Epidermolysis Bullosa Junctional, other
|Disease group||Epithelial adhesion disorders|
|DISEASE NAME||EPIDERMOLYSIS BULLOSA JUNCTIONAL, other|
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 organization, proliferation and differentiation of epithelial cells and extracellular matrix substitutes .
The consequences of these mutations at mRNA and protein levels, epigenetically influenced by the individuals' 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).
Junctional EB-other (JEB-o)
According to the latest classification JEB-o comprises junctional EB variant with pyloric atresia (JEB-PA) and Laryngo-onycho-cutaneous (LOC) syndrome. These are dealt with in separate chapters.
Figure 1: Schematic of the basement membrane zone (BMZ).
© graphic design by R. Hametner
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 a6b4 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 a6b4 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.
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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 blasenbildende 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