GeNeViSTA Epidermolysis Bullosa: An Update Neetu Bhari1, Neerja Gupta2 1Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India 2Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India Correspondence to: Dr Neerja Gupta Email: [email protected] Abstract Classification and pathogenesis Epidermolysis bullosa (EB) is caused by mutation in Mutation in various components of the basement various components of the basement membrane membrane zone responsible for structural support zone and is characterized by increased fragility of in keratinocytes and adhesion of epidermis and skin and mucous membrane. There are four major dermis, results in different types of epidermol- types based on the level of split at the basement ysis bullosa (Figure 1). The new approach for membrane zone – involvement of basal layer of classification in EB is termed as “onion skinning” epidermis in epidermolysis bullosa simplex (EBS), and sequentially takes account of the level of split lamina lucida in junctional EB (JEB) and sublamina at the dermato-epidermal basement membrane densa in dystrophic EB (DEB) while Kindler syn- zone, phenotypic features and genetic characteris- drome (KS) can exhibit multiple levels of split. More tics such as mode of inheritance, targeted protein than 19 genes have been described resulting in the and its relative expression in the basement mem- various subtypes of these 4 major types giving rise brane zone, the involved gene and the type of to diversity of phenotypic expressions. Diagnosis mutation (Fine et al., 2014). is based on the “onion skin approach” which in- The level of split is the basal layer of the cludes clinical presentation, family history, antigen epidermis in epidermolysis bullosa simplex (EBS) mapping and genetic mutation analysis. The main while it is at the level of lamina lucida in junctional stay of management is supportive and wound EB (JEB) and sublamina densa in dystrophic EB care. The newer experimental therapies include (DEB). Kindler syndrome (KS) can exhibit multiple gene therapy, fibroblast and protein therapy and levels of split. More than 19 genes have been mesenchymal and bone marrow transplantation. described resulting in the various subtypes of these 4 major types giving rise to diversity of phenotypic Introduction expressions (Tables 1-6). According to the Na- Epidermolysis bullosa (EB) is a heterogeneous tional Epidemiology Epidermolysis Bullosa Registry group of genetic blistering disorders character- in USA, 92% of the total number of patients with EB ized by increased fragility of skin and mucous have EB simplex, 5% have dystrophic EB, 1% have membrane resulting in blisters and erosions re- junctional EB while 2% of the cases are unclassified solving with or without scarring. According to (Fine et al., 2016). the National Epidemiology Epidermolysis Bullosa The mode of inheritance of EB can be either Registry in USA, the incidence and prevalence of autosomal dominant (AD) or autosomal recessive epidermolysis bullosa are estimated to be 19.60 (AR). The majority of EBS are autosomal dominant per million live births and 8.22 per million popu- while JEB and KS are autosomal recessive. Auto- lation, respectively (Fine et al., 2016). The disease somal recessive form of EBS due to mutation in results in significant morbidity in these children keratin (KRT) 14 has been reported and requires due to cutaneous and extracutaneous involvement special attention due to difference in genetic coun- as there is no specific treatment available yet and seling (Liu et al., 2012). Dystrophic EB can show the current management strategies focuses on the both AD and AR inheritance. The autosomal re- prevention of trauma and wound care. In this cessive type of dystrophic EB is much more severe review, we will focus on different genotypic and compared to the dominant form (Yenamandra et phenotypic expression of this diverse disease. al., 2017). Genetic Clinics 2019 | April - June | Vol 12 | Issue 2 11 GeNeViSTA Table 1 Differences between the clinical features of major types of Epidermolysis Bullosa Features EB simplex Junctional EB Dystrophic EB Kindler syndrome Skin fragility + (with little or no + (with little or no + (with little or no + (with little or no trauma) trauma) trauma) trauma) Blisters Age Birth-12-18 Birth Birth Birth months* Distribution Hands and feet Periorificial areas, Hands, feet, knees, Acral (Localized fingers and toes, and elbows (mild form)/generalized trunk and the upper forms)-whole body airway mucosa including mucosa (in severe forms)** Characteristic Annular or Excessive Localized or Pattern curvilinear groups periorificial generalized with or clusters granulation tissue scarring and milia formation Mucosal + (generalized + (oral and airway + (severe forms) + severe forms) mucous membrane**) Post + hyper/hypo + hyper/hypo + scarring + skin atrophy inflammatory pigmentation pigmentation changes (generalized forms) Skin scarring No -/+ (generalized + (scarring, + severe form) pseudosyndactyly, “mitten” hands and feet & contractures) Nail -/+ (generalized -/+ + and nail loss -/+ dystrophy severe forms) especially toenails Milia -/++ (generalized - + - severe forms) Others Varying degree of Prone to sepsis, Oral and/or Esophageal palmar and plantar amelogenesis esophageal scarring stricture, hyperkeratosis imperfecta, and strictures. photosensitivity, (generalized severe congenital Corneal erosions telangiectasia, forms) malformations of resulting in corneal colitis, urethral the urinary tract opacity leading to stenosis/strictures, and bladder, aplasia loss of vision. and severe cutis, non-scarring High risk of phimosis or scarring alopecia squamous cell carcinoma Inheritance AD/AR AR AD/AR AR EB – Epidermolysis bullosa; AD – Autosomal dominant; AR – Autosomal recessive * Varies depending upon the severity, gene and the variant ** Mucosal involvement of the mouth, upper respiratory tract, esophagus, bladder, urethra, and corneas Genetic Clinics 2019 | April - June | Vol 12 | Issue 2 12 GeNeViSTA EB types Mutated protein Transglutaminase 5 Desmoplakin EBS suprabasal Plakoglobin Plakophilin 1 EB simplex Keratin 5, 14 BP240, Plectin Junctional EB Laminin 332, type XVII collagen Lamina lucida Kindler syndrome α6β4 Integrin, Kindlin 1 Lamina densa Dystrophic EB Sublamina densa Collagen VII Figure 1 Structure of basement membrane zone and classification of epidermolysis bullosa based on the affected gene. Clinical features hypo pigmentation but without scarring. The split is deeper in dystrophic EB and thus results in The onset of EB is usually at birth or immediately milia formation and scarring, nail dystrophy and after the birth except a late onset in some patients various complications such as mitten-like hand de- with EB simplex. formity, pseudosyndactyly and joint contractures (Yenamandra et al., 2017). Epidermolysis Bullosa simplex (EBS): In EB simplex• localized, blisters are late in onset and are mostly localized to trauma prone areas (Figure 2). Generalized severe form of EB starts at birth resulting in extensive and grouped blistering re- solving with hypo or hyperpigmentation (Figure 3). Palmoplantar keratoderma is common and begins in childhood. Nail dystrophy and milia can be seen. The blistering is less severe in the generalized intermediate form of EBS. Various genes implicated in various subtypes of EBS are shown in Tables 2 and 3. Most cases of EBS are caused by mutations in KRT5 and KRT14 (keratin Figure 2 Localized blister on palm in a patient 5 and 14) genes (Pfendner and Bruckner, 1998). of epidermolysis bullosa simplex local- EBS patients with mutation in the TGM5 (trans- ized. glutaminase 5) gene have mild blistering of skin over the acral areas consistent with the diagnosis The hallmark clinical characteristic of this group of acral peeling syndrome. Biallelic mutations in of disorders is skin fragility resulting in spon- the DSP (desmoplakin) gene result in lethal acan- taneous or minor trauma-induced blistering and tholytic EB simplex characterized by skin fragility, erosions. The blistering is superficial in EB simplex universal alopecia, malformed ears, anonychia and and junctional EB, thus it resolves with hyper or cardiomyopathy. Mutation in the EXPH5 (exophilin- Genetic Clinics 2019 | April - June | Vol 12 | Issue 2 13 GeNeViSTA 5) and KRT14 genes causes mild form of EBS with Generalized intermediate type is a less severe an autosomal recessive inheritance. Biallelic mu- clinical presentation of JEB where blistering may tations in PLEC (plectin) gene are known to have be localized to trauma-prone areas and systemic EBS with associated muscular dystrophy and rela- complications are rare. tively higher morbidity and systemic complications. Site-specific monoallelic missense mutation in PLEC Table 2 Various genes involved in suprabasal gene results in EBS Ogna type (EBS-O). Patients with EBS with migratory circinate erythema and subtypes of epidermolysis bullosa sim- mottled pigmentation have been found to have plex. mutation in KRT5. There are also reports of EBS with mottled pigmentation caused by mutation in Subtype Gene KRT14. Recently, some patients of EBS have been Acral peeling skin syndrome TGM5 (Transg- shown to have mutation in KLHL24 gene. Digenic (APSS) lutaminase 5) inheritance with mutations in KRT5 and KRT14 has Epidermolysis bullosa simplex - also been described. superficialis (EBSS) Acantholytic Epidermolysis DSP bullosa simplex (EBS-acanth)