Epidermolysis Bullosa Junctional, generalized intermediate
|Disease group||Epithelial adhesion disorders|
|DISEASE NAME||EPIDERMOLYSIS BULLOSA JUNCTIONAL, GENERALIZED INTERMEDIATE (formerly JEB non-Herlitz)|
|Estimated prevalence||0,4 / 1.000.000 in the United States (all junctional epidermolysis bullosa subtypes)|
|Gene (s)||COL17A1 (113811), LAMA3 (600805), LAMB3 (150310), LAMC2 (150292)|
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 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).
In the group of junctional EB generalized intermediate (JEB-gen intermediate) is the most prevalent one. In adults, JEB-gen intermediate is characterized by generalized blisters on mechanically challenged body sites. Lesions may progress to form superficial ulcers, crusted lesions, fissures or deep ulcers. Recurrent blistering leads to atrophy, pigmentary disturbances, erythema (poikilodermatous appearance) and faint stellate scars, while severe scarring and milia are rare . In contrast, infants and children often fail to demonstrate many of these clinical manifestations and resemble patients with other forms of EB. Other clinical features include a progressive, typically diffuse, incomplete alopecia that -after normal scalp hair growth in childhood- becomes apparent by end of first or second decade. Dystrophic or absent nails with age after repeated trauma , dental enamel hypoplasia and caries, as well as EB nevi are also seen. Involvement of mucous membranes tends to be more notable in infancy and early childhood and is, in contrast to JEB-gen severe, usually moderate and without scarring. However, 12% of JEB-gen intermediate patients experience potentially life-threatening airway obstruction due to tracheolaryngeal stenosis or obstruction. This complication almost exclusively occurs within the first 2 years of life . Affected individuals may also suffer from esophageal webs and strictures, urogenital alterations resulting in renal dysfunction and eye manifestations. Development of squamous cell carcinomas is uncommon in JEB-gen intermediate [9, 10].
JEB-gen intermediate is mostly autosomal recessively inherited in the COL17A1 gene, although dominant inheritance has been documented [11, 12]. As a consequence, triple helix formation, leading to partial unfolding of the ectodomain, decreased thermal stability and intracellular acculuation, as well as posttranslational modifications or protein targeting to the plasma membrane are interrupted .
Despite the fact that most mutations lead to premature termination codons, their consequences and resulting phenotypes are difficult to predict and require analysis on mRNA and protein level. A molecular profile of a PTC on one allele and a missense or in-frame splice site mutation on the alternate allele may thus allow the production of small amounts of a truncated or altered polypeptide with certain residual functionality. Such variants then retain the ability to be incorporated together with laminin-332 within hemidesmosome-anchoring filament complexes, thereby mediating a milder/moderate phenotype compared to JEB-gen severe.
In addition, presence of revertant mosaicisms can interfere with the disease severity, presenting with an atypically mild phenotype of nonlethal JEB . Different genetic mechanisms have been implicated for this phenomenon, including intragenic crossover, second-site mutation, mitotic gene conversion or true back mutation [15, 16]. In some cases, nonsense mutations cause mild phenotypes because of alternative splicing mechanisms . Alternatively, JEB-o may underlie PTC-prone insertions, deletions, splicing and nonsense mutations as well as missense mutations within the LAM genes that code for the subchains of laminin332 may be found .
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.
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 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
Darling TN, Bauer JW, Hintner H, Yancey KB. Generalized atrophic benign epidermolysis bullosa. Adv Dermatol. 1997;13:87-119
Bruckner-Tuderman L, Schnyder UW, Baran R. Nail changes in epidermolysis bullosa: clinical and pathogenetic considerations. Br J Dermatol. 1995 Mar;132(3):339-44
Fine JD, Johnson LB, Weiner M, Suchindran C. Trachelolaryngeal complications of inherited epidermolysis bullosa: cumulative experience of the national epidermolysis bullosa registry. Laryngoscope. 2007 Sep;117(9):1652-60
Weber F, Bauer JW, Sepp N, Hogler W, Salmhofer W, Hintner H, Fritsch P: Squamous cell carcinoma in junctional and dystrophic epidermolysis bullosa. Acta Dermatol. Venereol. 2001;81:189-192
Mallipeddi R, Keane FM, McGrath JA, Mayou BJ, Eady RA. Increased risk of squamous cell carcinoma in junctional epidermolysis bullosa. J Eur Acad Dermatol Venereol. 2004 Sep;18(5)521-6
Bauer JW, Lanschuetzer C. Type XVII collagen gene mutations in junctional epidermolysis bullosa and prospects for gene therapy. Clin Exp Dermatol. 2003 Jan;28(1):53-60
Almaani N, Liu L, Doppings-Hepenstal PJ, Lovell PA, Lai-Cheong JE, Graham RM, Mellerio JE, McGrath JA. Autosomal dominant junctional epidermolysis bullosa. Br J Dermatol. 2009 May;160(5):1094-7
Huilaja L, Hurskainen T, Autio-Harmeinen H, Sormunen R, Tu H, Hofmann SC, Pihlajaniemi T, Bruckner-Tuderman L, Tasanen K. Glycine substitution mutations cause intracellular accumulation of collagen XVII and affect its post-translational modifications. J Invest Dermatol. 2009 Sep;129(9):2302-6
Frank J, Happle R. Cutaneous mosaicism: right before our eyes. J Clin Invest. 2007 May;117(5):1216-9
Darling TN, Yee C, Bauer JW, Hintner H, Yancey KB: Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation. J Clin Invest 1999;103:1371-1377
Jonkman MF, Pasmooij AM. Revertant mosaicism-patchwork in the skin. N Engl J Med. 2009 Apr 16;360816):1680-2
Nakano A, Chao SC, Pulkkinen L, Murrell D, Bruckner-Tuderman L, Pfendner E, Uitto J. Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs. non-Herlitz phenotypes. Hum Genet. 2002 Jan;110(1):41-51
Ruzzi L, PasH, Posteraro P, MazzantiC, DidonaB, OwaribeK, MeneguzziG, Zambruno G, Castiglia D, D'Alessio M. A Homozygous Nonsense Mutation in Type XVII Collagen Gene (COL17A1) Uncovers an Alternatively Spliced mRNA Accounting for an Unusually Mild Form of Non-Herlitz Junctional Epidermolysis Bullosa. J Invest Dermatol. 2001 Jan;116(1):182-7