Hereditary Epidermolysis Bullosa Research Articles

A case of Neonatal generalized atrophic benign epidermolysis bullosa due to variants of COL17A1 gene

To diagnose and explore the genetic etiology of a neonate with Hereditary epidermolysis bullosa. A neonate who was admitted to Suqian Hospital Affiliated to Xuzhou Medical University on July 10, 2021 was selected as the study subject. Peripheral blood samples were collected from the child and his parents for the extraction of genomic DNA. And target gene capture and next-generation sequencing were carried out. Candidate variants were verified by Sanger sequencing and pathogenicity analysis. The child was found to harbor compound heterozygous variants of the COL17A1 gene, namely c.997C>T (p.Q333X) and c.3481dupT (p.Y1161fs*2), which were respectively inherited from his father and mother. Both variants were predicted to be pathogenic. The child was diagnosed with Generalized atrophic benign epidermolysis bullosa due to the compound heterozygous variants of the COL17A1 gene.

Cutaneous squamous cell carcinomas: a complication of severe forms of hereditary epidermolysis bullosa

Despite an increase in life expectancy and quality of life for patients suffering from severe forms of hereditary epidermolysis bullosa, the occurrence of one or more cutaneous squamous cell carcinomas remains a sometimes serious complication, sometimes life-threatening as early as adolescence. These carcinomas occur preferably on chronic wounds or dystrophic scars in areas not exposed to the sun, and are generally multifocal and recurrent. Their clinical and histological diagnosis is difficult. Regular medical and paramedical monitoring of the skin during dressing repairs enables early detection and rapid, curative surgical management. The pathophysiology of these cutaneous carcinomas is the subject of research aimed at proposing non-surgical alternatives to the patients concerned.

Epidermolysis Bullosa Simplex Caused by a Rare Homozygous Mutation in the EXPH5 Gene.

Recurrent blister formation in children may be a sign of hereditary epidermolysis bullosa even if no salient family history can be elicited. In a case of a 5-year-old boy with recurrent occasional skin blistering, we diagnosed epidermolysis bullosa simplex and found a causative rare homozygous mutation in EXPH5. Precise molecular genetic analysis is a prerequisite for the accurate diagnosis and adequate counselling of affected families.

Consider Zinc Deficiency in Infants with Periorificial Lesions

Background: Zinc is an essential trace element required for proper bodily function. Its deficiency can lead to various manifestations, including dermatological issues. There are two forms of zinc deficiency: hereditary and acquired. Case Report: We present two cases. The first case involved a child with a family history of two brothers who passed away at the age of 1 year, exhibiting a similar symptomatology. The second case involved a patient with hereditary epidermolysis bullosa and malnutrition. Both cases presented with erosive erythematous lesions around the mouth and extremities, which were unresponsive to symptomatic treatments. Additionally, they experienced diarrhea. A definitive diagnosis was made by measuring the levels of zinc in their blood, which were found to be low. Treatment with oral zinc sulfate was prescribed. The first patient showed rapid improvement with the treatment, but experienced recurrence when it was discontinued and subsequently improved again upon reinstatement. Unfortunately, the second infant passed away due to complications from an infection. Conclusion: The presence of periorificial and extremity lesions in infants should raise suspicion of zinc deficiency. Measuring zinc levels in the blood can help confirm the diagnosis and guide appropriate treatment

065 Evaluating pathogenicity of skin autoantibodies in hereditary epidermolysis bullosa hints towards predisposition of autoimmunity

Skin blistering disorders result from damaged proteins involved in the dermal-epidermal adhesion. The damage is either caused by genetically induced defects or by autoantibodies targeting those proteins. In hereditary epidermolysis bullosa (EB) skin blistering is pathogenetically linked to genetic deficiency of distinct proteins of the epidermis or the dermal-epidermal junction, but circulating autoantibodies against these proteins have also been identified in EB patients. So far, the pathogenetic role of these autoantibodies is unclear, as they do not bind the respective skin structures, as shown by negative indirect immunofluorescence (IIF).

Occurrence of autoantibodies against skin proteins in patients with hereditary epidermolysis bullosa predisposes to development of autoimmune blistering disease.

Skin blistering disorders are associated with inherited defects in proteins involved in the dermal-epidermal adhesion or autoantibodies targeting those proteins. Although blistering in hereditary epidermolysis bullosa (EB) is pathogenetically linked to genetic deficiency of distinct proteins of the epidermis or the dermal-epidermal junction, circulating autoantibodies against these proteins have also been identified in EB patients. So far, autoantibodies have been considered bystanders in EB and active pathogenicity of them in EB has not been disclosed. In sera of a cohort of 258 EB patients, we found by ELISA in 22% of the patients autoantibodies against the bullous pemphigoid antigen BP180. The titers correlated negatively with collagen VII skin expression and positively with disease severity. Among those patients, we identified six (2.33%) with clinical features of an autoimmune bullous disorder (AIBD) and positive indirect immunofluorescence (IIF) staining. In literature, we found four more cases of EB patients developing disease-aggravating AIBD. Co-existence of these two rare skin disorders suggests that EB patients have a predisposition for the development of AIBD. Our work highlights that EB patients with increased itch or blister formation should be evaluated for additional AIBD and repeated screening for changes in autoantibody titers and skin-binding specificities is advised.

183 Dystrophic epidermolysis bullosa pruriginosa: a new case series of a rare phenotype unveils skewed Th2 immunity

Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a rare subtype of hereditary epidermolysis bullosa, with a poorly understood pathogenesis and no satisfactory treatment. Our objective was to assess the clinical, biological features and genetic basis, to better characterize this rare genodermatosis. We conducted a retrospective study, reviewing the clinical presentation, genetic diagnosis, biological analyses and management of patients with DEB-Pr seen between 2010 and 2020. Seven patients were included, average age of 50.1 years. Pruriginous lichenified papules or nodules appeared at 27.6 years on average on pretibial areas and forearms, associated with milia and toenails dystrophy. All patients received multiple therapies but none could sustainably reduce pruritus. Immunohistopathological analysis of lesion skin revealed subepidermal blister with fibrosis, milia and mast cell infiltration. Serum TNFα, IL1β and IL6 levels were elevated in 2/6 patients. Total serum IgE levels were increased in 7/7 patients. Immunophenotyping of circulating T-cells revealed an increased Th2 subset in 4/4 patients, with reduced Th1 and Th17 subpopulations. Genetic analysis of COL7A1 identified 8 distinct causative mutations, 6 of which were new. Intra-familial clinical variability was documented in 5/7 patients and was associated with the co-inheritance of a recessive COL7A1 mutation or an FLG2 mutation in 2 families. Our study confirms the stereotyped presentation of DEB-Pr with large intra-familial variability in disease expression. Mast cell infiltration, elevated IgE and increased Th2 subset without atopy strongly support a role of Th2-mediated immunity in DEB-Pr, and further argue for new targeted therapeutic options such as dupilumab.

Immunological mechanisms underlying progression of chronic wounds in recessive dystrophic epidermolysis bullosa.

Hereditary epidermolysis bullosa (EB) is a mechanobullous skin fragility disorder characterized by defective epithelial adhesion, leading to mechanical stress‐induced skin blistering. Based on the level of tissue separation within the dermal‐epidermal junction, EB is categorized into simplex (EBS), junctional (JEB), dystrophic (DEB) and Kindler syndrome. There is no cure for EB, and painful chronic cutaneous wounds are one of the major complications in recessive (RDEB) patients. Although RDEB is considered a cutaneous disease, recent data support the underlying systemic immunological defects. Furthermore, chronic wounds are often colonized with pathogenic microbiota, leading to excessive inflammation and altered wound healing. Consequently, patients with RDEB suffer from a painful sensation of chronic, cutaneous itching/burning and an endless battle with bacterial infections. To improve their quality of life and life expectancy, it is important to prevent cutaneous infections, dampen chronic inflammation and stimulate wound healing. A clear scientific understanding of the immunological events underlying the maintenance of chronic poorly healing wounds in RDEB patients is necessary to improve disease management and better understand other wound healing disorders. In this review, we summarize current knowledge of the role of professional phagocytes, such as neutrophils, macrophages and dendritic cells, the role of T‐cell‐mediated immunity in lymphoid organs, and the association of microbiota with poor wound healing in RDEB. We conclude that RDEB patients have an underlying immunity defect that seems to affect antibacterial immunity.

A Novel Heterozygous Missense Mutation in COL7A1 Gene in Dystrophic Epidermolysis Bullosa

ABSTRACT Hereditary Epidermolysis Bullosa is categorized by blister formation on the skin which includes Dystrophic Epidermolysis Bullosa as one of its types. It is characterized by blister formation on hands, feet, knees, and elbows. The severe condition leads to vision loss and blemishes. The objectives included the identification of COL7A1 gene mutation for DEB susceptibility through sequence analysis of hot spot regions of 73, 74 and 75 exons. The experimental design included the enrolment of DEB-affected two families. The genetic analysis techniques included inorganic DNA extraction, Polymerase Chain Reaction and Sanger sequencing method. The study inferred the identification of novel missense mutation in exon 75 of COL7A1 gene at (c. 6223 G>T) where the aspartic acid is converted into tyrosine in the heterozygous condition in affected families. The recognized novel missense mutation is silent (heterozygous) which becomes severe when homozygous. However, whole-exome sequencing strategy may identify the causative mutations.

Epidermolysis bullosa dystrophica pretibialis - Clinical snapshot and management of a rare orphan disease.

If blistering occurs in childhood, the possibility of hereditary epidermolysis bullosa should be considered even if the symptoms are mild. Besides clinical and histological examination, molecular genetic screening is diagnostically relevant. For localized forms, symptomatic, topical therapy options are currently still the primary choice. Of particular interest is the new option of topical therapy with diacerein 1% cream. In the case of a pronounced clinical picture with extracutaneous organ involvement, multidisciplinary management is required. In the future, new forms of therapy such as autologous epidermal stem cell transplantation and gene therapeutic procedures may be applied. Human genetic counselling is indispensable.

Growth, lifetime, directional movement and myosin-dependent motility of mutant keratin granules in cultured cells

Intermediate filament polypeptides (IFPs) are prominent components of cytoplasmic aggregates, which are pathognomonic for multiple diseases. Recent observations in cultured cells suggest that they are dynamic and subject to regulated turnover. The emerging concept is that multiple factors contribute to motility and turnover of IFP-containing aggregates. To understand their relative contribution, quantitative tools are needed. The current study addresses this need using epithelial cells producing mutant keratin IFPs that have been identified as the cause of the hereditary blister-forming skin disease epidermolysis bullosa simplex. Digital image analysis of individual granules allowed mapping of their complete life cycle, with information on multiple characteristics at any given time-point. The deduced signet features revealed rapid granule fusion and directed transport from the periphery towards the cell centre, and a limited, ~ 30 min lifetime with a slow, continuous growth phase followed by fast disassembly. As paradigmatic proof-of-principle, we demonstrate that inhibition of myosin II selectively reduces granule movement, linking keratin granule motility to retrograde cortical acto-myosin flow. The newly developed methods and established parameters will help in the characterization of known and the identification of novel regulators of IFP-containing aggregates.

Utility of Immunofluorescence Antigen Mapping in Hereditary Epidermolysis Bullosa.

Background:Epidermolysis bullosa (EB) is characterized by blisters and erosions on the trauma-prone areas of the body. It occurs as a result of mutation in the genes encoding structural proteins. Transmission electron microscopy (TEM) is considered the gold standard test in the laboratory diagnosis of EB. However, this test requires a lot of expertise and is not widely available. Immunofluorescence antigen mapping (IFM) is considered a suitable alternative with comparable sensitivity and specificity. However, there is paucity of studies analyzing the utility of IFM in the diagnosis of EB.Aims and Objectives:To study the utility of IFM in the laboratory diagnosis of EB.Materials and Methods:A cross-sectional study was conducted involving 179 biopsy specimens of patients with EB. IFM was carried out using a panel of monoclonal antibodies against K14, laminin 332, type IV collagen, and type VII collagen.Results:Diagnosis of EB simplex (EBS), junctional EB (JEB), and dystrophic EB (DEB) was made in 104, 28, and 26 biopsy specimens, respectively. The overall concordance rate was 41.3% with higher concordance rates in EBS.Conclusion:The present study is conducted to assess the efficacy of IFM in the diagnosis of EB with large sample size. Our study serves to establish IFM as an important tool in the diagnostic armamentarium of EB as the prognosis mainly rests on diagnosing the type of EB.

Kindler Syndrome : Clinical Particularities about Two Cases Reports in Two Siblings

The Kindler syndrome, the fourth major type of hereditary epidermolysis bullosa (HEB), is a rare autosomal recessive genodermatoses, characterized by trauma-induced blistering, cutaneous atrophy, and progressive poikiloderma, in association with mucosal inflammation. We report tow new sibling cases of this rare syndrome.

Next-generation sequencing through multigene panel testing for the diagnosis of hereditary epidermolysis bullosa in Chinese population.

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.

遗传性大疱性表皮松解症367例问卷调查

Objective To investigate the nursing care burden, medical assurance and comorbidities of patients with hereditary epidermolysis bullosa (EB) in China. Methods From September to December in 2018, a cross-sectional telephone/internet-based questionnaire survey was conducted in EB patients registered at DebRA China between January 2013 and September 2018. Results Totally, 377 participants (EB patients or their parents) were enrolled into this survey, and a total of 367 valid questionnaires were collected. Of the 367 registered patients with EB, 275 (74.9%) were minors, and 319 (92%) reported wound care costs per month less than 3 000 RMB Yuan, and 211 (57.5%) reported that medical expenses were mainly paid by themselves. These patients were distributed in 30 provinces, autonomous regions or municipalities directly under the central government of China, and no patient was from Tibet. The largest number of registered patients was from Jiangsu province (49/367) , followed by Henan (35/367) , Guangdong (27/367) , Hebei (23/367) and Shandong (20/367) provinces. Of the 367 patients, 168 received genetic testing. The most common comorbidities of EB patients were nail peeling and itching, with the prevalence rate being 66.2% and 55.3% respectively. Disabilities occurred in 122 (33.2%) patients, 102 (27.8%) of which had physical disabilities. Conclusion Most of EB patients cannot obtain appropriate diagnosis, nursing care and medical assurance, comorbidities and disabilities are common, and their quality of life is very low. Key words: Epidermolysis bullosa; Cross-sectional studies; Disabled person; Comorbidity

The Management of Hereditary Epidermolysis Bullosa: Experience of a Moroccan Sub-Population

The Management of Hereditary Epidermolysis Bullosa: Experience of a Moroccan Sub-Population

Epidermolysis bullosa in Greece: the patients’ journey so far

<p class="abstract"><strong>Background:</strong> Hereditary epidermolysis bullosa (EB) represents a group of rare, inherited disorders with different penetrance patterns characterized by skin fragility and easy inducibility of blisters. Mucosal involvement of internal organs may occur. As no published data on EB in Greece exist, this study aimed to record demographics and clinical characteristics of EB patients. Another objective was to identify the associations among clinical characteristics of different types in connection with immunofluorescence mapping (IMF) findings and molecular analysis (MA) used for the laboratory diagnosis of the disease.</p><p class="abstract"><strong>Methods:</strong> This is a descriptive study conducted at the outpatient clinic of rare diseases of Andreas Sygros Hospital, Athens, Greece from March 2012 until February 2015. Adults and children presenting with EB were enrolled. Patients underwent a thorough clinical and laboratory assessment. Specific laboratory analyses were performed in Rome and two sets of data based on IFM and MA were collected.<strong></strong></p><p class="abstract"><strong>Results:</strong> In total, 41 patients were enrolled. Prevalence rate of EB was 0.024%. The most frequent type was dystrophic EB, as it affected 20 patients (48.8%). Twelve patients (29.3%) were diagnosed with EB simplex, 6 patients (14.6%) with Kindler syndrome and 3 (7.3%) with junctional EB. IFM was performed in 26 patients and MA in 8 patients. The concordance among clinical and laboratory diagnosis was 88.5%.</p><p class="abstract"><strong>Conclusions:</strong> This study is the first report on hereditary EB in Greece. Since there is a lack in diagnostic management of EB, we would strongly encourage an effort to perform the required laboratory tests in Greece.</p>

Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas - Diagnostic algorithm and principles of therapy.

Hereditary palmoplantar keratodermas (PPKs) comprise a large and heterogeneous group of disorders characterized by persistent thickening of the epidermis at palmar and plantar surfaces. Clinical and genetic features of isolated and complex PPKs have been reviewed in part I of this 2-part review. Here we focus on clinical and molecular classification of syndromic PPKs which are recognized by additional extracutaneous manifestations, in particular deafness, specific mucosal lesions, cardiomyopathy, inborn errors of metabolism, involvement of internal organs or disorders of sexual development. Other genetic diseases, which may show palmoplantar involvement, such as selected subtypes of hereditary epidermolysis bullosa, various hereditary ichthyoses and other keratinization disorders, several ectodermal dysplasias and some multisystem genetic disorders, are also briefly summarized. PPK diagnosis is based on inheritance pattern, age at onset, morphology, distribution and severity of hyperkeratosis, pattern of additional dermatological and systemic manifestations and laboratory findings. Molecular analysis is at present the gold standard to confirm the diagnosis in PPK forms due to mutations in known causative genes. No specific and curative therapy is currently available for PPKs which highly impair patients' quality of life. Topical treatments are symptomatic and offer only temporary relief. Among systemic treatments, retinoids improve disease symptoms in the majority of patients.

Study of a family with epidermolysis bullosa simplex resulting from a novel mutation of KRT14 gene

To determine the molecular etiology for a Chinese pedigree affected with epidermolysis bullosa simplex (EBS). Target region sequencing using a hereditary epidermolysis bullosa capture array combined with Sanger sequencing and bioinformatics analysis were used. Mutation taster, PolyPhen-2, Provean, and SIFT software and NCBI online were employed to assess the pathogenicity and conservation of detected mutations. One hundred healthy unrelated individuals were used as controls. Target region sequencing showed that the proband has carried a unreported heterozygous c.1234A>G (p.Ile412Val) mutation of the KRT14 gene, which was confirmed by Sanger sequencing in other 8 affected individuals but not among healthy members of the pedigree. Bioinformatics analysis indicated that the mutation is highly pathogenic. Remarkably, 3 members of the family (2 affected and 1 unaffected) have carried a heterozygous c.1237G>A (p.Ala413Thr) mutation of the KRT14 gene, which was collected in Human Gene Mutation Database (HGMD). Bioinformatics analysis indicated that the mutation may not be pathogenic. Both mutations were not detected among the 100 healthy controls. The novel c.1234A>G(p.Ile412Val) mutation of the KRT14 gene is probably responsible for the disease, while c.1237G>A (p.Ala413Thr) mutation of KRT14 gene may be a polymorphism. Compared with Sanger sequencing, target region capture sequencing is more efficient and can significantly reduce the cost of genetic testing for EBS.

Prevalence of hereditary epidermolysis bullosa in the Russian Federation

Prevalence of hereditary epidermolysis bullosa in the Russian Federation