Epidermolysis Bullosa Junctional, generalized intermediate


Disease group Epithelial adhesion disorders
Synonymous None
Estimated prevalence 0,4 / 1.000.000 in the United States (all junctional epidermolysis bullosa subtypes)
OMIM 226650
Inheritance Autosomal recessive
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) [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 individuals' 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).

Clinical Desciription

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 [6]. 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 [7], 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 [8]. 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 [13].

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 [14]. 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 [17]. 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 [18].


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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