Ancestral patterns of recessive dystrophic epidermolysis bullosa mutations in Hispanic populations suggest sephardic ancestry.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genodermatosis caused by mutations in the gene coding for type VII collagen (COL7A1). More than 800 different pathogenic mutations in COL7A1 have been described to date; however, the ancestral origins of many of these mutations have not been precisely identified. In this study, 32 RDEB patient samples from the Southwestern United States, Mexico, Chile, and Colombia carrying common mutations in the COL7A1 gene were investigated to determine the origins of these mutations and the extent to which shared ancestry contributes to disease prevalence. The results demonstrate both shared European and American origins of RDEB mutations in distinct populations in the Americas and suggest the influence of Sephardic ancestry in at least some RDEB mutations of European origins. Knowledge of ancestry and relatedness among RDEB patient populations will be crucial for the development of future clinical trials and the advancement of novel therapeutics.

Patient-reported outcomes and quality of life in recessive dystrophic epidermolysis bullosa: A global cross-sectional survey.

BACKGROUND: A spectrum of skin disease severity exists in patients with recessive dystrophic epidermolysis bullosa (RDEB). OBJECTIVE: To characterize the patient-reported outcomes and quality of life (QOL) in patients with RDEB. METHODS: A cross-sectional study of patients with RDEB surveyed through the global EBCare Registry. Patient-reported outcomes included skin disease severity, wound characteristics, pain, itch, extracutaneous symptoms, and medications. QOL was measured by using the validated Quality of Life in Epidermolysis Bullosa instrument. RESULTS: A total of 85 patients with RDEB reported 1226 wounds (937 recurrent wounds and 289 chronic open wounds). Overall skin disease severity was self-reported as mild (26%; 22/83), moderate (48%; 40/83), or severe (25%; 21/83). Worsening skin disease severity was significantly associated with larger wounds, increased opiate use, anemia, gastrostomy tube use, infections, osteoporosis, and squamous cell carcinoma. Larger wound size was associated with worse quality of life scores. LIMITATIONS: All data were self-reported from an online epidermolysis bullosa patient registry. CONCLUSIONS: This study shows a significant correlation between larger wound size with worsening skin disease severity and quality of life in participants with RDEB. Worsening skin disease severity significantly correlated with key clinical manifestations. These results show that patients with RDEB are able to self-report their skin disease severity and wounds.

Genotype-Phenotype Correlations of Dystrophic Epidermolysis Bullosa in India: Experience from a Tertiary Care Centre.

Recent advances in the field of genomics have seen the successful implementation of whole exome sequencing as a rapid and efficient diagnostic strategy in several genodermatoses. The aim of this study was to explore the potential of molecular studies in dystrophic epidermolysis bullosa (DEB) in India. Whole exome sequencing was performed using genomic DNA from each case of epidermolysis bullosa, followed by massively parallel sequencing. Resulting reads were mapped to the human reference genome hg19. Sanger sequencing subsequently confirmed the potentially pathogenic mutations. Whole exome sequencing of 18 patients with DEB from 17 unrelated Indian families revealed 20 distinct sequence variants in the COL7A1 gene including 2 widely prevalent mutations. Dominant inheritance was seen in 7 patients, while 11 patients showed a highly variable recessive DEB. This preliminary study using exome sequencing is clearly encouraging and will serve as the basis for future large-scale molecular studies to actively identify and understand DEB in the Indian population.

Epidemiology of inherited epidermolysis bullosa in Romania and genotype-phenotype correlations in patients with dystrophic epidermolysis bullosa.

BACKGROUND: Epidermolysis bullosa (EB) is a rare and so far incurable genetic disease, affecting mainly the skin and mucosal membranes, manifesting with blisters triggered by minor mechanical trauma. Since only few epidemiological data on EB are available, we established a Registry for EB and implemented molecular diagnostic methods. OBJECTIVE: We present epidemiologic data from the EB Registry and genotype-phenotype correlations. METHODS: In 2006, a registry of patients with EB was initiated in the Department of Dermatology of the University of Medicine, as well as molecular diagnostic tools. The patients were diagnosed on clinical bases, and whenever possible, immunofluorescence mapping and molecular analysis were performed. RESULTS: 89 EB patients were enrolled in the study from 2006 to 2012: 58 patients with dystrophic EB (DEB), 20 with EB simplex, one patient was diagnosed with Kindler syndrome; in 10 patients, the type of EB could not be determined. DISCUSSION AND CONCLUSION: We have estimated, the total number of EB patients in Romania and we have estimated the incidence and the prevalence of EB. We have also managed to approximate the distribution of EB types in Romania. Moreover, we performed a phenotypic and genotypic characterization in some of the patients included in the EB register.

Prevalencia de la epidermólisis ampollosa distrófica en España: estudio poblacional usando el método de captura-recaptura con 3 fuentes de datos. Evidencia de la necesidad de mejora en la atención sociosanitaria / Prevalence of Dystrophic Epidermolysis Bullosa in Spain: A Population-Based Study Using the 3-Source Capture-Recapture Method. Evidence of a Need for Improvement in Care

Antecedentes: No existen datos sobre la prevalencia de la epidermólisis ampollosa distrófica en España (EAD). La EAD es una enfermedad rara que conlleva una gran carga para el paciente que la sufre y para el sistema de salud que le atiende. Objetivo: Describir la prevalencia de la EAD en España. Métodos: Hemos empleado datos procedentes de 3 fuentes incompletas de pacientes: departamentos de Dermatología, 2 laboratorios de diagnóstico y la Asociación española de pacientes con epidermólisis ampollosa, DEBRA España, y los hemos combinado usando el método de captura-recaptura. Resultados: Hemos identificado 152 pacientes vivos. La prevalencia estimada de EAD fue de 6,0 casos por millón de habitantes (IC 95%: 4,2-11,8). La prevalencia en niños menores de 18 años fue de 15,3 por millón (IC 95%: 10,4-40,8). De acuerdo con el modelo de captura-recaptura el 77% no son seguidos en unidades de referencia, el 65% no tienen diagnóstico genético y el 76% no pertenecen a DEBRA. Conclusiones: La prevalencia de EAD en España es de 6,0 pacientes por millón de habitantes (IC 95%: 4,2 a 11,8), un número mayor que el estimado en otras zonas del mundo, pero similar a otros encontrados en otros países del Sur de Europa. Este resultado puede ser debido a auténticas variaciones geográficas, o a que los otros registros recogen un número incompleto de casos. La mayoría de los pacientes no son seguidos en unidades de referencia, no tienen diagnóstico genético y no son miembros de la asociación de pacientes, lo cual quiere decir que su situación sociosanitaria es muy mejorable (AU)

Background: Dystrophic epidermolysis bullosa (DEB) is a rare disease that represents a heavy burden for both the patient and the health care system. There are currently no data on the prevalence of DEB in Spain. Objective: To determine the prevalence of DEB in Spain. Methods: We used data from 3 incomplete population-based sources (hospital dermatology departments, diagnostic laboratories performing antigenic mapping, genetic testing or both, and the Spanish Association of Epidermolysis Bullosa Patients [DEBRA]) and combined them using the 3-source capture–recapture methodology. Results: We identified 152 living DEB patients. The estimated prevalence of DEB was 6.0 cases per million (95% CI, 4.2–11.8) in adults and 15.3 (95% CI, 10.4–40.8) in children under 18 years of age. The data indicated that 77% of the patients were not being followed up in specialized centers of reference; 65% had not had a genetic diagnosis, and 76% were not members of DEBRA. Conclusions: The prevalence of DEB in Spain is 6.0 patients per million (95% CI, 4.2–11.8), a figure higher than previous estimates in many areas, but similar to those found in other southern Europe countries. The north–south difference may represent real geographic differences in prevalence, but it might be due to the fact that most of the data come from registries with a lower than expected catchment. Many patients are not being followed up in centers of reference, do not have genetic diagnosis, and are not members of patients’ associations, suggesting that there is room for considerable improvement in their care (AU)

Prevalence of dystrophic epidermolysis bullosa in Spain: a population-based study using the 3-source capture-recapture method. Evidence of a need for improvement in care.

BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is a rare disease that represents a heavy burden for both the patient and the health care system. There are currently no data on the prevalence of DEB in Spain. OBJECTIVE: To determine the prevalence of DEB in Spain. METHODS: We used data from 3 incomplete population-based sources (hospital dermatology departments, diagnostic laboratories performing antigenic mapping, genetic testing or both, and the Spanish Association of Epidermolysis Bullosa Patients [DEBRA]) and combined them using the 3-source capture-recapture methodology. RESULTS: We identified 152 living DEB patients. The estimated prevalence of DEB was 6.0 cases per million (95% CI, 4.2-11.8) in adults and 15.3 (95% CI, 10.4-40.8) in children under 18 years of age. The data indicated that 77% of the patients were not being followed up in specialized centers of reference; 65% had not had a genetic diagnosis, and 76% were not members of DEBRA. CONCLUSIONS: The prevalence of DEB in Spain is 6.0 patients per million (95% CI, 4.2-11.8), a figure higher than previous estimates in many areas, but similar to those found in other southern Europe countries. The north-south difference may represent real geographic differences in prevalence, but it might be due to the fact that most of the data come from registries with a lower than expected catchment. Many patients are not being followed up in centers of reference, do not have genetic diagnosis, and are not members of patients' associations, suggesting that there is room for considerable improvement in their care.

Epidermolysis bullosa: where do we stand?

Epidermolysis bullosa, a genetically determined skin fragility disorder can severely incapacitate the life of the afflicted patient. Although the clinical features are multiple and varied, treatment still remains a major challenge. There have been major changes in the classification of the disease recently. Although there is still a long way to go, good nursing care, and gene therapy could possibly significantly alleviate the suffering of the patients in the future.

The international dystrophic epidermolysis bullosa patient registry: an online database of dystrophic epidermolysis bullosa patients and their COL7A1 mutations.

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.

Restrictions in oral functions caused by oral manifestations of epidermolysis bullosa.

Several forms of epidermolysis bullosa (EB) present oral manifestations. Blistering of the (peri)oral mucosa affects the opening of the mouth, the mobility of the tongue and lips, thereby restricting oral functions. We describe the prevalence and characteristics of oral manifestations of EB in relation to loss of oral functions in a cross-sectional study of different types of EB patients using standardized measurement techniques. Twenty-two patients were included. The mobility of the mandible, lips and tongue was measured, the mandibular function impairment questionnaire (MFIQ) was filled out and additional questions regarding hindrance of EB during oral hygiene and intelligibility of speech (being understood) were asked in structured interviews. The median age was 11.8 yrs. Mobility of the mandible, tongue and lip was restricted, oral hygiene procedures were hindered in most patients. A data comparison was made between the recessive dystrophic EB (RDEB) and junctional EB (JEB) groups. Mandibular function was impaired in both groups but more severely in the RDEB-population. Intelligibility in both groups was almost unaffected. Restrictions in mobility of the mouth, tongue and lips are frequently present in EB patients. These are most severe in the RDEB group and support the clinical relevance of optimizing symptomatic treatment.

Epidermolysis bullosa in Australia and New Zealand.

This article describes the clinical services for EB in Australia and New Zealand. The history and epidemiology of EB in Australia is described. Current treatment and research achievements are described.

The clinical spectrum of dystrophic epidermolysis bullosa.

BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is a genodermatosis resulting from mutations in COL7A1, the gene encoding type VII collagen. The site and specific nature of the underlying mutation determine the clinical phenotype, which ranges widely from a severe mutilating condition to a relatively mild disorder. OBJECTIVES: To document the clinical spectrum of DEB within a defined complete population. METHODS: Since 1992, when compilation of the U.K. epidermolysis bullosa register began, an exhaustive search for DEB sufferers within the Scottish population has been undertaken and their clinical features comprehensively recorded. RESULTS: One hundred and twenty-eight DEB sufferers have been identified within the Scottish population. In descending order, the frequencies of the different forms of DEB were dominant DEB (DDEB) in 88 individuals (68%), DEB of uncertain inheritance in 24 (19%) and recessive DEB (RDEB) in 16 patients (13%). Within this latter group, nine (7%) had the mutilating Hallopeau-Siemens subtype (RDEB-HS), five (4%) had localized (RDEB-loc) and two (2%) had a predominantly flexural (inverse) form of RDEB. During the study, two patients with RDEB died from squamous cell carcinomas (SCCs), one originating in the skin and the second arising in the oesophagus. Gastrointestinal problems such as dysphagia, constipation and anal fissures, and restriction of mouth opening were experienced by the majority of patients with RDEB and by a significant minority of DDEB sufferers. Pseudosyndactyly was most severe in RDEB-HS, all those over 9 years of age having mitten deformities of the hands. Milder pseudosyndactyly or flexion contractures of the fingers were present in younger patients with this subtype, in most adults suffering from other subtypes of RDEB and in 6% of those with DDEB. External ear involvement, a feature not often reported in DEB, was common in RDEB and also occurred in a minority of those with DDEB. Pruriginous lesions and albopapuloid lesions were each present in both DDEB and RDEB. CONCLUSIONS: Most patients with DEB have relatively mild dominantly inherited disease, only a minority suffering from severe recessive subtypes. Scarring, gastrointestinal involvement, albopapuloid lesions and a pruriginosa-like pattern each occur in both DDEB and RDEB. With increasing age, SCC is a major cause of morbidity and mortality.

Identification of the glycine-to-arginine substitution G2043R in type VII collagen in a family with dominant dystrophic epidermolysis bullosa from Hungary.

Epidermolysis bullosa (EB) represents a group of genodermatoses characterized by fragility and easy blistering of the skin. In the dystrophic forms of EB (DEB), blisters occur below the basement membrane, at the level of the anchoring fibrils. In the dominantly inherited forms (DDEB), the predominant type of mutation detected thus far is the substitution of a glycine residue which occurs within the collagenous domain of the molecule characterized by the repeating Gly-X-Y amino acid sequence. In this study, we searched for mutations in DDEB in a family from Hungary, by PCR amplification of segments of COL7A1, followed by heteroduplex analysis. Examination of the PCR fragment corresponding to exon 73 revealed a heteroduplex in affected individuals from the family. Sequence analysis revealed a G-to-A transition at nucleotide 6127 in the triple-helical domain of COL7A1, which converted a glycine residue at amino acid position 2043 to an arginine. This report represents the second incidence of this mutation, G2043R, described first in a family with DDEB from Italy.

Novel glycine substitution mutations in COL7A1 reveal that the Pasini and Cockayne-Touraine variants of dominant dystrophic epidermolysis bullosa are allelic.

Mutations in the type VII collagen gene (COL7A1) have been shown to underlie dystrophic epidermolysis bullosa (DEB). The dominantly inherited forms of DEB have been divided into two clinical subcategories, the Pasini (DDEB-P) and the Cockayne-Touraine (DDEB-CT) variants, on the basis of the presence or absence of albopapuloid lesions. In this study, we have examined the molecular basis of DDEB in two Japanese families, one with DDEB-P and the other with DDEB-CT. Mutation detection strategy consisted of polymerase chain reaction amplification of COL7A1 from genomic DNA, followed by heteroduplex analysis and direct nucleotide sequencing. The results revealed heterozygous glycine substitution mutations, G2076D and G2034R, in these families, respectively. Thus, these two variants of DDEB are allelic, and subtle differences in the clinical presentation may reflect the precise position of the mutation along the type VII collagen molecule. Alternatively, the nature of the substituting amino acid (D versus R) may influence the clinical phenotype. This is the first demonstration of a COL7A1 mutation in DDEB-P, and brings the total number of dominant DEB variants with underlying glycine substitutions in COL7A1 to five, including the pretibial and localized variants as well as the Bart's syndrome, in addition to DDEB-P and DDEB-CT.

The prevalence of epidermolysis bullosa in Scotland.

The prevalence of epidermolysis bullosa (EB) in Britain and most other countries is unknown. Patients suffering from the inherited forms of EB and living in Scotland have been traced. Two hundred and fifty-nine affected people from 76 families have been identified, of whom 211 were clinically assessed. One-third of these Scottish EB sufferers had never been seen by a dermatologist. In Lothian, where there appears to be a relatively high prevalence of EB, 75% of patients were unknown to their general practitioners. The point prevalence of all forms of EB at the outset of the study was 49.0 per million, comprising EB simplex 28.6 per million and dystrophic EB 20.4 per million. Extrapolation of accurate data available for the Lothians suggests that the point prevalence of all forms of EB in Scotland is in excess of these figures.