Junctional epidermolysis bullosa and pyloric atresia in two siblings

Pyloric atresia is a rare disorder that has been seen in association with epidermolysis bullosa. Two male siblings with pyloric atresia and the junctional form of epidermolysis bullosa, confirmed by electron microscopy, are described herein. These cases strengthen the relationship between junctional epidermolysis bullosa and pyloric atresia, which are probably transmitted together in an autosomal-recessive pattern.     

Categorizing immunofluorescence mapping in epidermolysis bullosa with pyloric atresia: Use as a broad prognostic indicator

Epidermolysis bullosa with pyloric atresia is a form of junctional epidermolysis bullosa associated with gastrointestinal abnormalities, which may include pyloric atresia. Genotype phenotype correlation is poorly understood and prognosis is difficult, if not impossible, to predict. Immunofluorescence mapping is an ideal candidate for developing a broad prognostic indicator for epidermolysis bullosa with pyloric atresia without the need for genetic mutation analysis. However, the tool developed in this paper does have limitations due to the small number of cases available and the effects of deleterious mutations in highly conserved cysteine residues on the predicted length of survival.     

Alpha 6 beta 4 integrin abnormalities in junctional epidermolysis bullosa with pyloric atresia

Junctional epidermolysis bullosa with pyloric atresia (JEB-PA) (MIM 226730) is an autosomal recessive disorder resulting from mutations in the genes encoding alpha 6 beta 4 integrin (ITGA6 and ITGB4). Clinically, it is characterized by mucocutaneous fragility and gastrointestinal atresia, which most commonly affects the pylorus. Additional features of JEB-PA include involvement of the urogenital tract, aplasia cutis and failure to thrive. While most affected individuals have a poor prognosis resulting in death in infancy, others have milder clinical features and a better prognosis. We report two previously undescribed homozygous ITGB4 mutations in two unrelated families, which resulted in severe skin blistering, pyloric atresia and lethality in infancy. Delineation of the mutations was used to undertake DNA-based prenatal diagnosis in subsequent pregnancies at risk for recurrence in both families. We review all previously published ITGA6 and ITGB4 mutation reports to help define genotype--phenotype correlation in this rare genodermatosis.     

Junctional epidermolysis bullosa: a mild variant in two Indian sisters

Two sisters developed a bullous skin disease in early childhood. The disease had features of junctional epidermolysis bullosa but differed clinically from previously recorded variants.     

Junctional epidermolysis bullosa in two siblings: clinical observations, collagen studies and electron microscopy

Two siblings with junctional epidermolysis bullosa are described: both survived beyond parturition. They were treated with the usual therapeutic doses of phenytoin, dapsone, prednisolone, and zinc supplements without effect. Investigation of the skin of one of the patients showed that his fibroblasts, collagen synthesis and collagenase levels were normal. In view of the normality of the collagenase levels, it is probably not surprising that phenytoin was ineffective. Electron microscopy demonstrated junctional cleavage without pathology in the dermis itself: abnormal hemidesmosomes were seen as described previously, though it is suggested that this is not the primary abnormality which results in the disease process.     

Junctional epidermolysis bullosa in the Middle East: clinical and genetic studies in a series of consanguineous families

BACKGROUND: Junctional epidermolysis bullosa (JEB) is a group of inherited blistering diseases characterized by epidermal-dermal separation resulting from mutations that affect the function of critical components of the basement membrane zone. This group of autosomal recessive diseases is especially prevalent in regions where consanguinity is common, such as the Middle East. However, the clinical and genetic epidemiology of JEB in this region remains largely unexplored. OBJECTIVE: The aim of the present study was to assess a series of consanguineous JEB families originating from the Middle East. METHODS: We identified 7 families referred to us between 1998 and 1999 and originating from the United Arab Emirates, Saudi Arabia, Sudan, Yemen, and Israel. Histologic, immunofluorescence, and electron microscopy studies were performed to direct the subsequent molecular analysis. DNA obtained from all family members was amplified by means of polymerase chain reaction and analyzed by conformation-sensitive gel electrophoresis with subsequent direct sequencing. RESULTS: In 6 families presenting with the clinical and histologic features distinctive for JEB, mutations in genes encoding 1 of the 3 subunit polypeptides of laminin-5 were identified. Two families each had mutations in LAMB3, 2 in LAMA3, and 2 in LAMC2. Out of 7 distinct mutations, 5 were novel and 2 were recurrent. No relationship was found between the presence of nonsense/frameshift mutations in laminin-5 genes and perinatal mortality, contradicting a major genotype-phenotype correlation previously reported in the European and US literature. Similarly, none of the recurrent LAMB3 hot spot mutations previously described in other populations was found in our series. Finally, in a family with the clinical diagnosis of generalized atrophic benign epidermolysis bullosa, a homozygous non-sense mutation in Col17A1 gene (encoding the BPAG2 antigen) was identified. CONCLUSION: The present report suggests (1) the existence of a unique spectrum of mutations in the Middle East populations and (2) the need for the implementation of a diagnostic strategy tailored to the genetic features of JEB in this region.     

Immunofluorescence analysis of villous trophoblasts: a tool for prenatal diagnosis of inherited epidermolysis bullosa with pyloric atresia

Genetic mutations invalidating the genes for integrin alpha6beta4 and, in some cases, plectin are associated with junctional and simplex epidermolysis bullosa with pyloric atresia (PA-JEB and PA-EBS), respectively. These recessive inherited conditions are characterized by pregnancies with fetal bullae, pyloric atresia, polyhydramnios, and neonatal mucocutaneous blistering, which often results in early postnatal demise. To date, first-trimester DNA-based prenatal diagnosis is not applicable to affected kindred carrying as yet unidentified genetic mutations. Here, we show that first-trimester chorionic villi strongly express both integrin alpha6beta4 and plectin, which persist throughout the pregnancy. Based on this observation, we implemented 25 prenatal diagnoses in kindred at risk for PA-EB by immunomapping, which identified three PA-JEB-affected fetuses and 22 healthy ones. In 19 cases, including the three PA-JEB pregnancies that were prematurely terminated, the results were confirmed by chorionic villous DNA-based tests, which also led to the identification of seven previously unreported mutations in the alpha6beta4 integrin genes. Our prediction was further sustained by the birth of 22 healthy babies. These results validate chorionic villi immunofluorescence examination as a tool for prenatal diagnosis of PA-JEB and PA-EBS and indicate that this procedure could be devised for EB with muscular dystrophy, which is also associated with genetic mutations in plectin.     

Junctional epidermolysis bullosa gravis (Herlitz): diagnostic and genetic aspects

We report on a boy suffering from lethal junctional epidermolysis bullosa gravis (JEBH) (Herlitz-type) (OMIM 226700). Screening for mutations of LAMB3 gene with polymerase chain reaction (PCR) amplification of all exons from genomic DNA and subsequent heteroduplex analysis and dideoxynucleotide sequencing of heteroduplex forming PCR products disclosed two mutations: the recurrent maternal mutation R635X and the novel paternal mutation 1629insG, both in exon 14 of LAMB3. Both mutations lead to a premature termination code, non-sense mediated mRNA decay and to absence of the synthesis of the beta3 chain of laminin 5. During the mutation screening of the index patient a second pregnancy was ascertained. After amniocentesis (14 + 1 week of pregnancy), prenatal diagnosis from fetal cells was performed and compound heterozygosity for both mutations was evident. The consultants decided to have a termination of pregnancy shortly after the diagnosis. Remarkable skin fragility of the fetus was evident by clinical examination. Complete absence of laminin 5 could be demonstrated by immunofluorescence staining. By the third pregnancy of this couple so far screened for mutations by chorionic villus sampling for prenatal molecular diagnosis a healthy but heterozygous child is expected.     

Identification of two rare and novel large deletions in ITGB4 gene causing epidermolysis bullosa with pyloric atresia

Epidermolysis bullosa with pyloric atresia (EB‐PA) is a rare autosomal recessive hereditary disease with a variable prognosis from lethal to very mild. EB‐PA is classified into Simplex form (EBS‐PA: OMIM #612138) and Junctional form (JEB‐PA: OMIM #226730), and it is caused by mutations in ITGA6, ITGB4 and PLEC genes. We report the analysis of six patients with EB‐PA, including two dizygotic twins. Skin immunofluorescence epitope mapping was performed followed by PCR and direct sequencing of the ITGB4 gene. Two of the patients presented with non‐lethal EB‐PA associated with missense ITGB4 gene mutations. For the other four, early postnatal demise was associated with complete lack of β4 integrin due to a variety of ITGB4 novel mutations (2 large deletions, 1 splice‐site mutation and 3 missense mutations). One of the deletions spanned 278 bp, being one of the largest reported to date for this gene. Remarkably, we also found for the first time a founder effect for one novel mutation in the ITGB4 gene. We have identified 6 novel mutations in the ITGB4 gene to be added to the mutation database. Our results reveal genotype–phenotype correlations that contribute to the molecular understanding of this heterogeneous disease, a pivotal issue for prognosis and for the development of novel evidence‐based therapeutic options for EB management.     

Compound heterozygosity for novel splice site mutations of ITGA6 in lethal junctional epidermolysis bullosa with pyloric atresia

Junctional epidermolysis bullosa with pyloric atresia (PA‐JEB) is a rare congenital bullous disease with gastrointestinal disturbance that has been associated with mutations in ITGA6 or ITGB4 encoding the α6 or β4 subunit of integrin, respectively. Only six ITGA6 mutations in PA‐JEB have been reported while many ITGB4 mutations have been identified, and all the ITGA6 mutations were homozygous. Here, we report a case of lethal type PA‐JEB, in which immunofluorescence showed the lack of both α6 and β4 integrins resulting from compound heterozygous splice site mutation in ITGA6, c.387G>T and c.2506‐1G>C. Maternal c.387G>T induced the skipping of the entire exon 3 and both exons 3 and 4, resulting in premature termination codon and in‐frame deletion, respectively. Paternal c.2506‐1G>C caused the skipping of the exon 20 and resulted in in‐frame deletion. As a reason why the present case showed lethal phenotype despite the in‐frame deletion mutation, rapid degradation of neo‐synthesized α6 protein and/or impaired transport of integrin were suggested from previous reports, and the lack of localization of integrin α6β4 to the epidermal basement membrane resulted in skin fragility. Our case expands the variety of integrin α6 mutations in PA‐JEB.