Epidermolysis Bullosa Simplex, with Muscular Dystrophy

DISEASE CARD

Disease group Epithelial adhesion disorders
DISEASE NAME EPIDERMOLYSIS BULLOSA SIMPLEX WITH MUSCULAR DYSTROPHY
Synonymous None (old synonyms may be confusing and should not be used any more)
Estimated prevalence 4,6/1.000.000 in the United States (all epidermolysis bullosa simplex subtypes)
OMIM 226670
Inheritance Autosomal recessive
Gene (s) PLEC1 (601282)

Definition

Epidermolysis bullosa (EB) is the term applied to a clinically and genetically heterogeneous spectrum of rare inherited conditions that are characterized by a marked mechanical fragility of epithelial tissues with blistering and erosions following minor trauma. EB is based on mutations involving at least 14 structural genes expressed within the epidermis and mucocutaneous basement membrane zone (BMZ) [1]. In addition to the skin involvement, many EB forms present as a multisystemic disease associated with numerous extracutaneous manifestations. The resulting morbidity and mortality makes it necessary to approach the patients by multidisciplinary management.

Molecular pathogenesis of EB

Causative mutations target intracellular, transmembrane and extracellular matrix proteins of the BMZ that is the adhesive interface between epithelial cells and the underlying matrix (Fig. 1). These components mantain the integrity of the dermal-epidermal anchoring complex and barrier function, control organizations, proliferation and differentiation of epithelial cells and extracellular matrix substitutes [2]. The consequences of these mutations at mRNA and protein levels, epigenetically influenced by the indiviuals' genetic background and environmental trauma contribute to the pronounced phenotypic variability and severity within the broad spectrum of EB subtypes [3]. The genetic heterogeneity also highlights the relevance of identification and characterization of specific mutation as a prerequisite for exact diagnosis and targeted molecular therapy.

Epidemiology of EB

Accuracy and comparability of epidemiological data regarding EB are limited by frequent misdiagnosis, misclassification and restricted access to experts [4]. The first initiative to overcome these obstacles, the U.S. National EB registry (NEBR), was founded in 1986. It became the wolrd's largest cohort of well-characterized and systematically monitored EB patients that currently comprises more than 3200 individuals with long term follow-up and whose demographics have been shown to closely mirror that of the entire North American population, as well that of EB patient cohorts elsewhere in the world [5]. Referring to evidence-based data on the NEBR study population, the overall prevalence and incidence rates of EB have been estimated to be 8.22 and 19.60 per million, respectively, by extrapolation (EBS: 4.60/10.75; JEB: 0.44/2.04; DDEB: 0.99/2.86; RDEB: 0.92/2.04).

Epidermolysis bullosa simplex (EBS)

EBS is the most common subtype of EB, accounting for 75-85% of all cases in western countries [6]. It is characterized by trauma- or friction- induced skin blistering with either localized or more disseminated anatomic distribution. Local variants can present with a very subtle phenotype and thus may be underdiagnosed. Unless there is a secondary infection, erosions usually heal without scarring, but may leave hyperpigmentation. Additional clinical features may comprise palmoplantar keratoderma (skin thickening of palms and soles), nail dystrophy, nail shedding and alopecia. Mucosal involvement is seen rarely. High ambient temperatures or sweating (summer) are often aggravating factors. Severe blistering in EBS is associated with marked morbidity. Transcutaneous protein loss and involvement of mucosa lead to malnutrition, anemia, fluid and electrolyte loss and even bone mineralization defects [7]. Severe forms are associated with sometimes overwhelming infections as the most common cause of mortality as well as an increased risk for skin cancer and death [8]. Besides these devastating somatic aspects, EB additionally has a significant psychological, social and economic impact. Disabling deformities, management of chronic pain and worsened wound healing impair quality of life in any EB variant may lead to depression and, sometimes, suicidal ideation. Moreover, divorce is common among parents of a severely affected EB child, complicated by extreme financial burdens imposed on these patients [9].

Pathogenesis

EBS is usually caused by dominant negative missense muations in KRT5 and KRT14 genes that are mostly expressed in the basal epidermal layer [10]. Phenotype-genotype analysis revealed that mutations affecting conserved areas at the beginning (N-terminal end-domain) and end (C-terminal end-domain) of the central alpha-helical rod segment of keratin molecules are usually associated with a more severe disruption of cytoskeleton and clinical phenotype probably due to an inhibited end to end aggregation of keratin filaments [11]. Mutations affecting less conserved areas, like the head or tail domain commonly cause a milder phenotype, although many exceptions from this rule have also been reported [12]. Disease severity is further influenced by homozygosity (severe manifestations) or heterozygosity (milder manifestations) of the genetic defect as well as the kind of point mutation. Ultrastructural findings in EBS are cell vacuolization, keratin filament clumping, cytolysis and blister formation [13]. Decreased mechanical resistance to cell deformation, excessive apoptotic activity, possibly induced by keratin clumps, and up-regulation of the inflammatory response have been implicated in the pathogenesis of the disease and represent novel therapeutic targets [14].

A distinct variant of EBS is associated with congenital pyloric atresia (EBS-PA) [15]. Poorly functional or absent anchoring complexes cause intracellular tissue separation within the lower basal cell layer ot the epidermis and intestinal mucosa. An inflammatory response contributes to development of secondary fibrosis, leading to obstruction of intestinal lumina, especially in anatomically narrow spaces like the pylorus, although duodenal, anorectal and urogenital atresia are possbile [16]. Notably, EBS-PA shares common clinical features with the more prevalent variant of JEB-PA (see there).

Phenotypic improvement with age in some EBS variants has been described. Possible mechanisms are compensatory overexpression of keratins such as KRT15, somatic genetic events (revertant mosaicism [17]), the influence of silent sequence alterations on phenotypic manifestations of the EBS causing mutations [18].

Unusual EBS variants

  • EBS caused by mutations affecting other components of the hemidesmosomal plaque [19].

  • EBS superficialis due to mutated COL7A1, suggested to represent a subset of dystrophic EB [20].

  • Recessive EBS caused by missense or nonsense mutations [21], resulting in loss of gene function rather than a dominant negative effect. Groves et al. recently identified a homozygous nonsense mutation in the dystonin gene (DST) in a new form of autosomal recessive EBS [22]. DST encodes the coiled-coil domain of the epithelial isoform of bullous pemphigoid antigen 1 (BPAG1-e). The mutation led to the loss of hemidesmosomal inner plaques and a complete absence of skin immunostaining for BPAG1-e, as well as reduces labeling for plectin, the β4 integrin subunit, and for type XVII collagen.

  • EBS with mottled pigmentation is strongly associated with a missense mutation (p.P25L) affecting the KRT5 head domain [23]. This aberration is suggested to impair melanin granule aggregation and keratin filament function by interfering with post-translational processing. Other data, however, suggest the same phenotype to result from other mutations in KRT5 and KRT14 or unrelated genes like plectin [24].

  • EBS with migratory circinate seems to be specifically caused by a recurrent frameshift mutation affecting the structure of KRT5 tail domain [25].

  • Several distinct variants of EBS are due to mutated PLEC1 that encodes plectin. The hemidesmosomal protein is expressed in various tissues, including gastrointestinal epithelia and stratified muscle. Within skeletal muscle, it localizes to sacrolemma and Z-lines, thus participating in formation of the intermyofibrillar-desmin cytoskeleton [26].

    • In EBS with muscular dystrophy (EBS-MD), aberrant plectin is implicated to affect plasma membrane-cytoskeletal interactions in skin and muscle, thereby leading to epidermal blistering and muscle weakness. Many plectin mutations cluster in exon 31 that encodes the rod domain [27]. Mutations outside of exon 31 may account for EBS with pyloric atresia (EBS-PA) and blister formation within basal keratinocytes. The phenotypic differences between EBS-MD and EBS-PA are suggested to result from distinct pathogenic pathways of plectin mutations. In mutations within exon 31, the residual expression of the rodless isoform, as detected in some EBS-MD patients, may be the reason for milder skin manifestations compared to EBS-PA, yet being associated with late-onset muscle dystrophy [28, 29].

    • Plectin mutations are further also associated with autosomal dominant Ogna type of EBS (due to heterozygous missense mutations within rod-encoding exon 31) [30] and variants of lethal acantholytic EBS.

  • Lethal acantholytic EBS (LAEB) is mostly due to molecular aberrations of desmosomal desmoplakin (DSP) [31]. Lack of DSP tail results in impaired attachment/connection between the keratin intermediate filaments and the desmosomal inner dense plaque in all layers of the epidermis, leading to profound fragility and extensive suprabasal acantholysis in several epithelial tissues [32].

  • Ectodermal dysplasia-skin fragility syndrome(EDS) is a mostly homozygous inherited disorder of desmosomes now classified as a specific suprabasal form of EBS [1]. Desmosomes are multiprotein complexes which mediate intercellular adhesion by anchoring intermediate filaments to cell membrane but also play key structural and signaling roles in several aspects of cell biology and tissue homeostasis [33]. EDS is caused by loss-of-function mutations on both alleles of the PKP1 gene that codes for plakophilin1, a component of the desmosomal plaque [34]. Published PKP1 mutations include nonsense, frameshift and splice site mutations [35].

© graphic design by R. Hametner

Figure legend

Schematic of the basement membrane zone (BMZ).Intermediate filaments composed of keratin 5 and 14 insert on the keratin (cytoskeletal) linker proteins plectin and BPAG1 (BP230) at the superior aspect of the BMZ. Plectin and BPAG1 interact with transmembrane α6β4 integrin and type XVII collagen (BP180/BPAG2), forming hemidesmosomes that attach basal keratinocytes to the underlying basement membrane. Anchoring filaments reach out below the hemidesmosome and include laminin-332 and laminin-311 that associate with type XVII collagen and α6β4 integrin, but also laminin-511, type IV collagen and nidogen, thereby forming the lamina densa. Anchoring fibrils extend as banded projections from the lamina densa and contain type VII collagen molecules. Type VII collagen triple helices attach the lamina densa to papillary dermis and are critical for the integrity of the epidermal-dermal junction through their ability to bind laminin-332.

References

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