Cases Of Epidermolysis Bullosa Simplex Research Articles

Epidermolysis Bullosa in Chinese Patients: Genetic Analysis and Mutation Landscape in 57 Pedigrees and Sporadic Cases.

Epidermolysis bullosa encompasses a group of inherited blistering skin disorders. The pathogenic mutations in 10–25% of patients with epidermolysis bullosa have not been identified by Sanger sequencing. The aims of this study were to identify the pathogenic sequence alterations in a large cohort of Chinese patients with epidermolysis bullosa and to clarify the relationship between clinical phenotypes and genotypes. Whole-exome sequencing was performed on 44 pedigrees and 13 sporadic cases. The results were further confirmed by Sanger sequencing. In total, 52 mutations, comprising 19 novel and 33 previously reported mutations, were identified in 5 genes, with a mutation detection rate of 100%. A relationship between subtypes and pathogenic genes was established: 12 cases of epidermolysis bullosa simplex were associated with mutations in KRT5/14 and PLEC; one case of junctional epidermolysis bullosa carried mutations in ITGB4; and 44 cases of dystrophic epidermolysis bullosa were caused by mutations in COL7A1. The results of this study support whole-exome sequencing as a promising tool in the genetic diagnosis of epidermolysis bullosa.

经外显子组测序确诊一例伴斑点状色素沉着的单纯型大疱性表皮松解症

经外显子组测序确诊一例伴斑点状色素沉着的单纯型大疱性表皮松解症

An unusual case of bullae and scars

<p align="center">The term epidermolysis bullosa (EB) encompasses a group of inherited mechano-bullous disorders, clinically characterized by blisters over skin and mucosae following minor frictional trauma. The diagnosis is predominantly clinical, but further classification is carried out by defining the histological level of the split. Histopathology tends to be ambiguous, as it was in this case. Our case is of a twelve-year-old male child who came with complaints of recurrent painful fluid filled lesions all over the body since 10 days of birth, aggravated by trauma, with exacerbations in the summer, and with a history of similar lesions in the mother and maternal uncle. On examination, there were multiple flaccid bullae, crusted erosions, scars and milia over trauma prone sites, such as the elbows, back, knees, shins and knuckles, with nail dystrophy and pitting of the teeth. The clinical impression as well as histopathology suggested a dominant dystrophic or a junctional EB, but immunofluorescence antigen mapping revealed it to be a case of EB simplex. We must thus bear in mind that histopathology is not definitive in EB, and immunofluorescence antigen mapping or transmission electron microscopy is imperative to correctly diagnose it.</p>

A comprehensive next-generation sequencing assay for the diagnosis of epidermolysis bullosa.

Historically, diagnosis of epidermolysis bullosa has required skin biopsies for electron microscopy, direct immunofluorescence to determine which gene(s) to choose for genetic testing, or both. To avoid these invasive tests, we developed a high-throughput next-generation sequencing (NGS)-based diagnostic assay called EBSEQ that allows simultaneous detection of mutations in 21 genes with known roles in epidermolysis bullosa pathogenicity. Mutations are confirmed with traditional Sanger sequencing. We present our EBSEQ assay and preliminary studies on the first 43 subjects tested. We identified 11 cases of epidermolysis bullosa simplex, five cases of junctional epidermolysis bullosa, 11 cases of dominant dystrophic epidermolysis bullosa, 15 cases of recessive dystrophic epidermolysis bullosa, and one case that remains without diagnosis. We also found an additional 52 variants of uncertain clinical significance in 17 of the 21 epidermolysis bullosa-associated genes tested. Three of the variants of uncertain clinical significance were also found in three other patients, for a total of 49 unique variants of uncertain clinical significance. We found the clinical sensitivity of the assay to be 75% to 98% and the analytical sensitivity to be 99% in identifying base substitutions and small deletions and duplications. Turnaround time was 3 to 6 weeks. EBSEQ is a sensitive, relatively rapid, minimally invasive, comprehensive genetic assay for the diagnosis of epidermolysis bullosa.

P.46 - A case of epidermolysis bullosa simplex and muscular dystrophy with myasthenic symptoms caused by two novel PLEC mutations

P.46 - A case of epidermolysis bullosa simplex and muscular dystrophy with myasthenic symptoms caused by two novel PLEC mutations

Monoallelic Large Intragenic KRT5 Deletions Account for Genetically Unsolved Cases of Epidermolysis Bullosa Simplex

Monoallelic Large Intragenic KRT5 Deletions Account for Genetically Unsolved Cases of Epidermolysis Bullosa Simplex

Renal Involvement in Epidermolysis Bullosa Simplex: An Unusual Presentation

To the Editor: Epidermolysis bullosa (EB) includes a heterogeneous group of congenital, hereditary blistering disorders [1]. There are few reports of its association with renal dysfunction. We report a case of epidermolysis bullosa simplex (EBS) with persistent proteinuria detected to have IgA nephropathy on renal biopsy. A 4-yold developmentally normal boy born to consanguineous parents, who was diagnosed to have EBS in the neonatal period, developed anasarca since 1 wk. There was history of two similar episodes of edema with proteinuria, treated with diuretics elsewhere. He did not have nail, hair or mucosal surface involvement. He had past history of recurrent pus discharge from the bullous lesions, resolving with cloxacillin. Examination revealed multiple flaccid bullae, some with purulent discharge and post-inflammatory hyperpigmentation. There were no areas of scarring. The child had proteinuria (2+; urine protein: creatinine ratio 0.5) with microscopic hematuria. Blood urea was 35 mg/dL, serum creatinine 0.7 mg/dL, serum cholesterol 167 mg/dL, serum albumin 3.1 g/dL; Anti-streptolysin O and C3 levels were normal. Skin biopsy revealed subepidermal bulla with Laminin 5 staining expression (Fig. 1). Ultrasound showed normal renal system. Histopathological examination and immunofluorescence of the renal biopsy showed IgA nephropathy with mesangioproliferative glomerulonephritis (Fig. 1). Treatment with enalapril led to improvement in proteinuria over 3 mo (urine protein: creatinine ratio 0.23). EB has 4 major variants: EBS, junctional EB [JEB], dominant dystrophic EB [DDEB], and recessive dystrophic EB [RDEB] [1]. Our patient had clinical (absence of scarring ; non-involvement of nails or mucosal surfaces) and histopathological evidence of EBS. Laminin-5 expression is absent in JEB [2]. Renal dysfunction in EB, may be due to skin infections leading to poststreptococcal glomerulonephritis, IgA mesangiopathy or amyloidosis [3]. There is paucity in literature of EB in association with IgA nephropathy, with RDEB, DDEB and JEB subtypes reported previously [2, 4, 5]. Our patient had a different variant (EBS). Although intuitively,

Epidermolysis bullosa simplex: A case report

Epidermolysis bullosa (EB) is a rare hereditary cutaneous disorder inherited mainly in an autosomal dominant fashion. It consists of a group of conditions that cause the skin to be fragile and blister easily. EB has been classified into three types namely; simplex, junctional and dystrophic. Although all three types of EB have different causes, their symptoms are similar, manifesting as painful blisters and sores. Epidermolysis bullosa is a very rare condition but may probably be more common in clinical practice than reported in literature, especially in places like Nigeria where there is under reporting of clinical cases. To the knowledge of the authors, there are few reported cases in Nigeria and none from Bayelsa State in the delta region of the country. We herein present a case of epidermolysis bullosa simplex (Dowling Meara type) in a 35 day old infant. This case is reported with the aim of increasing awareness of its existence in Nigeria and Bayelsa State in particular. Key words: epidermolysis bullosa simplex, case, skin ulcers

A novel keratin 5 mutation in a familial cluster

We report a case of epidermolysis bullosa simplex (EBS) associated with a family cluster of EBS and a novel KRT5 mutation. The case is presented in the context of recent advances in the study of the disease.

Two new cases of epidermolysis bullosa simplex with mottled pigmentation: A father and son

Two new cases of epidermolysis bullosa simplex with mottled pigmentation: A father and son

A case of epidermolysis bullosa simplex with a newly found missense mutation and polymorphism in the highly conserved helix termination motif among type I keratins, which was previously reported as a pathogenic missense mutation

A case of epidermolysis bullosa simplex with a newly found missense mutation and polymorphism in the highly conserved helix termination motif among type I keratins, which was previously reported as a pathogenic missense mutation

Epidermolysis Bullosa Simplex Associated with Severe Mucous Membrane Involvement and Novel Mutations in the Plectin Gene

We report a novel case of epidermolysis bullosa simplex with severe mucous membrane involvement and mutations in the plectin gene (PLEC1). The patient suffered from extensive blistering of the skin and oral and laryngeal mucous membranes. Electron microscopy of a lesional skin biopsy showed cleft formation within the basal cell layer of the epidermis. Antigen mapping displayed entirely negative staining for plectin, a large (>500 kDa) multifunctional adhesion protein present in hemidesmosomes of the basal keratinocytes. Mutation analysis revealed compound heterozygous, previously undisclosed nonsense mutations, Q1713X and R2351X, of paternal and maternal origin, respectively, within exon 32 of PLEC1. Based on earlier reports, plectin deficiency is associated with late onset muscular dystrophy in patients with epidermolysis bullosa. No signs of muscle weakness have been observed during the 4 y follow-up of our patient. This case illustrates the fact that molecular pathological analyses have prognostic implications in identification and evaluation of patients who appear to be at risk for development of muscular dystrophy later in life.

Animal models of psoriasis

We report a novel case of epidermolysis bullosa simplex with severe mucous membrane involvement and mutations in the plectin gene (PLEC1). The patient suffered from extensive blistering of the skin and oral and laryngeal mucous membranes. Electron microscopy of a lesional skin biopsy showed cleft formation within the basal cell layer of the epidermis. Antigen mapping displayed entirely negative staining for plectin, a large (>500 kDa) multifunctional adhesion protein present in hemidesmosomes of the basal keratinocytes. Mutation analysis revealed compound heterozygous, previously undisclosed nonsense mutations, Q1713X and R2351X, of paternal and maternal origin, respectively, within exon 32 of PLEC1. Based on earlier reports, plectin deficiency is associated with late onset muscular dystrophy in patients with epidermolysis bullosa. No signs of muscle weakness have been observed during the 4 y follow-up of our patient. This case illustrates the fact that molecular pathological analyses have prognostic implications in identification and evaluation of patients who appear to be at risk for development of muscular dystrophy later in life.

Epidermolysis Bullosa of the Dowling-Meara Type: Clinical and Ultrastructural Findings in Five Patients

Clinical and pathologic features of five cases of epidermolysis bullosa simplex, Dowling-Meara type (EBS-DM), are described. Four patients were children, and two were related (father and daughter). Clinical history revealed blistering at birth in three patients; in all of them the signs and symptoms improved with age. Histopathologic and ultrastructural examinations showed cytolysis of the basal cells and clumping of the tonofilaments within the cytoplasm of keratinocytes. Two distinct types of clumps were observed: round (3 patients) and whisklike (2 patients). Two patients had both types of clumps. The presence of both types in the same patient suggests that subtyping of the disease is still premature.

Temperature sensitivity of the keratin cytoskeleton and delayed spreading of keratinocyte lines derived from EBS patients.

Point mutations in the keratin intermediate filament genes for keratin 5 or keratin 14 are known to cause hereditary skin blistering disorders such as epidermolysis bullosa simplex, in which epidermal keratinocytes are extremely fragile and the skin blisters on mild trauma. We show that in 2 phenotypically diverse cases of epidermolysis bullosa simplex, the keratin mutations result in a thermoinstability of the intermediate filament cytoskeleton which can be reproducibly demonstrated even in the presence of tissue culture-induced keratins and in conditions where filament fragility is not otherwise obvious. SV40-T antigen and HPV16 (E6--E7) immortalised keratinocyte cell lines were examined, established from control and epidermolysis bullosa simplex-affected individuals with either severe (Dowling-Meara) or mild (Weber-Cockayne) forms of the disease. In standard tissue culture conditions no significant and consistent abnormality of the keratin cytoskeleton could be demonstrated. However after thermal stress a reduced stability of the keratin filaments was demonstrable in the epidermolysis bullosa simplex cell lines, with filaments breaking into aggregates similar to those seen in skin from EBS patients. These aggregates were maximal at 15 minutes after heat shock and the filament network structure was substantially reversed by 60 minutes. Differences were also seen in the cells during respreading after replating: cells containing mutant keratins were slower to respread than controls and fine aggregates were seen at the cell margins in the Dowling-Meara derived cell line. Such delays in restoring the normal intermediate filament network after physiological processes involving cytoskeleton remodelling may render the cells vulnerable to cytolysis in vivo if physically challenged during this time window. The steady reduction in the mitotic index of the epidermis during the first few years of life could then explain the clinical improvement which is frequently observed in growing children.

Recessive Dystrophic Epidermolysis Bullosa Skin Displays a Chronic Growth-Activated Immunophenotype

Epidermolysis bullosa represents a grouping of inherited skin diseases characterized by epidermal fragility and frequently wounded skin. The recessive dystrophic subtype of epidermolysis bullosa (RDEB) is characterized by extensive dermal scarring after healing of repeated epidermal injuries and by an unusually high incidence of squamous cell carcinoma occurring in chronically wounded skin. In contrast, the simplex form of epidermolysis bullosa usually heals without scarring and does not predispose to malignant neoplasms of the skin. The differences in scarring and the neoplastic potential of these two forms of epidermolysis bullosa prompted us to investigate growth activation and differentiation characteristics in epidermal keratinocytes in individuals with these disorders. The expression of filaggrin, involucrin, cytokeratins, and the growth activation marker psi-3 was examined by immunohistochemistry in skin biopsy specimens from four individuals with epidermolysis bullosa simplex and six individuals with RDEB. Previous experiments using this technique have demonstrated that these antibodies are good markers for identifying growth-activated keratinocytes in wounded and hyperplastic epidermis. All biopsy specimens of healed wounds in skin from patients with RDEB showed epidermis that reacted with antibodies to filaggrin, involucrin, specific cytokeratins, and psi-3 in a growth-activated pattern. This growth-activated phenotype was maintained in keratinocytes from previously wounded skin that had been healed for more than 2 years. The RDEB growth-activated phenotype detected by immunohistochemistry was not associated with microscopically detectable epidermal hyperplasia. In contrast, all cases of epidermolysis bullosa simplex examined showed an epidermal phenotype similar to that of keratinocytes in normal skin. Thus, healing with dermal scar formation in RDEB is associated with a persistent growth-activated immunophenotype of epidermal keratinocytes. This chronic growth activation state or failure of cells to differentiate in a normal fashion may be directly linked to the high incidence of squamous cell cancers in individuals with RDEB.

Epidermolysis bullosa simplex in five consecutive generations.

SUMMARYFour cases of epidermolysis bullosa simplex are described in a family. In five generations comprising thirty‐four subjects, twelve members suffered from the disease, suggesting an autosomal dominant transmission. Histological examination suggested the disease to be of epidermal origin. without implicating the dermal elastic tissue.