Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa.

The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the ear, nose, and throat department of a tertiary pediatric hospital linked to the United Kingdom's national EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants in laminin subunit alpha-3 (LAMA3) were found in 10/15 patients where genotype was available. LAMA3 encodes a subunit of the laminin-332 heterotrimeric extracellular matrix protein complex and is expressed by airway epithelial basal stem cells. We investigated the benefit of restoring wild-type LAMA3 expression in primary EB patient-derived basal cell cultures. EB basal cells demonstrated weak adhesion to cell culture substrates, but could otherwise be expanded similarly to non-EB basal cells. In vitro lentiviral overexpression of LAMA3A in EB basal cells enabled them to differentiate in air-liquid interface cultures, producing cilia with normal ciliary beat frequency. Moreover, transduction restored cell adhesion to levels comparable to a non-EB donor culture. These data provide proof of concept for a combined cell and gene therapy approach to treat airway disease in LAMA3-affected EB.

Advantages of whole-exome sequencing over immunomapping in 67 Brazilian patients with epidermolysis bullosa.

BACKGROUND: Epidermolysis bullosa (EB) is characterized by skin fragility and blistering. In Brazil, the diagnosis is usually obtained through immunomapping, which involves a skin biopsy. Most recently, whole exome sequencing (WES) has become an important tool for the diagnosis of the subtypes of EB, providing information on prognosis as well as allowing appropriate genetic counseling for the families. OBJECTIVE: To compare the results of immunomapping and molecular analysis and to describe the characteristics of a Brazilian cohort of patients with EB. METHODS: Patients were submitted to clinical evaluation and WES using peripheral blood samples. WES results were compared to those obtained from immunomapping testing from skin biopsies. RESULTS: 67 patients from 60 families were classified: 47 patients with recessive dystrophic EB (DEB), 4 with dominant DEB, 15 with EB simplex (EBS), and 1 with junctional EB (JEB). Novel causative variants were: 10/60 (16%) in COL7A1 associated with recessive DEB and 3 other variants in dominant DEB; one homozygous variant in KRT5 and another homozygous variant in PLEC, both associated with EBS. Immunomapping was available for 59 of the 67 patients and the results were concordant with exome results in 37 (62%), discordant in 13 (22%), and inconclusive in 9 patients (15%). STUDY LIMITATIONS: Even though EB is a rare disease, for statistical purposes, the number of patients evaluated by this cohort can still be considered limited; other than that, there was a significant difference between the proportion of types of EB (only one case with JEB, against more than 50 with DEB), which unfortunately represents a selection bias. Also, for a small subset of families, segregation (usually through Sanger sequencing) was not an option, usually due to deceased or unknown parent status (mostly the father). CONCLUSION: Although immunomapping has been useful in services where molecular studies are not available, this invasive method may provide a misdiagnosis or an inconclusive result in about 1/3 of the patients. This study shows that WES is an effective method for the diagnosis and genetic counseling of EB patients.

Emerging Gene Therapeutics for Epidermolysis Bullosa under Development.

The monogenetic disease epidermolysis bullosa (EB) is characterised by the formation of extended blisters and lesions on the patient's skin upon minimal mechanical stress. Causal for this severe condition are genetic mutations in genes, leading to the functional impairment, reduction, or absence of the encoded protein within the skin's basement membrane zone connecting the epidermis to the underlying dermis. The major burden of affected families justifies the development of long-lasting and curative therapies operating at the genomic level. The landscape of causal therapies for EB is steadily expanding due to recent breakthroughs in the gene therapy field, providing promising outcomes for patients suffering from this severe disease. Currently, two gene therapeutic approaches show promise for EB. The clinically more advanced gene replacement strategy was successfully applied in severe EB forms, leading to a ground-breaking in vivo gene therapy product named beremagene geperpavec (B-VEC) recently approved from the US Food and Drug Administration (FDA). In addition, the continuous innovations in both designer nucleases and gene editing technologies enable the efficient and potentially safe repair of mutations in EB in a potentially permanent manner, inspiring researchers in the field to define and reach new milestones in the therapy of EB.

Hereditary epidermolysis bullosa: clinical-epidemiological profile of 278 patients at a tertiary hospital in São Paulo, Brazil.

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare hereditary diseases, characterized by fragility of the skin and mucous membranes. Epidemiological data on EB in Brazil are scarce. OBJECTIVES: To describe epidemiological aspects of patients with EB diagnosed in the Dermatology Department of a tertiary hospital, from 2000 to 2022. METHODS: An observational and retrospective study was conducted through the analysis of medical records. The evaluated data included clinical form, sex, family history, consanguinity, age at diagnosis, current age, time of follow-up, comorbidities, histopathology and immunomapping, presence of EB nevi and squamous cell carcinomas (SCC), cause of and age at death. RESULTS: Of 309 patients with hereditary EB, 278 were included. The most common type was dystrophic EB (DEB), with 73% (28.4% dominant DEB, 31.7% recessive DEB and 12.9% pruriginous DEB). Other types were junctional EB with 9.4%, EB simplex with 16.5% and Kindler EB with 1.1%. Women accounted for 53% and men for 47% of cases. Family history was found in 35% and consanguinity in 11%. The mean age at diagnosis was 10.8 years and the current age was 26 years. The mean time of follow-up was nine years. Esophageal stenosis affected 14%, dental alterations affected 36%, malnutrition 13% and anemia 29%. During diagnostic investigation, 72.6% underwent histopathological examination and 92% underwent immunomapping. EB nevi were identified in 17%. Nine patients had SCC. Eleven patients died. STUDY LIMITATIONS: Insufficient data included to medical records, loss to follow-up, and unavailability of genetic testing. CONCLUSIONS: In this study, dystrophic EB predominated and the need for multidisciplinary care for comorbidities and complications was highlighted.

[Adapting technical care to EBH patients]. / Adapter les soins techniques aux patients atteints d'EBH.

The skin of patients with hereditary epidermolysis bullosa (HEB) is extremely fragile. When providing care, nurses must be extremely vigilant to avoid inducing lesions. Whether inserting a peripheral venous line, taking blood pressure or monitoring the patient, nurses are likely to injure the patient's skin by compressing it, rubbing it, applying dressings and so on. It is therefore essential that they adapt this care to the person suffering from HEB.

Evaluation of Clinical and Oral Findings in Patients with Epidermolysis bullosa.

Introduction: Epidermolysis bullosa (EB) is a genetically inherited disease characterized by recurrent bullae and erosions on the skin with numerous signs of dental caries and poor oral hygiene. The aim of this study was to investigate the general clinical and oral findings of patients with EB. Materials and Methods: In this prospective study, the clinical and oral findings and family history of 26 cases with EB were evaluated. The type of EB, gender, age, parental consanguinity, dental caries, oral findings, distribution of lesions and presence of associated anomalies, clinical and oral findings correlated with gender were recorded. Results: All 26 patients with EB had a history of consanguinity and siblings with EB to varying degrees. In our study, malnutrition, anemia and growth retardation, gastrointestinal system complications, hair thinning, hand and nail deformity, ocular problems and renal disease (in one case) were observed with variable frequencies. When the intraoral findings of the patients were investigated, extensive dental caries in all EB types, enamel hypoplasia in junctional EB (JEB) and the presence of tooth-root to be extracted in dystrophic EB (DEB), intraoral bullae and lesions, ankyloglossia, vestibular sulcus insufficiency, microstomia and maxillary atrophy were observed. Three cases had restorative treatment and one case had prosthetic rehabilitation. Conclusions: Oral involvement can be seen with varying frequencies depending on the type of EB and the severity of the disease. It may result from delayed oral and dental rehabilitation due to physical disabilities, limitations and more pressing medical problems. Microstomy, pain from mucosal lesions, and restricted access to the mouth can be caused by poor oral hygiene. Oral complications and caloric needs of individuals with EB should be determined, and individual prophylaxis should be applied to prevent caries formation and protect teeth.

Phenotype and genotype correlation of inherited epidermolysis bullosa in Indonesia.

BACKGROUND: Inherited epidermolysis bullosa (EB) is a group of genodermatoses with considerable clinical and genetic heterogeneity. Clinical diagnosis of the EB subtypes is frequently imprecise and requires confirmation with genetic testing. There is still limited study using genetic testing to identify EB subtypes in Indonesia. This study aims to identify the pathogenic variants of inherited EB patients at the Department of Dermatology and Venereology, Universitas Padjadjaran-Dr Hasan Sadikin General Hospital in Bandung, West Java, Indonesia and to describe the correlation between the phenotype and genotype of our patients. METHODS: Twelve patients clinically diagnosed with EB were included in this study. Genetic testing was performed in collaboration with KK Women's and Children's Hospital, Singapore. RESULTS: Pathogenic variants were identified in the COL7A1 gene in seven patients, namely Dominant Dystrophic EB (DDEB) with mutation types c.5945G>T, c.6218G>A, Recessive Dystrophic EB (RDEB) c.2005C>T, c.6081dup, c.1268C>T, c.1784C>T which are all known mutations. Novel mutations were found in the COL7A1 gene in two patients namely DDEB c.6253G>T and RDEB c.6740C>T. Two EB Simplex (EBS) patients showed mutation KRT14 gene as c.356T>C, c.373C>T which are known mutation. In addition, a novel mutation in LAMA3 gene c.2649del was found in one Junctional EB (JEB) patient. CONCLUSION: The molecular diagnoses of 12 Indonesian EB patients were identified, of which three were novel pathogenic variants. Concordance between the initial clinical diagnosis and genetic testing was only 33%. This demonstrated the importance of early genetic testing for accurate diagnosis, prognostication, management and genetic counselling.

Characteristics and Outcomes of Squamous Cell Carcinoma and Other Cutaneous Malignancies in Epidermolysis Bullosa: A Systematic Review.

OBJECTIVE: To identify cases and summarize outcomes of cutaneous malignancies in patients with epidermolysis bullosa (EB). DATA SOURCES: MEDLINE and EMBASE databases were searched on February 8, 2022. STUDY SELECTION: Original observational or experimental studies with cases of cutaneous malignancy in patients with inherited EB were included. DATA EXTRACTION: Data were extracted by two reviewers in duplicate. DATA SYNTHESIS: A total of 87 articles with 367 patients were included in this systematic review. Squamous cell carcinomas were the most common malignancy (94.3%) with a median survival of 60 months. The presence of metastasis was investigated at diagnosis in 77 patients; 18.8% of patients had detectable metastasis. Patients with squamous cell carcinoma with metastasis at diagnosis had significantly shorter median survival (16.8 months) than those without (72 months; P = .027). The remission rate was 47.6%. At the end of follow-up, 15.1% were alive with disease, and 41.6% were deceased. Other malignancies included malignant melanoma and basal cell carcinoma. The most common initial modes of management were excisions (71.9%) and amputations (17.6%). Other modes included chemotherapy (4.6%), radiation (3.9%), and no treatment (2.6%). The overall rate of recurrence or new lesions was 38.8%, with a median time of 16 months to recurrence or new lesions. Immediate recurrence was lowest following amputation (4.3%). There were no statistically significant differences in median survival among initial excision, amputation, and all other modes combined ( P = .30). CONCLUSIONS: Squamous cell carcinomas in patients with EB have a high likelihood of metastasis and mortality. Surgical excision is the most common intervention. There are no significant differences in survival among different initial management options. There is a need for research that documents and monitors outcomes of the treatment options.

Adaptation of home nocturnal hemodialysis for a patient with epidermolysis bullosa: A call to personalized care!

Epidermolysis bullosa (EB) is a genetic disease characterized by skin fragility presenting with blistering and skin erosions. Recurrent skin infections are noted to be associated with the pathogenesis of IgA nephropathy. End stage kidney disease (ESKD) is a rare complication in patients with EB (Ducret F., et al., Nephrol Ther, 2008). Kidney replacement therapy is very challenging in this vulnerable patient population (Fine JD. et al., Am J Kidney Dis, 2004). Herein, we describe the adaptations to our home nocturnal hemodialysis training and operations to facilitate a patient with EB and ESKD to undergo personalized home nocturnal hemodialysis therapy.

Excess KLHL24 Impairs Skin Wound Healing through the Degradation of Vimentin.

Start codon variants in ubiquitin ligase KLHL24 lead to a gain-of-function mutant KLHL24-ΔN28, which mediates the excessive degradation of keratin 15, desmin, and keratin 14, resulting in alopecia, cardiopathy, and epidermolysis bullosa syndrome. Patients with alopecia, cardiopathy, and epidermolysis bullosa syndrome normally present atrophic scars after wounds heal, which is rare in KRT14-related epidermolysis bullosa. The mechanisms underlying the formation of atrophic scars in epidermolysis bullosa of patients with alopecia, cardiopathy, and epidermolysis bullosa syndrome remain unclear. This study showed that KLHL24-ΔN28 impaired skin wound healing by excessively degrading vimentin. Heterozygous Klhl24c.3G>T knock-in mice displayed delayed wound healing and decreased wound collagen deposition. We identified vimentin as an unreported substrate of KLHL24. KLHL24-ΔN28 mediated the excessive degradation of vimentin, which failed to maintain efficient fibroblast proliferation and activation during wound healing. Furthermore, by mediating vimentin degradation, KLHL24 can hinder myofibroblast activation, which attenuated bleomycin-induced skin fibrosis. These findings showed the function of KLHL24 in regulating tissue remodeling, atrophic scarring, and fibrosis.

Cuidados de enfermagem com crianças e adolescentes com epidermólise bolhosa: revisão sistemática / Cuidados de enfermería a niños y adolescente con epidermólisis ampollosa: revisión sistemática / Nursing care for children and adolescents with epidermolysis bullosa: a systematic review

Resumo Objetivo Analisar a produção científica referente às ações/Intervenções de Enfermagem no ambiente hospitalar relacionadas ao cuidado com crianças e adolescentes com epidermólise bolhosa. Métodos Revisão sistemática, cuja busca se deu nas bases Cinahl, MEDLINE®/PubMed®, SCOPUS, LILACS e SciELO, realizada no período de setembro de 2020 a janeiro de 2021. Para a busca, foram utilizados os descritores "epidermólise bolhosa" AND "criança" AND "adolescente" AND "enfermagem", nas bases Lilacs e SciELO, e "epidermolysis bullosa" AND "children" AND "adolescent" AND, "nursing" nas demais bases em inglês. Resultados Houve maior registro de artigos publicados com base na pergunta norteadora tendo como país de origem os Estados Unidos (22%). A maioria da classificação era no nível VI (44%) da evidência científica. Ainda, 86% dos estudos envolveram pesquisas para o plano de cuidados. As evidências encontradas decorreram de opiniões de especialistas, estudos de casos e consenso. Os fatores de cuidados mais citados foram planos de cuidados voltados à pele; troca de fraldas; cuidados com as roupas e uso de coberturas antiaderentes. Conclusão As pesquisas reportaram dificuldades quanto à disponibilidade de materiais, tratamento e profissionais especializados, além das limitações dos conhecimentos na prática clínica voltada às características da epidermólise bolhosa. Dentre os cuidados, houve destaque para informação sobre a complexidade e as características da ferida como forma de antecipar as estratégias de cuidado.

Resumen Objetivo Analizar la producción científica referente a las acciones/intervenciones de enfermería en el ambiente hospitalario relacionadas con el cuidado a niños y adolescentes con epidermólisis ampollosa. Métodos Revisión sistemática, cuya búsqueda se realizó en las bases Cinahl, MEDLINE®/PubMed®, SCOPUS, LILACS y SciELO, realizada en el período de septiembre de 2020 a enero de 2021. Para la búsqueda se utilizaron los descriptores "epidermólisis ampollosa" AND "niño" AND "adolescente" AND "enfermería", en las bases Lilacs y SciELO, y "epidermolysis bullosa" AND "children" AND "adolescent" AND, "nursing" en las demás bases en inglés. Resultados Con base en la pregunta orientadora, hubo un mayor registro de artículos publicados que tenían como país de origen Estados Unidos (22 %). La mayoría de la clasificación era de nivel VI (44 %) de la evidencia científica. Además, el 86 % de los estudios incluyeron investigaciones en el plano de los cuidados. Las evidencias encontradas derivaban de opiniones de especialistas, estudios de casos y consenso. Los factores de cuidados más citados fueron planos de cuidados orientados a la piel, cambio de pañales, cuidados con la ropa y uso de coberturas antiadherentes. Conclusión Las investigaciones indicaron dificultades en cuanto a la disponibilidad de material, tratamiento y profesionales especializados, además de las limitaciones de conocimientos en la práctica clínica orientada hacia las características de la epidermólisis ampollosa. Entre los cuidados, se destacó la información sobre la complejidad y las características de la herida como forma de anticipar las estrategias de cuidado.

Abstract Objective To analyze the scientific production regarding actions/Nursing Interventions in hospital environments related to the care of children and adolescents with epidermolysis bullosa. Methods This is a systematic review, which was searched in the CINAHL, MEDLINE®/PubMed®, Scopus, LILACS and SciELO databases, carried out from September 2020 to January 2021. For the search, the descriptors "epidermólise bolhosa" AND "criança" AND "adolescente" AND "enfermagem" were used, in Portuguese, in the LILACS and SciELO databases, and "epidermolysis bullosa" AND "children" AND "adolescent" AND "nursing" in the other databases. Results There was a greater number of articles published based on the guiding question having the United States as the country of origin (22%). Most of the classification was at level VI (44%) of scientific evidence. Still, 86% of studies involved research for the care plan. The evidence found resulted from expert opinions, case studies and consensus. The most cited care factors were skin care plans, diaper changing, clothing care and non-stick coating use. Conclusion The surveys reported difficulties regarding the availability of materials, treatment and specialized professionals, in addition to limitations of knowledge in clinical practice focused on the characteristics of epidermolysis bullosa. Among the care, there was emphasis on information about the wound complexity and characteristics as a way of anticipating care strategies.

Folliculitis decalvans and dystrophic epidermolysis bullosa: a significant association.

This work reports 30 cases of folliculitis decalvans (FD) in patients with dystrophic epidermolysis bullosa (DEB) among a cohort of 125 DEB patients seen between 2010 and 2021 in 2 French expert centers for the management of inherited epidermolysis bullosa. Such an association between two rare diseases cannot be fortuitous and implies a physiopathological link that we discuss in this paper. This association is a new significant fact to add to the reflexion on FD causes, suggesting that skin abnormality of DEB could act as a factor of a specific skin barrier alteration which could favor FD. Scarring alopecia with tufted folliculitis and pustules on inflamed skin at the vertex of a woman with dominant dystrophic epidermolysis bullosa.

Squamous Cell Carcinoma in Patients with Inherited Epidermolysis Bullosa: Review of Current Literature.

Epidermolysis bullosa (EB) is a group of rare congenital diseases caused by mutations in structural proteins of the dermal/epidermal junction that are characterized by extreme epithelial fragility, which determines the formation of bullae and erosions either spontaneously or after local mechanical traumas. In EB patients, skin fragility leads to many possible complications and comorbidities. One of the most feared complications is the development of cutaneous squamous cell carcinomas (SCCs) that particularly in the dystrophic recessive EB subtype can be extremely aggressive and often metastatic. SCCs in EB patients generally arise more often in the extremities, where chronic blisters and scars are generally located. SCCs represent a big therapeutic challenge in the EB population. No standard of care exists for the treatment of SCC in these patients, and therapy is based on small case studies. Moreover, the pathogenesis of cSCC in EB patients is still unclear. Many theories have been indeed postulated in order to explain why cSCC behaves so much more aggressively in EB patients compared to the general population. cSCC in EB seems to be the result of many complex interactions among cancer cells, skin microenvironment, susceptibility to DNA mutations and host immune response. In this review, we analyze the different pathogenetic mechanisms of cSCC in EB patients, as well as new therapies for this condition.

First report of the c.1676G>A homozygous variant in a family with Kindler syndrome.

Kindler syndrome (KS) was first described by Theresa Kindler in 1954, and since then > 60 pathogenic variants have been identified in the FERMT1 gene for KS. Most FERMT1 variants associated with KS are null variants. We present the case of a child with poikilodermic changes on the forehead and cheeks, who was found to have a homozygous c.1676G>A mutation. To our knowledge, this is the first report of this mutation in a family with KS.

Omaveloxolone attenuates squamous cell carcinoma growth and disease severity in an Epidermolysis Bullosa mouse model.

Patients with epidermolysis bullosa (EB) are susceptible to development of squamous cell carcinomas (SCC) at sites of chronic inflammation and fibrosis. While triterpenoids such as RTA 408 (Omaveloxolone) have been shown to reduce inflammation and inhibit tumour growth in various cancer models, the utility of this class of drugs in the treatment of SCC has not been investigated. Given the dual anti-inflammatory and anti-neoplastic properties of triterpenoids, we hypothesized RTA 408 would be an effective treatment for SCCs that arise in the chronic inflammatory setting in EB. We tested the effects of topical RTA 408 on a mouse model of non-Herlitz, junctional EB. RTA 408 significantly reduced phenotypic severity in the affected ears of Lamc2jeb mice. In cultures, RTA 408 reduced cell viability in EB-associated SCC cell lines and normal human epidermal keratinocytes. When administered in vivo, RTA 408 inhibited SCC tumour growth in mice without cutaneous or systemic toxicity. These results suggest that RTA 408 can be a promising new therapy to reduce inflammation and inhibit SCC growth in patients with EB.

Surgical management and oncological follow-up of cutaneous squamous cell carcinomas arising in epidermolysis bullosa patients.

BACKGROUND: Hereditary epidermolysis bullosa (EB) is a rare genodermatosis characterized by skin fragility and blistering of the skin and mucous membranes in reaction to minimal traumas. The development of cutaneous squamous cell carcinomas (cSCCs) is one of the most common medical complications in junctional and dystrophic forms of the disease. Complete surgical excision of cutaneous tumors represents the gold standard of treatment. However, not only recognition of cSCCs can be challenging in the affected skin but also wound closure after surgical excision poses a great therapeutic challenge in EB patients. The aim of our study was to analyze the postoperative outcomes of such patients in order to have a better knowledge of the main critical issues in their surgical management and oncological follow-up. METHODS: We retrospectively identified a cohort of five EB patients treated at Modena University Hospital. Collected data included patient age and sex, date of cSCC diagnosis, relapses/recurrences, site of the neoplasm, number of surgical interventions, use of dermal substitutes, and postoperative infections. RESULTS: A total of 26 cSCCs were detected in our cohort. Forty-one surgical interventions were necessary to achieve excision of cSCCs with clear margins, varying from 1 to 4 surgical sessions per cSCC. Dermal substitutes were used in most cases but carried a higher infectious risk. CONCLUSIONS: EB patients tend to develop numerous cSCCs that often relapse even after complete excision with clear margins. These results stress the importance of early cSCC diagnosis and strict postsurgical follow-up.

Epidermolysis bullosa aquisita following immune-checkpoint inhibitor treatment for metastatic melanoma.

A case of epidermolysis bullosa aquisita following immunotherapy for melanoma. This adds to the repertoire of subepidermal blistering disorders documented following immune checkpoint therapy.