Facing the complex challenges of people with epidermolysis bullosa in Austria: a mixed methods study on burdens and helpful practices.

BACKGROUND: With approximately 500 people affected in Austria, epidermolysis bullosa (EB) is a rare genetic skin disease reducing the quality of life of those affected and their relatives. The intensive efforts of the patient organisation DEBRA Austria during the last decades have led to a unique situation of those affected and their relatives, with increased support and broader knowledge about the disease in the general population. The aim of the study is to evaluate the current situation of patients and their relatives living in Austria, with a focus on burdens and helpful practices. RESULTS: The mixed-methods study consisted of two parts: a qualitative interview study to identify psychosocial aspects of EB in those affected and their relatives, and a subsequent online survey to further assess those aspects in a larger sample, resulting in a total of n=78 Austrian participants. The impact of EB on the quality of life of EB patients and their relatives in Austria is related to the current health status, psychological burden, mobility, visibility, financial situation as well as job prospects. Personal and social resources and external support have a significant influence on the individual situation. CONCLUSIONS: The outcome is mapped to concrete implications regarding targeted support for EB patients and their relatives on an individual level and their needs in regard to the Austrian health care system.

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

OBJECTIVE: To diagnose and explore the genetic etiology of a neonate with Hereditary epidermolysis bullosa. METHODS: 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. RESULTS: 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. CONCLUSION: The child was diagnosed with Generalized atrophic benign epidermolysis bullosa due to the compound heterozygous variants of the COL17A1 gene.

Epidermolysis Bullosa: Two rare case reports of COL7A1 and EBS-GEN SEV KRT14 variants with review of literature.

EPIDERMOLYSIS: Bullosa is a rare hereditary skin condition that causes blisters. Genes encoding structural proteins at or near the dermal-epidermal junction are mutated recessively or dominantly, and this is the primary cause of EB. Herein, two Chinese boys were diagnosed with the condition, each with a different variant in a gene that serves as a reference for EB genetic counseling. Skincare significantly impacted their prognosis and quality of life. CASE PRESENTATION: Two Chinese boys, with phenotypically normal parents, have been diagnosed with distinct blister symptoms, one with Dominant Dystrophic Epidermolysis Bullosa and the other with a severe form of Epidermolysis Bullosa Simplex. The first patient had a G-to-A variant in the COL7A1 allele, at nucleotide position 6163 which was named "G2055A". The proband is heterozygous for Dystrophic Epidermolysis Bullosa due to a COL7A1 allele with a glycine substitution at the triple helix domain. A similar variant has been discovered in his mother, indicating its potential transmission to future generations. Another patient had severe Epidermolysis Bullosa Simplex with a rare c.377T > A  variant resulting in substitution of amino acid p.Leu126Arg (NM_000526.5 (c.377T > G, p.Leu126Arg) in the Keratin 14 gene. In prior literature, Keratin 14 has been associated with an excellent prognosis. However, our patient with this infrequent variant tragically died from sepsis at 21 days old. There has been a reported occurrence of the variant only once. CONCLUSION: Our study reveals that Epidermolysis Bullosa patients with COL7A1 c.6163G > A and KRT14 c.377T>A variants have different clinical presentations, with dominant forms of Dystrophic EB having milder phenotypes than recessive ones. Thus, the better prognosis in the c.6163G > A patient. Furthermore, c.377T>A patient was more prone to infection than the patient with c.6163G>A gene variant. Genetic testing is crucial for identifying the specific variant responsible and improving treatment options.

"Quality of Life in Epidermolysis Bullosa" and "Epidermolysis Bullosa Burden of Disease": Italian translation, cultural adaptation, and pilot testing of two disease-specific questionnaires.

BACKGROUND: Inherited epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of skin fragility disorders characterized by blister formation following minor trauma. Four major types are distinguished based on the level of cleavage within the skin. Most EB forms present severely disabling cutaneous and systemic signs and symptoms. Management relies on daily time-consuming and distressing topical medications, and symptomatic treatment of systemic findings. Disease manifestations, symptoms, and daily care strongly affect patient and caregiver quality of life (QoL). To date, there are two validated EB-specific questionnaires, the "Quality of Life in Epidermolysis Bullosa" (QOLEB) and the "Epidermolysis Bullosa Burden of Disease" (EB-BoD) for the evaluation of patient and family disease burden, respectively. The aim of our study was to develop an Italian translation of the two questionnaires and to pilot-test them. METHODS: The guidelines for translation and cross-cultural adaptation of health-related QoL measures were followed. Initially, two separate translations were generated for each questionnaire, and subsequently reconciled by an expert committee. This was followed by a back-translation process. The original texts and all translations underwent revision by the expert committee, resulting in definitive versions. The final versions were then tested in a pilot study involving cognitive debriefing in a group of 17 families, representative of all EB major types. RESULTS: The translation and reconciliation process led to minor changes to obtain semantic/idiomatic/cultural equivalence of the Italian versions with the original ones and to reconcile the questions with the answer options. The cognitive debriefing process showed a good understanding and did not require text modifications. CONCLUSIONS: The Italian versions of the QOLEB and EB-BoD provide valuable tools in everyday clinical practice of reference centers, and they allow the participation in multicenter international real-life observational studies as well as in controlled clinical trials. They enable the identification of disease-specific psychological and socioeconomic challenges for EB patients and their families, guiding targeted interventions to ensure appropriate and timely care.

Health-related quality of life and clinical severity in people with epidermolysis bullosa - a proposal for assessing nutritional compromise by body mass index (birmingham Epidermolysis bullosa Severity Score) / Calidad de vida relacionada con la salud y gravedad clínica en personas con epidermólisis bullosa: una propuesta para evaluar el deterioro nutricional por el índice de masa corporal (Birmingham Epidermolysis Bullosa Severity Score)

Introduction and objectives: epidermolysis bullosa (EB) is a rare genetic disease characterised by skin fragility with blisters and erosions on the skin and/or mucous membranes. People with EB often experience several extracutaneous manifestations, including clinical and health-related quality of life (HRQoL) complications. Herein, we evaluate their HRQoL and clinical severity and propose an objective criterion for estimating nutritional compromise using the Birmingham Epidermolysis Bullosa Severity Score (BEBS) tool. Methods: this series of cases included people with EB, monitored by a multi-professional team. Clinical severity was assessed with the BEBS, using body mass index ranges by age, as an objective proposal, to estimate the degree of nutritional compromise. To assess HRQoL, the Children's Dermatology Life Quality Index (individuals aged 4-16 years) and the Quality of Life Evaluation in Epidermolysis Bullosa – Brazilian Portuguese (individuals 17 years and over) were used. Results: of the nine individuals with recessive dystrophic EB (88.9 % female and 12.91 (SD = 11.71) years), the mean total BEBS score was 24.47 (SD = 12.80) points on a scale of 0 to 100 points. Six participants had significant nutritional compromise according to the proposed criteria. Five of the six participants evaluated for HRQoL reported experiencing some impact, with individuals aged 17 and over being more affected and with greater clinical severity. Conclusions: individuals with greater clinical severity of EB experience a more significant impact on their HRQoL. The proposed quantitative criteria for assessing nutritional compromise may help standardise assessments by professionals monitoring the nutritional status of individuals with EB. Keywords: Quality of life. Epidermolysis bullosa. Body mass index.(AU)

Introducción y objetivos: la epidermólisis bullosa (EB) es una rara enfermedad genética caracterizada por fragilidad de la piel con ampollas yerosiones. Las personas con EB experimentan manifestaciones extracutáneas y complicaciones clínicas y de calidad de vida relacionada con la salud (CVRS). Evaluamos la CVRS y la gravedad clínica y proponemos un criterio objetivo para estimar el deterioro nutricional con la herramienta Birmingham Epidermolysis Bullosa Severity Score (BEBS). Métodos: esta serie de casos incluyó pacientes con EB monitoreadas por un equipo multiprofesional. Se evaluó la gravedad clínica con el BEBS utilizando rangos de índice de masa corporal por edad. Para evaluar la CVRS se utilizaron el Children's Dermatology Life Quality Index (individuos de 4 a 16 años) y el Quality of Life Evaluation in Epidermolysis Bullosa – Brazilian Portuguese (individuos de 17 años y más). Resultados: de los nueve individuos con EB distrófica recesiva (88,9 % mujeres y 12,91 (DE = 11,71) años), la puntuación total media del BEBS fue de 24,47 (DE = 12,80) puntos en una escala de 0 a 100 puntos. Seis participantes tenían un deterioro nutricional significativo según los criterios propuestos. Cinco de los seis participantes evaluados en la CVRS informaron experimentar algún impacto, siendo los individuos de 17 años y más los más afectados y con mayor gravedad clínica. Conclusiones: los pacientes con mayor gravedad clínica experimentan un impacto más significativo en su CVRS. Los criterios cuantitativos propuestos para evaluar el deterioro nutricional pueden ayudar a estandarizar las evaluaciones de los profesionales que monitorean el estadonutricional de las personas con EB.

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.

Orofacial Anomalies in Kindler Epidermolysis Bullosa.

Importance: Kindler epidermolysis bullosa is a genetic skin-blistering disease associated with recessive inherited pathogenic variants in FERMT1, which encodes kindlin-1. Severe orofacial manifestations of Kindler epidermolysis bullosa, including early oral squamous cell carcinoma, have been reported. Objective: To determine whether hypoplastic pitted amelogenesis imperfecta is a feature of Kindler epidermolysis bullosa. Design, Settings, and Participants: This longitudinal, 2-center cohort study was performed from 2003 to 2023 at the Epidermolysis Bullosa Centre, University of Freiburg, Germany, and the Special Care Dentistry Clinic, University of Chile in association with DEBRA Chile. Participants included a convenience sampling of all patients with a diagnosis of Kindler epidermolysis bullosa. Main Outcomes and Measures: The primary outcomes were the presence of hypoplastic pitted amelogenesis imperfecta, intraoral wounds, gingivitis and periodontal disease, gingival hyperplasia, vestibular obliteration, cheilitis, angular cheilitis, chronic lip wounds, microstomia, and oral squamous cell carcinoma. Results: The cohort consisted of 36 patients (15 female [42%] and 21 male [58%]; mean age at first examination, 23 years [range, 2 weeks to 70 years]) with Kindler epidermolysis bullosa. The follow-up ranged from 1 to 24 years. The enamel structure was assessed in 11 patients, all of whom presented with enamel structure abnormalities. The severity of hypoplastic pitted amelogenesis imperfecta varied from generalized to localized pitting. Additional orofacial features observed include gingivitis and periodontal disease, which was present in 90% (27 of 30 patients) of those assessed, followed by intraoral lesions (16 of 22 patients [73%]), angular cheilitis (24 of 33 patients [73%]), cheilitis (22 of 34 patients [65%]), gingival overgrowth (17 of 26 patients [65%]), microstomia (14 of 25 patients [56%]), and vestibular obliteration (8 of 16 patients [50%]). Other features included chronic lip ulcers (2 patients) and oral squamous cell carcinoma with lethal outcome (2 patients). Conclusions and Relevance: These findings suggest that hypoplastic pitted amelogenesis imperfecta is a feature of Kindler epidermolysis bullosa and underscore the extent and severity of oral manifestations in Kindler epidermolysis bullosa and the need for early and sustained dental care.

Stop codon readthrough as a treatment option for epidermolysis bullosa-Where we are and where we are going.

In the context of rare genetic diseases caused by nonsense mutations, the concept of induced stop codon readthrough (SCR) represents an attractive avenue in the ongoing search for improved treatment options. Epidermolysis bullosa (EB)-exemplary for this group of diseases-describes a diverse group of rare, blistering genodermatoses. Characterized by extreme skin fragility upon minor mechanical trauma, the most severe forms often result from nonsense mutations that lead to premature translation termination and loss of function of essential proteins at the dermo-epidermal junction. Since no curative interventions are currently available, medical care is mainly limited to alleviating symptoms and preventing complications. Complementary to attempts of gene, cell and protein therapy in EB, SCR represents a promising medical alternative. While gentamicin has already been examined in several clinical trials involving EB, other potent SCR inducers, such as ataluren, may also show promise in treating the hitherto non-curative disease. In addition to the extensively studied aminoglycosides and their derivatives, several other substance classes-non-aminoglycoside antibiotics and non-aminoglycoside compounds-are currently under investigation. The extensive data gathered in numerous in vitro experiments and the perspectives they reveal in the clinical setting will be discussed in this review.

Epidemiological Assessment of a Pediatric Palliative Care Clinic at a Brazilian Quaternary Hospital: 20 Years of Experience.

Background: The pediatric palliative care (PPC) sets up an interdisciplinary approach of chronic complex diseases throughout birth to adolescence. It encompasses countless contrasts in development and diagnosis scopes, which make this area a challenge to nonpediatric practitioners. Objective: We sought to assess the most prevalent diseases in follow-up of the PPC team. Methods: We analyzed the medical records of PPC clinic during the years 2001 and 2021 and the diagnosis of outpatients. We established a parallel with the world scientific literature concerning the epidemiology of PPC. Results: The most prevalent diseases were epidermolysis bullosa (36.9%), followed by neurological Inherited Errors of Metabolism (IEM) diseases (19.0%), IEM diseases (14.3%), dysmorphological and chromosomal disorders (8.5%), skeletal disorders mainly osteogenesis imperfecta (6.9%), and liver transplantation conditions (5.5%) (p < 0.001). The less frequent conditions were external causes, such as neonatal insults or traffic accidents (2.8%), cancer (1.7%), congenital cardiopathies (1.4%), congenital infectious diseases (1.1%), gastrointestinal and hepatic conditions (0.8%), and rheumatological conditions (0.3%). The patients were older at diagnosis (6.9 years) and at PPC referral (13.2 years) than patients with epidermolysis bullosa and skeletal disorders and dysmorphological and chromosomal disorders were younger on referral. Conclusion: There are a lot of complex chronic conditions which could benefit from palliative care in pediatric setting. However, epidemiological and symptomatological assessment of the health service is necessary to provide an appropriate care to the country's reality.

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.

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.

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.

Patients suffering from dystrophic epidermolysis bullosa are prone to developing autoantibodies against skin proteins: A longitudinal confirmational study.

Epidermolysis bullosa (EB) is a heritable skin blistering disease caused by variants in genes coding for proteins that secure cell-cell adhesion and attachment of the epidermis to the dermis. Interestingly, several proteins involved in inherited EB are also associated with autoimmune blistering diseases (AIBD). In this study, we present a long-term follow-up of 15 patients suffering from recessive dystrophic or junctional EB. From these patients, 62 sera were analysed for the presence of autoantibodies associated with AIBD. We show that patients suffering from recessive dystrophic EB (RDEB) are more susceptible to developing autoantibodies against skin proteins than patients suffering from junctional EB (70% vs. 20%, respectively). Interestingly, no correlation with age was observed. Most patients showed reactivity to Type XVII collagen/linear IgA bullous dermatosis autoantigen (n = 5; 33%), followed by BP230 (n = 4; 27%), Type VII collagen (n = 4; 27%) and laminin-332 (n = 1; 7%). The pathogenicity of these autoantibodies remains a subject for future experiments.