Epidermolysis Bullosa Junctional, with Pyloric Atresia


Disease group Epithelial adhesion disorders
Synonymous None (old synonyms may be confusing and should not be used any more)
Estimated prevalence 0,4/1.000.000 in the United States (all junctional epidermolysis bullosa subtypes)
OMIM 226730
Inheritance Autosomal recessive
Gene (s) ITGB4 (147557), ITGA6 (147556)


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

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).

Junctional EB with Pyloric Atresia (JEB-PA)

Infants affected with epidermolysis bullosa with pyloric atresia (JEB-PA) are born with widespread blistering and areas of missing skin. Blisters continue to appear in response to minor injury or friction, such as rubbing or scratching. Most often, blisters occur over the whole body and affect mucous membranes.

Infants with JEB-PA are born with pyloric atresia. Signs of pyloric atresia include vomiting, a swollen (distended) abdomen, and an absence of stool. Pyloric atresia is life-threatening and must be repaired with surgery soon after birth.

Other complications of JEB-PA can include fusion of the skin between the fingers and toes, abnormalities of the fingernails and toenails, contractures that restrict movement, and alopecia. In some patients malformations of the urinary tract, including the kidneys and bladder are seen.


Thejunctional EB variant with pyloric atresia (JEB-PA) is caused by mutations in the genes encoding hemidesmosomal α6β4 integrin (ITGB4, ITGA6). The level of tissue separation in JEB-PA is just above the plasma membrane. Characteristically, small fragments of the basal keratinocyte plasma membrane remain attached to the dermal side of separation (hemidesmosomal EB). Besides a genetically based total lack of functional α6β4 integrin with a severe disease course, milder variants caused by compound-heterozygous mutations were described [6]. Recently, also recurrent ITGB4 mutations indicative for founder effect have been reported [7].


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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Natsuga K, Nishie W, Shinkuma S, Nakamura H, Arita K, Yoneda K, Kusaka T, Yanagihara T, Kosaki R, Sago H, Akiyama M, Shimizu H. A founder effect of c.1938delC in ITGB4 underlies junctional epidermolysis bullosa and its application for prenatal testing. Exp Dermatol. 2011 Jan;20(1):74-6