Long-term follow-up of patients with recessive dystrophic epidermolysis bullosa in the Netherlands: Expansion of the mutation database and unusual phenotype-genotype correlations
ABSTRACT The current classification of recessive dystrophic epidermolysis bullosa (RDEB) comprises two major subtypes: 'severe generalized RDEB' (RDEB-sev gen) with early-onset, extensive, generalized blistering and scarring, complete absence of type VII collagen, and bi-allelic COL7A1 null mutations; milder 'generalized other RDEB' (RDEB-O) with reduced-to-normal type VII collagen expression, and non-null genotypes.
To search for previously unrecognized phenotype-genotype correlations in 33 Dutch RDEB families.
We analyzed extensive clinical follow-up data, available for all patients up to 19 years, detailed type VII collagen immunostaining and genotypes, and correlated clinical phenotype to molecular phenotype and genotype.
We identified 20 novel COL7A1 mutations. In 14 of 15 RDEB-sev gen patients type VII collagen was completely absent, one had strongly reduced type VII collagen, and all carried bi-allelic null mutations. Five of 11 RDEB-O patients developed pseudosyndactyly of the fingers preceded by skin atrophy and flexion contractures later in childhood and adolescence. All five had esophageal involvement and growth retardation. Type VII collagen immunostaining ranged from strongly reduced to slightly reduced in RDEB-O patients with pseudosyndactyly, whereas RDEB-O patients without pseudosyndactyly had slightly reduced to normal type VII collagen staining. There was no difference in genotypes between both groups, although we unexpectedly found bi-allelic null mutations in two of five RDEB-O patients with pseudosyndactyly.
Pseudosyndactyly occurs in approximately half of RDEB-O patients when type VII collagen is strongly reduced. The prognosis in RDEB cannot always be simply predicted from the COL7A1 genotype.
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ABSTRACT: Epidermolysis bullosa (EB) is a group of inherited, mechanobullous disorders caused by mutations in various structural proteins in the skin. There have been several advances in the classification of EB since it was first introduced in the late 19th century. We now recognize four major types of EB, depending on the location of the target proteins and level of the blisters: EB simplex (epidermolytic), junctional EB (lucidolytic), dystrophic EB (dermolytic), and Kindler syndrome (mixed levels of blistering). This contribution will summarize the most recent classification and discuss the molecular basis, target genes, and proteins involved. We have also included new subtypes, such as autosomal dominant junctional EB and autosomal recessive EB due to mutations in the dystonin (DST) gene, which encodes the epithelial isoform of bullouspemphigoid antigen 1. The main laboratory diagnostic techniques-immunofluorescence mapping, transmission electron microscopy, and mutation analysis-will also be discussed. Finally, the clinical characteristics of the different major EB types and subtypes will be reviewed.Clinics in dermatology 01/2012; 30(1):70-7. DOI:10.1016/j.clindermatol.2011.03.012 · 3.11 Impact Factor
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ABSTRACT: Dystrophic epidermolysis bullosa (DEB) is a rare hereditary skin disorder caused by mutations in COL7A1, encoding collagen type VII.1 Clinical manifestations of COL7A1 mutations range from generalized skin blistering to mild localized blistering or nail dystrophy.2 The investigation of the molecular basis of DEB has revealed more than 540 different mutations that cannot entirely explain phenotypic variations (HGMD Professional 2010.3, https://portal.biobase-international. com/hgmd/). Inversa recessive DEB (RDEB-I) is a subtype characterized by generalized blistering in the neonatal period. The condition improves with age, and in adults blistering is restricted to intertriginous areas, and severe lesions of the oral and genital mucosa and nail changes occur in the majority of described patients.2 Recent data suggested that amino-acid substitutions affecting arginines or glycines at borders of collagenic subdomains might cause this phenotype.3 We report a German patient with an unusually mild RDEB-I harbouring compound heterozygous mutations in COL7A1.British Journal of Dermatology 05/2011; 164(5):1104-6. DOI:10.1111/j.1365-2133.2011.10230.x · 3.76 Impact Factor
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ABSTRACT: Dystrophic epidermolysis bullosa (DEB) is a heritable blistering disorder that can be inherited autosomal dominantly (DDEB) or recessively (RDEB) and covers a group of several distinctive phenotypes. A large number of unique COL7A1 mutations have been shown to underlie DEB. Although general genotype–phenotype correlation rules have emerged, many exceptions to these rules exist, compromising disease diagnosing and genetic counseling. We therefore constructed the International DEB Patient Registry (http://www.deb-central.org), aimed at worldwide collection and sharing of phenotypic and genotypic information on DEB. As of May 2011, this MOLGENIS-based registry contains detailed information on 508 published and 71 unpublished patients and their 388 unique COL7A1 mutations, and includes all combinations of mutations. The current registry RDEB versus DDEB ratio of 4:1, if compared to prevalence figures, suggests underreporting of DDEB in the literature. Thirty-eight percent of mutations stored introduce a premature termination codon (PTC) and 43% an amino acid change. Submission wizards allow users to quickly and easily share novel information. This registry will be of great help in disease diagnosing and genetic counseling and will lead to novel insights, especially in the rare phenotypes of which there is often lack of understanding. Altogether, this registry will greatly benefit the DEB patients. Hum Mutat 32:1100–1107, 2011. ©2011 Wiley-Liss, Inc.Human Mutation 10/2011; 32(10):1100 - 1107. DOI:10.1002/humu.21551 · 5.05 Impact Factor