Epidermolysis Bullosa Simplex, with Muscular Dystrophy
|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)|
|Gene (s)||PLEC1 (601282)|
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) . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 .
EBS is usually caused by dominant negative missense muations in KRT5 and KRT14 genes that are mostly expressed in the basal epidermal layer . 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 . 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 . 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 . 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 .
A distinct variant of EBS is associated with congenital pyloric atresia (EBS-PA) . 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 . 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 ), the influence of silent sequence alterations on phenotypic manifestations of the EBS causing mutations .
Unusual EBS variants
EBS caused by mutations affecting other components of the hemidesmosomal plaque .
EBS superficialis due to mutated COL7A1, suggested to represent a subset of dystrophic EB .
Recessive EBS caused by missense or nonsense mutations , 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 . 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 . 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 .
EBS with migratory circinate seems to be specifically caused by a recurrent frameshift mutation affecting the structure of KRT5 tail domain .
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 .
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 . 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)  and variants of lethal acantholytic EBS.
Lethal acantholytic EBS (LAEB) is mostly due to molecular aberrations of desmosomal desmoplakin (DSP) . 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 .
Ectodermal dysplasia-skin fragility syndrome(EDS) is a mostly homozygous inherited disorder of desmosomes now classified as a specific suprabasal form of EBS . 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 . 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 . Published PKP1 mutations include nonsense, frameshift and splice site mutations .
© graphic design by R. Hametner
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.
Fine JD, Eady RA, Bauer EA, Bauer JW, Bruckner-Tuderman L, Heagerty A, Hintner H, Hovnanian A, Jonkman MF, Leigh I, McGrath JA, Mellerio JE, Murrell DF, Shimizu H, Uitto J, Vahlquist A, Woodley D, Zambruno G. The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol. 2008 Jun;58(6):931-50
Uitto J, Richard G. Progress in epidermolysis bullosa: genetic classification and clinical implications. Am J Med Genet C Semin Med Genet. 2004 Nov 15;131C(1):61-74
Laimer M, Lanschützer CM, Nischler E, Klausegger A, Diem A, Pohla-Gubo G, Bauer JW, Hintner H. Erbliche blasen¬bildende Erkrankungen. Klinik, Diagnostik und Therapie der Epidermolysis bullosa. Hautarzt 2009;60:378–388
Fine JD. Epidemiology of inherited Epidermolysis bullosa. In: Fine JD, Hintner H (Eds.) Life with Epidermolysis Bullosa (EB): Etiology, diagnosis, multidisciplinary care and therapy. Springer, Wien-New York 2008, pp 24-29
Fine JD, Johnson LB, Suchindran C, Carter M, Moshell A. The National Epidermolysis bullosa registry. In: Fine JD, Bauer EA, McGuire J, Moshell A (Eds). Epidermolysis bullosa. Clinical, epidemiologic, and laboratory findings of the National Epidermolysis Bullosa Registry. The Johns Hopkins University Press, Baltimore, Maryland, 1999, pp 79-100
Abu Sa'd J, Indelman M, Pfendner E, Falik-Zaccai TC, Mizrachi-Koren M, Shalev S, Ben Amitai D, Raas-Rothshild A, Adir-Shani A, Borochowitz ZU, Gershoni-Baruch R, Khayat M, Landau D, Richard G, Bergman R, Uitto J, Kanaan M, Sprecher E. Molecular epidemiology of hereditary epidermolysis bullosa in a Middle Eastern population. J Invest Dermatol. 2006 Apr;126(4):777-81. Erratum in: J Invest Dermatol. 2006 Jun;126(6):1427
Fewtrell MS, Allgrove J, Gordon I, Brain C, Atherton D, Harper J, Mellerio JE, Martinez AE. Bone mineralization in children with epidermolysis bullosa. Br J Dermatol. 2006 May;154(5):959-62
Fine JD, Johnson LB, Weiner M, Li KP, Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience,1986-2006. J Am Acad Dermatol. 2009 Feb;60(2):203-11
Tabolli S, Pagliarello C, Uras C, Di Pietro C, Zambruno G, Castiglia D, Sampogna F, Abeni D. Family burden in epidermolysis bullosa is high independent of disease type/subtype. Acta Derm Venereol. 2010 Nov;90(6):607-11
Lane EB, McLean WH. Keratins and skin disorders. J Pathol. 2004 Nov;204(4):355-66
Sørensen CB, Ladekjaer-Mikkelsen AS, Andresen BS, Brandrup F, Veien NK, Buus SK, Anton-Lamprecht I, Kruse TA, Jensen PK, Eiberg H, Bolund L, Gregersen N. Identification of novel and known mutations in the genes for keratin 5 and 14 in Danish patients with epidermolysis bullosa simplex: correlation between genotype and phenotype. J Invest Dermatol. 1999 Feb;112(2):184-90
Ciubotaru D, Bergman R, Baty D, Indelman M, Pfendner E, Petronius D, Moualem H, Kanaan M, Ben Amitai D, McLean WH, Uitto J, Sprecher E. Epidermolysis bullosa simplex in Israel: clinical and genetic features. Arch Dermatol. 2003 Apr;139(4):498-505. Erratum in: Arch Dermatol. 2003 Aug;139(8):1084
Uitto J, Richard G, McGrath JA. Diseases of epidermal keratins and their linker proteins. Exp Cell Res. 2007 Jun 10;313(10):1995-2009
Lu H, Chen J, Planko L, Zigrino P, Klein-Hitpass L, Magin TM. Induction of inflammatory cytokines by a keratin mutation and their repression by a small molecule in a mouse model for EBS. J Invest Dermatol. 2007 Dec;127(12):2781-9
Pulkkinen L, Kimonis VE, Xu Y, Spanou EN, McLean WH, Uitto J. Homozygous alpha6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia. Hum Mol Genet. 1997 May;6(5):669-74
Dang N, Klingberg S, Rubin AI, Edwards M, Borelli S, Relic J, Marr P, Tran K, Turner A, Smith N, Murrell DF. Differential expression of pyloric atresia in junctional epidermolysis bullosa with ITGB4 mutations suggests that pyloric atresia is due to factors other than the mutations and not predictive of a poor outcome: three novel mutations and a review of the literature. Acta Derm Venereol. 2008;88(5):438-48
Schuilenga-Hut PH, Scheffer H, Pas HH, Nijenhuis M, Buys CH, Jonkman MF. Partial revertant mosaicism of keratin 14 in a patient with recessive epidermolysis bullosa simplex. J Invest Dermatol. 2002 Apr;118(4):626-30
Yasukawa K, Sawamura D, McMillan JR, Nakamura H, Shimizu H. Dominant and recessive compound heterozygous mutations in epidermolysis bullosa simplex demonstrate the role of the stutter region in keratin intermediate filament assembly. J Biol Chem. 2002 Jun 28;277(26):23670-4
Fontao L, Tasanen K, Huber M, Hohl D, Koster J, Bruckner-Tuderman L, Sonnenberg A, Borradori L. Molecular consequences of deletion of the cytoplasmic domain of bullous pemphigoid 180 in a patient with predominant features of epidermolysis bullosa simplex. J Invest Dermatol. 2004 Jan;122(1):65-72
Martinez-Mir A, Liu J, Gordon D, Weiner MS, Ahmad W, Fine JD, Ott J, Gilliam TC, Christiano AM. EB simplex superficialis resulting from a mutation in the type VII collagen gene. J Invest Dermatol. 2002 Mar;118(3):547-9
Lanschuetzer CM, Klausegger A, Pohla-Gubo G, Hametner R, Richard G, Uitto J, Hintner H, Bauer JW. A novel homozygous nonsense deletion/insertion mutation in the keratin 14 gene (Y248X; 744delC/insAG) causes recessive epidermolysis bullosa simplex type Köbner. Clin Exp Dermatol. 2003 Jan;28(1):77-9
Groves RW, Liu L, Dopping-Hepenstal PJ, Markus HS, Lovell PA, Ozoemena L, Lai-Cheong JE, Gawler J, Owaribe K, Hashimoto T, Mellerio JE, Mee JB, McGrath JA. A homozygous nonsense mutation within the dystonin gene coding for the
coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex. J Invest Dermatol. 2010 Jun;130(6):1551-7
Uttam J, Hutton E, Coulombe PA, Anton-Lamprecht I, Yu QC, Gedde-Dahl T Jr, Fine JD, Fuchs E. The genetic basis of epidermolysis bullosa simplex with mottled pigmentation. Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9079-84
Hamada T, Yasumoto S, Karashima T, Ishii N, Shimada H, Kawano Y, Imayama S, McGrath JA, Hashimoto T. Recurrent p.N767S mutation in the ATP2A2 gene in a Japanese family with haemorrhagic Darier disease clinically mimicking epidermolysis bullosa simplex with mottled pigmentation. Br J Dermatol. 2007 Sep;157(3):605-8
Gu LH, Kim SC, Ichiki Y, Park J, Nagai M, Kitajima Y. A usual frameshift and delayed termination codon mutation in keratin 5 causes a novel type of epidermolysis bullosa simplex with migratory circinate erythema. J Invest Dermatol. 2003 Sep;121(3):482-5
Smith FJ, Eady RA, Leigh IM, McMillan JR, Rugg EL, Kelsell DP, Bryant SP, Spurr NK, Geddes JF, Kirtschig G, Milana G, de Bono AG, Owaribe K, Wiche G, Pulkkinen L, Uitto J, McLean WH, Lane EB. Plectin deficiency results in muscular dystrophy with epidermolysis bullosa. Nat Genet. 1996 Aug;13(4):450-7
Bauer JW, Rouan F, Kofler B, Rezniczek GA, Kornacker I, Muss W, Hametner R, Klausegger A, Huber A, Pohla-Gubo G, Wiche G, Uitto J, Hintner H. A compound heterozygous one amino-acid insertion/nonsense mutation in the plectin gene causes epidermolysis bullosa simplex with plectin deficiency. Am J Pathol. 2001 Feb;158(2):617-25
Nakamura H, Sawamura D, Goto M, Nakamura H, McMillan JR, Park S, Kono S, Hasegawa S, Paku S, Nakamura T, Ogiso Y, Shimizu H. Epidermolysis bullosa simplex associated with pyloric atresia is a novel clinical subtype caused by mutations in the plectin gene (PLEC1). J Mol Diagn. 2005 Feb;7(1):28-35
Yiu EM, Klausegger A, Waddell LB, Grasern N, Lloyd L, Tran K, North KN, Bauer JW, McKelvie P, Chow CW, Ryan MM, Murrell DF. Epidermolysis bullosa with late-onset muscular dystrophy and plectin deficiency. Muscle Nerve 2011 Jul;44(1):135-41
Koss-Harnes D, Høyheim B, Anton-Lamprecht I, Gjesti A, Jørgensen RS, Jahnsen FL, Olaisen B, Wiche G, Gedde-Dahl T Jr. A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations. J Invest Dermatol. 2002 Jan;118(1):87-93
Jonkman MF, Pasmooij AM, Pasmans SG, van den Berg MP, Ter Horst HJ, Timmer A, Pas HH. Loss of desmoplakin tail causes lethal acantholytic Epidermolysis bullosa. Am J Hum Genet. 2005 Oct;77(4):653-60
Hobbs RP, Han SY, van der Zwaag PA, Bolling MC, Jongbloed JD, Jonkman MF, Getsios S, Paller AS, Green KJ. Insights from a desmoplakin mutation identified in lethal acantholytic epidermolysis bullosa. J Invest Dermatol. 2010 Nov;130(11):2680-3
Green KJ, Simpson CL. Desmosomes: new perspectives on a classic. J Invest Dermatol. 2007 Nov;127(11):2499-515
McGrath JA, McMillan JR, Shemanko CS, Runswick SK, Leigh IM, Lane EB, Garrod DR, Eady RA. Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome. Nat Genet. 1997 Oct;17(2):240-4
McGrath JA, Mellerio JE. Ectodermal dysplasia-skin fragility syndrome. Dermatol Clin. 2010 Jan;28(1):125-9