolysis bullosa hereditaria (overview) Q81.-

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 08.05.2022

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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 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.

Classification
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Epidermolysis bullosa simplex group

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

Epidermolysis bullosasimplex Köbner (generalized) (EBS-K)

Epidermolysis bullosa simplex Dowling Meara (herpetiform type) ( EBS-DM)

Rare subtypes of the EB simplex group

Epidermolysis bullosa junctionalis group (EBJ)

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

Epidermolysis bullosa junctionalis generalizedintermediate (historically: JEB-non-Herlitz (JEB nH)

Epidermolysis bullosa junctionalis localized (historically: JEB nH)

Other rare subtypes of junctional EB

Epidermolysis bullosa dystrophica group (EBD)

Rare subtypes of dystrophic EB

Kindler syndrome

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

Etiopathogenesis
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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.

Differential diagnosis
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General therapy
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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.

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

Disease pattern

OMIM

Gene(s)/protein(s)

Gene locus
EBsimplex subtypes with suprabasal cleft formation
Acral peeling skin syndrome 270300 TGM5 (transglutmainase5) 15q15.2
Ectodermal dysplasia skin fragility syndrome 604536 PKP1 (plakophilin) 1q31.2
Skin fragility syndrome with woolly hairs and palmoplantar keratoses 607655 DSP/JUP(desmoplakin/plakoglobulin) 6p24.3/17q21.2
Acantholytic epidermolysis bullosa 609638 DSP/JUP(desmoplakin/plakoglobulin) 6p24.3/17q21.2
EBsimplex subtypes with basal cleavage (autosomal dominant)

Epidermolysis bullosa simplex, generalized (Köbner type)

131900

KRT 5 (keratin 5); KRT14 (keratin 14)

12q13/17q21.2

Epidermolysis bullosa simplex, localized (Weber-Cockayne type)

131800

KRT5 (keratin 5); KRT14 (keratin 14)

12q13.13/17q21.2
Epidermolysis bullosa simplex, localized (Weber-Cockayne type) 131800 ITGB4/Beta4 integrin 17q25.1

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

131760

KRT14 (keratin 14)

17q21.2

Epidermolysis bullosa simplex type Ogna (Gedde-Dahl)

131950

PLEC (plectin 1)

824.3

Epidermolysis bullosa simplex with mottled pigmentation

131960

KRT5 (Keratin 5)

12.q13
Epidermolysis bullosa simplex with mutations in KLHL24 617294 KLHL24 (Kelch like protein member 24) 3q27.1
EBsimplex subtypes with basal cleavage (autosomal recessive)
Epidermolysis bullosa simplex with muscular dystrophy and mutation in PLEC 226670 PLEC (plectin) 8q24.3
Epidermolysis bullosa simplex with pyloric atresia and mutation in PLEC 612138 PLEC (plectin) 8q24.3
Epidermolysis bullosa simplex with mutation in PLEC isoform 1a - PLEC (plectin isoform 1a (P1a)

Epidermolysis bullosa simplex, generalized, intermediate or severe, autosomal recessive with mutation in KRT14

601001 KRT14(keratin 14)

17q21.2

Epidermolysis bullosa simplex, basal, autosomal recessive, with mutation in DST

615425 DST (BP230) 6p12.1
Epidermolysis bullosa simplex, basal, autosomal recessive, with mutation in EXPH5 615028 EXPH5 (exophilin) 11q22.3
EBjunctionalis subtypes

Epidermolysis bullosa junctionalis, generalized severe (historically: Herlitz type)

226700

LAMA3,LAMB3,LAMC2 (Laminins alpha3, beta3, gamma2)

18q11.2/1q23.2/1q25.3

Epidermolysis bullosa junctionalis generalized intermediate (historical: type non-Herlitz)

226650

LAMA3/LAMB3/LAMC2(Laminins)/ COL17A1 (CollagenXVII)

18q11.2/1q23.2/1q25.3/1q24.3-q25.1
Epidermolysis bullosa junctionalis localized with subtypes: localized acral, localized inverse, LOC syndrome.

245560

LAMA3/LAMB3/LAMC2(laminins) / COL17A1 (collagenXVII)/ITGB4 (integrin beta4)

18q11.2/1q23.2/1q25.3/1q24.3-q25.1/17q25.4

Laryngo-onycho-cutaneous syndrome (LOC syndrome)

245560 LAMA3/LAMB3/LAMC2(Laminins) 18q11.2

Epidermolysis bullosa junctionalis with pyloric atresia (JEB-PA)

226730

ITGA6, ITGB4 (alpha6 integrin, beta4 integrin)

2q31.1/17q25.4
Epidermolysis bullosa junctionalis with lung and kidney involvement 614748 ITGA3 (Inteegrin alpha3) 17q21.33

Epidermolysis bullosa junctionalis with hypacusis

226730

ITGA6 (alpha6 integrin), ITGB4 (beta4 integrin)

2q31.1/17q11-qter
Epidermolyis bullosa dystrophica recessive

Epidermolysis bullosa dystrophica recessive, severe generalized (historically: Hallopeau-Siemens type)

226600

COL7A1 (CollagenVII)

3p21.31

Epidermolysis bullosa dystrophica recessive, generalized intermediate (historical: RDEB non-Hallopeau-Siemens)

226650

COL7A1 (CollagenVII)

3p21.31

Epidermolysis bullosa dystrophica inversa

226600 COL7A1 (CollagenVII) 3p21.31

Epidermolysis bullosa dystrophica, pretibial

131850 COL7A1 (CollagenVII) 3p21.31

Epidermolysis bullosa dystrophica, pruritic

604129 COL7A1 (CollagenVII) 3p21.31
Bullous dermolysis of the newborn 131705 COL7A1 (CollagenVII) 3p21.31
Epidermolyis bullosa dystrophica dominant
Epidermolysis bullosa dystrophica dominant, generalized COL7A1 (CollagenVII) 3p21.31
Epidermolysis bullosa dystrophica albopapuloidea (historical type Pasini) 131750) COL7A1 (CollagenVII) 3p21.31

Epidermolysis bullosa dystrophica, dominant, acral

131750 COL7A1 (CollagenVII) 3p21.31

Epidermolysis bullosa dystrophica, recessive with congenital absence of skin and nail dystrophy (see below for dominant phenotype)

132000 COL7A1 (collagenVII) 3p21.31

Epidermolysis bullosa dystrophica "nails only" (Isolated toe nail dystrophy)

607523 COL7A1 (CollagenVII) 3p21.31

Bullous dermolysis of the newborn, dominant

131705 COL7A1 (CollagenVII) 3p21.31
Kindler syndrome
Kindler syndrome 173650 FERMT1 (Kindlin-1) 20p12.3

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. Has C (2018) Hereditary epidermolyses. In: Plewig G et al. Braun-Falco`s dermatology, venereology and allergology. Springer Reference Medicine pp.823-838
  5. He Y et al.(2016) Monoallelic mutations in the translation initiation codon of KLHL24 cause skin
  6. Fragility. Am J Hum Genet 99:1395-1404.
  7. Jonkman MF et al (1999) Hereditary skin diseases of hemidesmosomes. J Dermatol Sci 20: 103-121.
  8. Laimer M et al.(2015) Hereditary epidermolyses JDDG 13: 1125-1134.
  9. Schumann H (2009) Epidermolysis bullosa. Dermatologist 60: 614-618
  10. Shimizu H, Suzumori K (1999) Prenatal diagnosis as a test for genodermatoses: its past, present and future. J Dermatol Sci 19: 1-8
  11. 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

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

Authors

Last updated on: 08.05.2022