RESUMEN
BACKGROUND: Epidermolysis bullosa is a group of rare inherited skin diseases characterized by blister formation following mechanical skin trauma. Epidermolysis bullosa is associated with increased skin cancer rates, predominantly squamous cell carcinomas, yet to our best knowledge, there is no reported case of dermatofibrosarcoma protuberans in a patient with Epidermolysis bullosa. CASE PRESENTATION: Here, we present a 26-year-old man with junctional epidermolysis bullosa, who developed a DFSP on the neck. Initial, the skin alteration was mistakenly not considered malignant, which resulted in inadequate safety margins. The complete resection required a local flap to close the defect, which is not unproblematic because of the chronic inflammation and impaired healing potential of the skin due to Epidermolysis bullosa. CONCLUSIONS: To our best knowledge, this is the first reported case of a skin-associated sarcoma in a patient with EB; however, further investigation is required to verify a correlation.
Asunto(s)
Dermatofibrosarcoma , Epidermólisis Ampollosa de la Unión , Neoplasias Cutáneas , Adulto , Dermatofibrosarcoma/diagnóstico , Dermatofibrosarcoma/cirugía , Epidermólisis Ampollosa de la Unión/epidemiología , Humanos , Masculino , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/cirugíaRESUMEN
BACKGROUND: To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS). METHODS: After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary. RESULTS: Of the 200 participants, 52 (26%) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West. CONCLUSION: A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.
Asunto(s)
Acil-CoA Deshidrogenasa/deficiencia , Enfermedad de Canavan/genética , Fibrosis Quística/genética , Epidermólisis Ampollosa de la Unión/genética , Galactosemias/genética , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Pérdida Auditiva Sensorineural/genética , Hiperoxaluria Primaria/genética , Errores Innatos del Metabolismo Lipídico/genética , Acil-CoA Deshidrogenasa/genética , Adulto , Enfermedad de Canavan/epidemiología , Conexina 26 , Conexinas/genética , Fibrosis Quística/epidemiología , Epidermólisis Ampollosa de la Unión/epidemiología , Femenino , Galactosemias/epidemiología , Expresión Génica , Tamización de Portadores Genéticos/estadística & datos numéricos , Asesoramiento Genético , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Pérdida Auditiva Sensorineural/epidemiología , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hiperoxaluria Primaria/epidemiología , India/epidemiología , Errores Innatos del Metabolismo Lipídico/epidemiología , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/genética , Serina Endopeptidasas/genética , Transportadores de Sulfato/genéticaRESUMEN
Epidermolysis bullosa (EB) is a heritable blistering disorder. We performed a next-generation sequencing-based multigene panel test and successfully predicted 100% of the EB types, including, 36 EB simplex (EBS), 13 junctional EB (JEB), 86 dystrophic EB (DEB), and 3 Kindler EB. Chinese JEB and recessive DEB (RDEB) patients have relatively mild phenotypes; for severe type separately accounts for 45.5% and 23.8%, respectively. We identified 96 novel and 49 recurrent pathogenic variants in 11 genes, although we failed to detect the second mutation in one JEB and five RDEB patients. We identified one novel p.E475K mosaic mutation in the clinically normal mother of one out of 13 EBS patients with KRT5 mutations, one recurrent p.G2034R mosaic mutation, and one novel p.G2043R mosaic mutation in the clinically normal relatives of two out of 19 dominant DEB patients. This study shows that next-generation technology could be an effective tool in diagnosing EB.
Asunto(s)
Colágeno Tipo VII/genética , Epidermólisis Ampollosa de la Unión/genética , Epidermólisis Ampollosa/genética , Queratina-14/genética , Queratina-5/genética , China/epidemiología , Epidermólisis Ampollosa/clasificación , Epidermólisis Ampollosa/epidemiología , Epidermólisis Ampollosa/patología , Epidermólisis Ampollosa de la Unión/clasificación , Epidermólisis Ampollosa de la Unión/epidemiología , Epidermólisis Ampollosa de la Unión/patología , Femenino , Predisposición Genética a la Enfermedad , Genética de Población , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Mosaicismo , Mutación/genética , FenotipoRESUMEN
Junctional epidermolysis bullosa (JEB) is a particularly devastating type of epidermolysis bullosa, especially in the newborn period. Data about the number of new cases of JEB in the United States were collected from the records of the Dystrophic Epidermolysis Bullosa Research Association of America (DebRA) nurse educator. Seventy-one children with JEB were reported to have been born in the 5 years between 2007 and 2011, reflecting an incidence of at least 3.59 per million per year, significantly higher than previously estimated (2.04 per million). There was a high prevalence of morbidity and infant mortality of at least 73%, as 52 of the 71 cases proved fatal by June 2012. These data emphasize the need for future research to develop treatment and ultimately a cure for this disorder.
Asunto(s)
Epidermólisis Ampollosa de la Unión/epidemiología , Epidermólisis Ampollosa de la Unión/mortalidad , Femenino , Humanos , Incidencia , Lactante , Mortalidad Infantil , Recién Nacido , Masculino , Prevalencia , Estudios Retrospectivos , Tasa de Supervivencia , Estados Unidos/epidemiologíaAsunto(s)
Moléculas de Adhesión Celular/genética , Epidermólisis Ampollosa de la Unión/genética , Mutación/genética , Adolescente , Adulto , Niño , Preescolar , Chile/etnología , Epidermólisis Ampollosa de la Unión/epidemiología , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Epidemiología Molecular , Prevalencia , Adulto Joven , KalininaRESUMEN
In this study we describe six Italian patients presenting an unusually mild variant of non-Herlitz junctional epidermolysis bullosa associated with a reduced expression of type XVII collagen. All patients are homozygous for a novel nonsense mutation (R795X) within exon 33 of COL17A1 and show a common haplotype, attesting propagation of an ancestral allele within the Italian population. Analysis of patients' COL17A1 transcripts showed the presence of two mRNA species: a normal-sized mRNA carrying mutation R795X that undergoes rapid decay, and a transcript generated by in-frame skipping of exon 33. Patients keratinocytes were shown to synthesize minute amounts of type XVII collagen, which appeared correctly localized along the cutaneous basement membrane. We therefore suggest that the exon 33-deleted COL17A1 splice variant encodes for type XVII collagen molecules that maintain a functional role and account for the mild phenotype of our patients.
Asunto(s)
Colágeno/genética , Epidermólisis Ampollosa de la Unión/genética , Adulto , Empalme Alternativo , Northern Blotting , Codón sin Sentido , Epidermólisis Ampollosa de la Unión/epidemiología , Femenino , Haplotipos , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Transcripción GenéticaRESUMEN
Patients with generalized atrophic benign epidermolysis bullosa (GABEB), an inherited subepidermal blistering disease, often have no immunologically detectable bullous pemphigoid antigen 2 (BPAG2) in their epidermal basement membrane. Recently, we analyzed the BPAG2 gene (GenBank no. M91669) in an Austrian family with GABEB and identified a homozygous deletion mutation, 4003delTC, that results in a downstream premature termination codon (PTC). This mutation has now been identified in additional descendants, suggesting transmission of this mutant allele through at least six generations. Screening of four other Austrian GABEB families revealed that affected members were homozygous for 4003delTC in two cases and heterozygous in two others. In the latter, mutational analysis identified two novel nonsense mutations, Q1403X and G803X, that were confirmed by restriction endonuclease digestions. Thus, PTCs on both alleles of BPAG2 are present in all of these GABEB families. Immunoprecipitation and northern blot studies of cultured keratinocytes from homozygous GABEB patients show that 4003delTC results in undetectable levels of BPAG2 protein and mRNA-findings consistent with the process of nonsense-mediated mRNA decay. Incubating keratinocytes with cycloheximide increased BPAG2 mRNA to a level detectable by northern analysis. When the latter was used in reverse transcription-PCR studies, the mutation was demonstrated, suggesting that cycloheximide may allow mutational analysis in cases where low transcript levels have previously thwarted RT-PCR studies. These findings account for the absence of BPAG2 in GABEB patients and attest to the importance of this protein in adhesion of epidermis to epidermal basement membrane.
Asunto(s)
Autoantígenos/genética , Proteínas Portadoras , Colágeno/genética , Proteínas del Citoesqueleto , Epidermólisis Ampollosa de la Unión/genética , Proteínas del Tejido Nervioso , Colágenos no Fibrilares , Alelos , Austria/epidemiología , Northern Blotting , Codón de Terminación , Cicloheximida/farmacología , Distonina , Epidermólisis Ampollosa de la Unión/epidemiología , Epidermólisis Ampollosa de la Unión/patología , Salud de la Familia , Femenino , Humanos , Queratinocitos/efectos de los fármacos , Masculino , Datos de Secuencia Molecular , Ácidos Nucleicos Heterodúplex/análisis , Linaje , Mutación Puntual , Reacción en Cadena de la Polimerasa/métodos , Colágeno Tipo XVIIRESUMEN
Epidermolysis bullosa (EB) is a clinically diverse group of conditions characterized by skin fragility and, in certain types, marked dental involvement. The purpose of this study was to determine the prevalence of dental caries in EB and control populations. Healthy individuals and participants from the Southern Clinical Center of the National EB Registry were examined with artificial light and a #23 dental explorer. Caries levels were evaluated by chi-square analysis, regression analyses, and ANOVA (P < 0.05 being significant). The study included 252 individuals with EB, aged 2.3-71 years, and 57 similarly aged controls. The prevalence of dental caries, scored as DMFS (decayed, missing, filled surfaces), was significantly higher in the junctional (mean = 58.6) and recessive dystrophic (mean = 37.6) EB types than controls (mean = 23.2). The simplex (mean = 25.6) and dominant dystrophic (mean = 21.6) EB groups had DMFS levels similar to the control group. Individuals with recessive dystrophic EB had the most severe oral blistering and scarring and did not have generalized enamel hypoplasia. In contrast, junctional EB always was associated with generalized enamel hypoplasia yet the intraoral blistering rarely involved scarring. This study shows that dental caries is increased in dystrophic and junctional EB compared with unaffected individuals or other EB types. While rampant caries appears related to the soft tissue and enamel involvement in these two EB types, other as yet unclear cofactors also must be involved.
Asunto(s)
Caries Dental/epidemiología , Epidermólisis Ampollosa/epidemiología , Adolescente , Adulto , Anciano , Análisis de Varianza , Niño , Preescolar , Cicatriz/epidemiología , Índice CPO , Hipoplasia del Esmalte Dental/epidemiología , Epidermólisis Ampollosa Distrófica/epidemiología , Epidermólisis Ampollosa Distrófica/genética , Epidermólisis Ampollosa Simple/epidemiología , Epidermólisis Ampollosa de la Unión/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de la Boca/epidemiología , North Carolina/epidemiología , Prevalencia , Sistema de Registros , Análisis de Regresión , Factores de RiesgoRESUMEN
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.
Asunto(s)
Epidermólisis Ampollosa/diagnóstico , Epidermólisis Ampollosa/terapia , Animales , Epidermólisis Ampollosa/epidemiología , Epidermólisis Ampollosa Distrófica/diagnóstico , Epidermólisis Ampollosa Distrófica/epidemiología , Epidermólisis Ampollosa Distrófica/terapia , Epidermólisis Ampollosa de la Unión/diagnóstico , Epidermólisis Ampollosa de la Unión/epidemiología , Epidermólisis Ampollosa de la Unión/terapia , Terapia por Ejercicio/tendencias , Terapia Genética/tendencias , HumanosRESUMEN
Junctional epidermolysis bullosa type Herlitz (JEB-H) is the autosomal recessively inherited, more severe variant of "lucidolytic" JEB. Characterized by generalized, extensive mucocutaneous blistering at birth and early lethality, this devastating condition is most often caused by homozygous null mutations in the genes LAMA3, LAMB3, or LAMC2, each encoding for 1 of the 3 chains of the heterotrimer laminin-332. The JEB-H subtype usually presents as a severe and clinically diverse variant of the EB group of mechanobullous genodermatoses. This article outlines the epidemiology, presentation, and diagnosis of JEB-H. Morbidity and mortality are high, necessitating optimized protocols for early (including prenatal) diagnosis and palliative care. Gene therapy remains the most promising perspective.
Asunto(s)
Epidermólisis Ampollosa de la Unión/genética , Epidermólisis Ampollosa de la Unión/patología , Laminina/genética , Moléculas de Adhesión Celular/genética , Epidermólisis Ampollosa de la Unión/epidemiología , Humanos , Piel/patología , KalininaRESUMEN
OBJECTIVE: To present epidemiologic and clinical data from the Australasian Epidermolysis Bullosa (EB) Registry, the first orphan disease registry in Australia. DESIGN: Observational study (cross-sectional and longitudinal). SETTING: Australian private dermatology practice, inpatient ward, and outpatient clinic. PATIENTS: Systematic case finding of patients with EB simplex, junctional EB (JEB), and dystrophic EB and data collection were performed throughout Australia and New Zealand from January 1, 2006, through December 31, 2008. Patients were consecutively enrolled in the study after clinical assessment and laboratory diagnosis. Medical records were retrospectively examined, and physicians involved in EB care were contacted to obtain patient history. A Herlitz JEB case series was prepared from registry data. MAIN OUTCOME MEASURES: Demographics and prognosis of patients with Herlitz JEB. RESULTS: A total of 259 patients were enrolled in the study: 139 with EBS, 91 with dystrophic EB, 28 with JEB, and 1 with Kindler syndrome. Most enrollees were Australian citizens (n = 243), with an Australian prevalence rate of 10.3 cases per million. The age range in the registry was birth to 99 years, with a mean and median age of 24.1 and 18.0 years, respectively. Ages were similar in patients with EBS and dominant dystrophic EB but were markedly lower in patients with JEB. Patients with Herlitz JEB (n = 10) had the highest morbidity and mortality rates, with a mean age at death of 6.8 months. Sepsis, failure to thrive, and tracheolaryngeal complications were the leading causes of death. CONCLUSIONS: The Australasian EB registry is the first registry in Australia and New Zealand to provide original data on age, sex, ethnicity, and geographical and disease subtype distribution. The Australasian Herlitz JEB cohort witnessed a high infant mortality rate and poor prognosis overall.
Asunto(s)
Epidermólisis Ampollosa de la Unión/epidemiología , Sistema de Registros , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Australasia/epidemiología , Biopsia , Niño , Preescolar , Estudios Transversales , Epidermólisis Ampollosa de la Unión/patología , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Estudios Retrospectivos , Piel/ultraestructura , Adulto JovenRESUMEN
BACKGROUND: Herlitz junctional epidermolysis bullosa (HJEB; MIM 226700) is a rare epithelial adhesion disorder caused by null mutations in any of the three genes encoding the alpha3, beta3 and gamma2 chains of laminin-5, and is mainly characterized by extensive mucocutaneous blistering, recurrent infections and early lethality. OBJECTIVES: To perform immunoepitope mapping, electron microscopy and molecular analysis of five Italian patients with HJEB in order to complete the clinical and molecular characterization of patients with HJEB collected in the Italian Registry of hereditary epidermolysis bullosa (IRHEB) and to calculate the HJEB carrier frequency in this population. METHODS: Skin biopsies from perilesional skin of all patients were employed for immunoepitope mapping and electron microscopy examination. Blood genomic DNA was used for mutation analysis in the LAMA3, LAMB3 and LAMC2 genes by heteroduplex scanning, preceded by a search for Italian recurrent mutations. Carrier frequency calculation was performed assuming Hardy-Weinberg equilibrium. RESULTS: Two novel mutations in the LAMA3 (p.R782X) and LAMC2 (c.3235delA) genes, as well as three known and recurrent mutations in the LAMB3 (c.31insC and p.R81X) and LAMC2 (p.Y355X) genes were identified. Based on disease incidence reported in the IRHEB and the prevalence of mutations in each laminin-5 gene, the population carrier risk for HJEB was calculated to be one in 375. CONCLUSIONS: Our delineation of a laminin-5 mutational spectrum in the general Italian population provides a solid basis for expedited diagnosis, accurate genetic counselling and DNA-based prenatal testing for Italian families at risk for recurrence of HJEB.
Asunto(s)
Moléculas de Adhesión Celular/genética , Epidermólisis Ampollosa de la Unión/genética , Mutación , Secuencia de Bases , Niño , Análisis Mutacional de ADN/métodos , Epidermólisis Ampollosa de la Unión/diagnóstico , Epidermólisis Ampollosa de la Unión/epidemiología , Epidermólisis Ampollosa de la Unión/patología , Mapeo Epitopo , Femenino , Genotipo , Heterocigoto , Humanos , Incidencia , Lactante , Recién Nacido , Italia/epidemiología , Masculino , Sistema de Registros , KalininaAsunto(s)
Cruzamiento , Enfermedades de los Perros/genética , Epidermólisis Ampollosa de la Unión/veterinaria , Animales , Modelos Animales de Enfermedad , Enfermedades de los Perros/epidemiología , Perros , Epidermólisis Ampollosa de la Unión/epidemiología , Epidermólisis Ampollosa de la Unión/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Alemania/etnología , Italia/epidemiología , Masculino , Reacción en Cadena de la Polimerasa/veterinaria , PrevalenciaRESUMEN
Cases of epidermolysis bullosa (EB) diagnosed in Northern Ireland during a 23-year period (1962-84) were identified from dermatology clinic files, paediatric hospital notes and cases known by general practitioners. A total of 48 confirmed new cases of EB were diagnosed during the screening period. This involved 31 families, with identification of 36 further cases. The distribution of incident EB subtypes was: simplex 31 (65%), junctional 1 (2%), dystrophic 12 (25%) and acquisita 4 (8%). The incidence rate of new cases of EB diagnosed per year is 1.4/million and prevalence of all forms estimated at 32/million. The prevalence of simplex, junctional and dystrophic forms is 28, 0.7 and 3/million, respectively.
Asunto(s)
Epidermólisis Ampollosa/epidemiología , Epidermólisis Ampollosa Adquirida/epidemiología , Epidermólisis Ampollosa Distrófica/epidemiología , Epidermólisis Ampollosa Simple/epidemiología , Epidermólisis Ampollosa de la Unión/epidemiología , Humanos , Incidencia , Irlanda del Norte/epidemiología , PrevalenciaRESUMEN
Generalised atrophic benign epidermolysis bullosa (GABEB) is a form of junctional epidermolysis bullosa with a recessive mode of inheritance. The gene considered likely to be involved in this disease is COL17A1, since in the majority of GABEB patients the product of that gene, the 180-kD bullous pemphigoid antigen (BP180), is undetectable in skin. We have identified an intragenic COL17A1 microsatellite marker for which 83% of randomly selected control individuals are heterozygous. We observed homozygosity for different alleles of this marker in five out of six collagen type XVII-negative GABEB patients of different European descent. Five of the six COL17A1 alleles of three patients originating from the eastern part of the Netherlands were identical, as were the haplotypes including flanking markers. The 2342delG mutation was identified in all these five alleles. This confirms the expectation that due to genetic drift and hidden inbreeding for an autosomal recessive disorder with low gene frequency, such as collagen type XVII-negative GABEB, most disease alleles from a restricted geographical area will be "identical by descent". Our results demonstrate that involvement of a candidate gene can be confirmed by looking for identity by descent of highly informative intragenic markers.
Asunto(s)
Colágeno/genética , Epidermólisis Ampollosa de la Unión/genética , Genes Recesivos , Adulto , Anciano , Niño , Epidermólisis Ampollosa de la Unión/epidemiología , Femenino , Efecto Fundador , Marcadores Genéticos , Haplotipos , Homocigoto , Humanos , Masculino , Repeticiones de Microsatélite , Datos de Secuencia Molecular , Mutación , Países Bajos/epidemiología , Linaje , Análisis de Secuencia de ADNRESUMEN
The Herlitz type of junctional epidermolysis bullosa (H-JEB) is a severe blistering disease affecting the skin and mucous membranes, which is usually lethal within the first year of life. The laminin 5 genes have been implicated as candidate genes for most patients with H-JEB. Recently, two hotspot mutations were delineated in the LAMB3 gene, known as R42X and R635X, and have been noted in over 50% of mutant LAMB3 alleles. Here, we present a case of H-JEB of Hungarian origin with a neonatal lethal outcome. Monoclonal antibody staining showed a lack of expression of the laminin 5 beta 3 chain, as a possible result of a mutation in one of the laminin 5 genes. Screening of the family identified the previously described mutation R635X in exon 14 of LAMB3 in each of the parents and one healthy sibling in the heterozygous form, while proband was homozygous for R635X, and the other sibling proved to be genotypically normal. These results underscore the widespread prevalence of R635X in H-JEB cases from around the world.
Asunto(s)
Epidermólisis Ampollosa de la Unión/genética , Mutación Puntual , Análisis Mutacional de ADN , Epidermólisis Ampollosa de la Unión/epidemiología , Epidermólisis Ampollosa de la Unión/patología , Resultado Fatal , Humanos , Hungría , Recién Nacido , Laminina/deficiencia , Laminina/genética , Masculino , Microscopía Electrónica , Microscopía Fluorescente , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Piel/patologíaRESUMEN
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.