Etiology

Genetic mutations lead to specific protein abnormalities, resulting in varying degrees of mechanical fragility and blister formation, which are the hallmark features of epidermolysis bullosa (EB). Mutations in 16 genes associated with over 30 clinical EB subtypes have been described to date.[8] These occur because epidermal-dermal adherence requires the presence of normal amounts, and the proper ultrastructural distribution, of many epidermal, dermal, and basement membrane proteins and proteoglycans.

Inherited EB may be transmitted in an autosomal dominant or autosomal recessive manner.[1][9]​ All subtypes of inherited EB are caused by mutations arising within the genes encoding or influencing specific structural proteins within the epidermis or skin basement membrane zone.[1][9]

EB simplex (EBS) is characterized by blistering within the plane of the basal keratinocyte. Most cases are due to dominant negative mutations, and 75% of cases are mutations in keratin genes (K5 and K14).[1][9][10]​ Rare cases have been shown to be caused by mutations in genes encoding for exophilin-5 (Slac2-b) and bullous pemphigoid antigen-1 (BP230; BPAG-1).[11] In 2016, mutations in the KLHL24 gene were identified in a subset of people with EBS who had particular clinical features.[12][13]

EBS with mottled pigmentation (EBS-MP) is caused by K5 mutations, whereas mutations in the plectin gene, a component of the hemidesmosome, cause EBS with muscular dystrophy (EBS-MD), and, rarely, EBS with pyloric atresia (EBS-PA).[14][15][16][17]

Whilst EBS-PA primarily results from mutations arising in genes encoding for the two chains of integrin alpha-6-beta-4, plectin mutations may also result in the same phenotype.[18][19][20]

Mutations within any of the genes encoding for the 3 laminin-332 chains are the cause of severe junctional EB (JEB) and most cases of intermediate junctional EB. These mutations affect the structural integrity of the lamina lucida and presumably the anchoring filament.[21]

Type XVII collagen (bullous pemphigoid antigen-2; BP180) gene mutations are the etiology of some cases of intermediate JEB, most notably the JEB subtype previously known as generalized atrophic benign EB (GABEB).[21]

Mutations in the gene for the integrin alpha-3 subunit have been seen in JEB patients with interstitial lung disease and nephrotic syndrome whilst truncation of the laminin alpha-3A subunit of laminin-332 gives rise to laryngo-onycho-cutaneous (LOC) syndrome.

All forms of dominant dystrophic EB (DDEB) and recessive dystrophic EB (RDEB) are caused by type VII collagen gene mutations.[22] A major component of the anchoring fibril, this protein helps attach the lamina densa to the uppermost dermis. Kindler EB is caused by kindlin-1 gene (fermitin family homolog 1) mutations.[23]

Pathophysiology

Genotype-phenotype correlation across EB subtypes remains to be fully resolved. However, broadly speaking, gene mutations encoding structurally critical regions of epidermal, dermal, and basement membrane proteins and proteoglycans are associated with severe disease activity.

The same mutations that cause skin blistering also cause many of the extracutaneous complications of EB, including those within the eyes, gastrointestinal and genitourinary tracts, and upper respiratory tract.[24][25]​​ Secondary abnormalities, including increased expression of tissue collagenase, undoubtedly contribute to abnormal wound healing.[26] Anemia and growth retardation are at least partially the result of chronic blood, protein, and nutrient loss from the skin and intestinal tract, as well as the presence of chronic systemic inflammation. The precise pathophysiology of highly aggressive carcinogenesis within the setting of severe EB subtypes, particularly severe RDEB, remains to be fully elucidated. In the setting of dystrophic EB (DEB), the site of mutation within the type VII collagen gene may play an important role.[27][28]​​ Chronic inflammation is well recognized to be pro-tumorigenic and, in addition, persistent fibrosis and scarring within a dysregulated tumor microenvironment has been associated with elevated TGF-beta activity in collagen VII deficiency.[29][30][31][32]​​​​​​​ It is clear, however, that human papillomavirus does not play a role in EB-squamous cell carcinomas arising in patients with RDEB.[33]

Classification

Fifth international consensus on diagnosis and subclassification of EB[2]​​

Since 1989, five successive international consensus meetings have been held to update the classification of EB patients, based on the following: where blisters arise ultrastructurally within the skin; their clinical phenotype (both cutaneous and extracutaneous); their genetic mode of inheritance; and their genotypic features.

Since the third report, several new variants of EB have been described, as well as new causative genes, with the fourth classification scheme encompassing molecular findings.[3]​ The fourth classification system was based upon modifications to three previously published reports on the diagnosis and classification of EB.[3] It employs a novel “onion skin” technique whereby patients are sequentially characterized, when data permit, by the ultrastructural level of skin cleavage present, mode of inheritance, clinical findings, immunohistochemical and/or electron microscopic features, targeted proteins, and finally by detected mutation(s).

The fifth report has reclassified a number of entities as genetic syndromes associated with skin fragility as minor or clinically superficial findings, as opposed to the primary defining characteristic that would render them a classical form of EB.[2] ​This includes peeling skin disorders such as acral peeling skin syndrome (associated with suprabasal fragility due to transglutaminase 5 [TGM5] abnormalities) or erosive skin disorders due to inherited abnormalities in desmosomal proteins.

1. EB simplex (EBS). By definition, all people with EBS blister within the epidermis.

EBS subtypes

Autosomal dominant:

  • EBS, localized (EBS-loc; formerly called Weber-Cockayne)

  • EBS, severe (EBS-sev; formerly EBS-gen sev or Dowling-Meara EBS)

  • EBS, intermediate (EBS int; formerly EBS-gen intermed or EBS, Koebner)

  • EBS intermediate with cardiomyopathy

  • EBS with mottled pigmentation (EBS-MP)

  • EBS migratory circinate erythema (EBS-migr)

Autosomal recessive:

  • EBS, severe

  • EBS, severe with pyloric atresia (EBS-PA)

  • EBS, intermediate

  • EBS, intermediate with muscular dystrophy (EBS-MD)

  • EBS, intermediate with cardiomyopathy

  • EBS, localized or intermediate with BP230 deficiency (EBS-AR BP230)

  • EBS, localized or intermediate with exophilin-5 deficiency (EBS-AR exophilin 5)

  • EBS, localized with nephropathy

2. Junctional EB (JEB). All patients blister within the lamina lucida of the dermoepidermal junction (DEJ); JEB is inherited in an autosomal recessive pattern.

  • JEB, severe (JEB-sev; formerly JEB-gen sev or JEB-Herlitz)

  • JEB, intermediate (JEB-intermed; formerly JEB-gen intermed, non-Herlitz, generalized JEB or generalized atrophic benign EB, [GABEB])

  • JEB, localized (JEB-loc)

  • JEB, inversa (JEB-inv or JEB-I)

  • JEB with pyloric atresia (JEB-PA)

  • JEB, late onset (JEB-lo)

  • JEB, with interstitial lung disease and nephrotic syndrome

  • LOC syndrome: JEB, laryngo-onycho-cutaneous syndrome (JEB-LOC; formerly Shabbir syndrome).

3. Dystrophic EB (DEB). All patients blister with DEB beneath the lamina densa of the DEJ.

Dominant dystrophic EB (DDEB)

Autosomal dominant:

  • DDEB, intermediate (formerly Cockayne-Touraine and Pasini subtypes)

  • DDEB, localized

  • DDEB, pruriginosa

  • DDEB, self-improving

Autosomal recessive:

  • RDEB, severe (formerly RDEB-gen sev or; Hallopeau-Siemens RDEB)

  • RDEB, intermediate

  • RDEB, inversa (RDEB-inv)

  • RDEB, localized

  • RDEB, pruriginosa (RDEB-pr)

  • RDEB, self-improving

Dominant and recessive (compound heterozygosity):

  • DDEB, severe

4. Kindler EB (inherited mechanobullous disease with associated photosensitivity and poikiloderma, and having multiple levels of cleavage within, beneath, and/or above the DEJ; formerly Kindler syndrome).

Indeterminate type

In neonates and some infants, insufficient clinical findings prevent accurate determination of specific EB subtypes (e.g., a newborn with confirmed junctional EB [JEB]). Infants are temporarily classified as having indeterminate forms of EB (e.g., indeterminate junctional JEB) and are only later reclassified when the extent of cutaneous and extracutaneous involvement can be better appreciated. This conservative approach is particularly important during the newborn period when, in the absence of other affected family members with a more characteristic clinical phenotype, any attempt at overly stringent subclassification may result in incorrect prognostic information being conveyed to the child's parents.

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