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Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of mechanobullous diseases characterized by non-scarring blisters and erosions on the skin and mucous membranes upon mechanical trauma. The simplex form (EBS) is characterized by recurrent blister formation within the basal layer of the epidermis. It most often results from dominant mutations in the genes coding for keratin (K) 5 or 14 proteins (KRT5 and KRT14). A disruptive mutation in KRT5 or KRT14 will not only structurally impair the cytoskeleton, but it will also activate a cascade of biochemical mechanisms contributing to EBS. Skin lesions are painful and disfiguring and have a significant impact on life quality. Several gene expression studies were accomplished on mouse model and human keratinocytes to define the gene expression signature of EBS. Several key genes associated with EBS were identified as specific immunological mediators, keratins, and cell junction components. These data deepened the understanding of the EBS pathophysiology and revealed important functional biological processes, particularly inflammation. This review emphasizes the three EBS subtypes caused by dominant mutations on either KRT5 or KRT14 (localized, intermediate, and severe). It aims to summarize current knowledge about the EBS expression profiling pattern and predicted molecular mechanisms involved and to outline progress in therapy.

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Epidermolysis bullosa (EB) is a genetic skin disorder characterized by skin fragility and blister formation. This review explores the genetic basis and management of EB in the Saudi population, emphasizing the need for genetic insights to enable precise diagnosis, targeted treatments, and effective counseling. Diagnosis in Saudi Arabia relies on clinical assessments and genetic testing. Prenatal diagnosis may be suggested in families with children affected by EB, but it is not widely used in the Middle East. Current management focuses on symptom relief, while emerging experimental approaches such as gene and stem cell therapies are under extensive research. Challenges in EB research include developing effective targeted therapies and understanding the variability in how genotypes manifest phenotypically. Continuous research is crucial to enhance diagnostic methods, therapeutic approaches, and overall patient care.

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The characteristics of epidermolysis bullosa (EB) demand higher than average provider support for transition from pediatric to adult care. We administered an online Qualtrics survey to members of the Epidermolysis Bullosa Clinical Research Consortium (EBCRC), a group of providers who care for patients with EB, in order to examine their practices and perspectives on transition of care (TOC) and identify barriers to successful implementation. Sixteen of eighteen medical centers completed the survey. Eighty-eight percent of center representatives expressed concerns about their patients transitioning/transferring from the pediatric to adult-centered care. Thirty-eight percent of providers reported having a formal TOC program in place. Our findings support the desire for formal TOC programs, the need for a team-based approach and, in particular, identification of adult providers to participate in the transition to improve this often challenging time.

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Junctional epidermolysis bullosa (JEB) is an intractable cutaneous disorder in humans causing skin fragility and blistering due to mutations in genes encoding essential molecules adhering epidermis and dermis including collagen XVII. However, the pathogenesis still remains to be not fully understood perhaps because of a lack of appropriate animal models. Here, we report novel mutant rats suffering from JEB, which was confirmed to be caused by a frameshift mutation of Col17a1 gene, as a rat model for investigating the underlying mechanism of pathogenesis. The mutant rats completely lacked the expression of collagen XVII and had blisters leading to infantile deaths as a homozygous condition, although their skin was apparently normal at birth by light microscopic evaluation except that immunohistochemical examination could not detect collagen XVII in any organs. These observations suggest that collagen XVII is not essential for the development of skin during the prenatal period but is indispensable for keeping epidermal-dermal connections stable after birth. Subsequent electron microscopic examinations further revealed an absence of hemidesmosomal inner plaques being composed of BP230, a binding partner of collagen XVII, and plectin in Col17a1-null newborns, albeit mRNA expressions of these molecules seemed to be unaffected at least during the fetal period. These results suggest that the lack of collagen XVII induces attenuation of hemidesmosomal inner plaques, which in turn destabilizes the epidermis-dermis connection and results in deterioration of epidermal physiology with formation of blisters after birth.

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The pemphigoid disease epidermolysis bullosa acquisita (EBA) is an autoimmune blistering skin disease characterized by autoantibodies against type VII collagen (COL7), immune cell infiltrates at the dermal-epidermal junction and subepidermal blistering. Proteases, particularly granzyme B (GzmB), have been established as therapeutic targets for the treatment of EBA and other pemphigoid diseases. We investigated the impact of the novel GzmB inhibitor SNT-6935 on anti-COL7 IgG-induced subepidermal blistering in a well-established EBA ex vivo model. Our findings demonstrate that pharmacological targeting of GzmB with its selective inhibitor SNT-6935 significantly reduced autoantibody-induced dermal-epidermal separation in human skin cryosections. Interestingly, treatment of skin cryosections with recombinant human GzmB alone did not cause dermal-epidermal separation, suggesting that additional mechanisms alongside GzmB are required for tissue damage in EBA. In conclusion, our study highlights the significant contribution of GzmB to the pathogenesis of EBA and supports the notion of GzmB as a therapeutic target in EBA and other pemphigoid diseases.

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Dehydration and malnutrition are common in infants with severe epidermolysis bullosa (EB), but their nutritional needs have been poorly studied. The principal aim was to assess the nutritional status, fluid and electrolyte balance, and nutritional intake of newborns with EB during the first month of life and estimate their needs during this period. This was a retrospective study over an eight-year period. Inclusion criteria were neonates with confirmed EB admitted to our neonatal referral unit during the first month of life. Exclusion criteria were hospitalisations <7 days. Twenty-seven patients with EB (mean [min-max] gestational age = 39 weeks [33; 41]; birth weight = 2986 g [1982; 4150]), were included. Four patients (15%) had hyponatraemia < 135 mmol/L at admission (age at admission = 4.8 days +/- 2.6 [2; 7]). Sixteen patients (59%) had a sodium deficit -requiring fluid and sodium intake well above recommendations from the World Health Organisation (WHO). The risk of hyponatraemia was significantly higher in infants with the greatest body surface area affected but did not appear to be related to EB subtype. Caloric and protein intake were well above the WHO's recommendations, preventing acquired growth restriction. The rate of sodium deficit in neonates with EB is high and related to the significance of skin exudate. The administration of nutrient intake greater than that recommended helps to prevent acquired growth restriction. We propose recommendations for nutritional intake and monitoring in neonates with EB in the first month of life.

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Secondary amyloidosis may complicate inherited dermatoses, but recessive dystrophic epidermolysis bullosa (RDEB) complicated by renal amyloidosis is rare. We report a case of a 12-year-old male child with RDEB presenting with progressive generalized anasarca for 20 days. Kidney biopsy showed diffuse expansion of mesangial matrix by pale acellular Periodic Acid-Schiff (PAS)-negative amorphous material, which was congophilic on Congo red stain and gave apple green birefringence on polarization and extending along the glomerular basement membrane, suggestive of amyloidosis. Genetic analysis showed a compound heterozygous pathogenic variant in the COL7A1 gene with autosomal recessive inheritance.

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Background: Epidermolysis bullosa (EB) is a clinically-heterogeneous genodermatosis with severe manifestations in the skin and other organs. The significant burden this condition places on patients justifies the development of gene therapeutic strategies targeting the genetic cause of the disease.Methods: Emerging RNA and DNA editing tools have shown remarkable advances in efficiency and safety. Applicable both in ex vivo- and in vivo settings, these gene therapeutics based on gene replacement or editing are either at the pre-clinical or clinical stage.Results: The recent landmark FDA approvals for gene editing based on CRISPR/Cas9, along with the first FDA-approved redosable in vivo gene replacement therapy for EB, will invigorate ongoing research efforts, increasing the likelihood of achieving local cure via CRISPR-based technologies in the near future.Conclusions: This review discusses the status quo of current gene therapeutics that act at the level of RNA or DNA, all with the common aim of improving the quality of life for EB patients.

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Advancements in the molecular genetics of epidermolysis bullosa (EB) and ichthyosis, two rare inherited skin conditions, have enabled the identification of genetic variants that cause these diseases. Alongside technological advancements in genetic medicine, the identification of variants causal of these rare skin conditions has led to preclinical research and the clinical development of various in vivo and ex vivo gene and cell therapies for their treatment. Gene and cell therapies are considered to be the most advanced forms of personalized medicine, demonstrating safety and efficacy in numerous rare diseases. Although the orphan drug development boom has resulted in regulatory approval of multiple gene and cell therapies for various rare conditions, the application of these modalities to rare inherited skin conditions remains limited. Nonetheless, there are successful examples of both in vivo gene therapy- and ex vivo cell therapy-based approaches developed to treat EB and ichthyosis. This review highlights preclinical research and the clinical development of gene and cell therapies for multiple subtypes of these two devastating congenital skin conditions, including a gene therapy recently approved by the U.S. Food and Drug Administration for the treatment of recessive dystrophic EB.

Advances in genetics research for skin diseases such as epidermolysis bullosa and ichthyosis have led to the discovery of many new subtypes of these severe skin conditions. Identifying new subtypes has in turn led to new treatments for these conditions, including gene and cell therapies. Gene and cell therapies aim to address the underlying genetic causes of disease and have already shown success in the clinic. While the development of such treatments for rare skin diseases has been limited, there are notable examples of gene and cell therapies developed for epidermolysis bullosa and ichthyosis. This review highlights recent developments in gene and cell therapy for epidermolysis bullosa and ichthyosis, including a newly approved gene therapy for recessive dystrophic epidermolysis bullosa.

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Objective: Epidermolysis bullosa simplex (EBS) is a common, well-characterized type of epidermolysis bullosa. However, some rare syndromic EBS phenotypes are not well described. The accumulation of clinical descriptions of patients with syndromic subtypes of EBS is important for understanding the natural history of the disease and assessing genotype-phenotype correlations. Case summary: We present a series of case reports of the syndromic subtype of EBS associated with mutations in the KLHL24 gene in seven patients from four unrelated families. The clinical features of this rare phenotype in children and adult patients are described in detail. In two families, we revealed pathogenic variant c.1A > G (p.Met1?) in the KLHL24 gene. The third family had c.3G > A (p.Met1?) mutation, and the fourth family had a novel de novo variant c.23del (p.Arg8AsnfsTer2). Conclusion: The description of the clinical manifestations of the disease in two generations of EBS families with different genetic variants allows the assessment and prediction of the natural course and severity of the disease in these families, the risk of complications, and the planning of the amount of medical care necessary.

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INTRODUCTION AND IMPORTANCE: Congenital epidermolysis bullosa (EB) is a group of rare genetic conditions characterized by fragile skin that blisters easily. Anaesthesia management in these patients is complex due to mucocutaneous fragility, which can complicate surgical procedures and airway management. Our study aimed to report a case of successful general anaesthesia in two patients with congenital epidermolysis bullosa undergoing oesophagal dilatation. CASE PRESENTATION: The case involved a brother and sister, aged 21 and 15 respectively, both of whom have congenital epidermolysis bullosa and presented with solid dysphagia due to double stenosis of the oesophagus. Anaesthesia management included meticulous preoperative planning, use of non-adhesive monitoring equipment, careful management with video laryngoscopy, and minimisation of skin trauma. CLINICAL DISCUSSION: Both patients underwent successful esophageal dilation under general anaesthesia without perioperative complications. Airway management was achieved in the first attempt using video laryngoscopy. Analgesia was effectively treated with paracetamol and tramadol. CONCLUSION: This case illustrates the complexities and necessary precautions for anaesthesia management in patients with epidermolysis bullosa. Detailed preoperative evaluation, careful monitoring, and specific handling techniques can mitigate perioperative risks and ensure patient safety.

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INTRODUCTION: At a single-center pediatric hospital, the neurokinin-1 receptor antagonist aprepitant was used to treat refractory pruritus in epidermolysis bullosa (EB) and atopic dermatitis (AD). METHODS: Thirty-seven patients were included (24 EB patients, 13 AD patients), ages 10 months to 37 years. RESULTS: 58% (14/24) of patients with EB and 85% (11/13) of patients with AD reported aprepitant was effective in decreasing their pruritus, with age-related differences in efficacy observed in EB patients, and access to the medication by insurance denial or availability of the drug as a barrier to use. CONCLUSIONS: Aprepitant shows promise in controlling refractory pruritus in pediatric EB and AD patients and deserves further study.

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BACKGROUND: Dystrophic epidermolysis bullosa (DEB) describes a rare genetic blistering disorder characterized by fragile skin. This study aimed to classify the frequency, demographics, cost, and comorbidities associated with emergency department (ED) visits due to DEB. METHODS: The Nationwide Emergency Department Sample (NEDS) was analyzed for pediatric (age <18) ED visits from 2015 to 2019. DEB was identified with ICD-10-CM code Q81.2. Weighted frequency, prevalence, and 95% confidence intervals (CIs) of comorbidities were determined among ED visits with and without a DEB diagnosis. RESULTS: From 2015 to 2019, 53 (weighted 242) cases of DEB among 27,223,220 pediatric ED visits were captured. Patients with DEB were more likely to visit the ED in summer compared with those without a diagnosis of DEB (35.7% vs. 21.4%, P < .05). More than half of patients with DEB were admitted to the hospital (56.2%, 95% CI: 39.3-72.5, P < .001) versus only 3.4% (95% CI: 3.1-3.7) of other patients. For ED visits with a secondary DEB diagnosis, the top three primary diagnoses were fever, constipation, and bone marrow transplant aftercare. Patients with DEB had higher rates of hypertension, cellulitis, sepsis, acute and chronic kidney injury, esophageal obstruction, gastroesophageal reflux disease, cardiomyopathy, and anxiety, compared to patients without DEB (all P < .001). CONCLUSIONS: DEB is a complex blistering disorder with multisystemic manifestations. Patients with DEB have significantly higher admission rates and commonly present with infectious or gastrointestinal complications. Understanding the features of ED visits due to DEB can better prepare healthcare teams and improve patient outcomes.

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Gene therapy based on the CRISPR/Cas9 system has emerged as a promising strategy for treating the monogenic fragile skin disorder recessive dystrophic epidermolysis bullosa (RDEB). With this approach problematic wounds could be grafted with gene edited, patient-specific skin equivalents. Precise gene editing using homology-directed repair (HDR) is the ultimate goal, however low efficiencies have hindered progress. Reframing strategies based on highly efficient non-homologous end joining (NHEJ) repair aimed at excising dispensable, mutation-harboring exons offer a promising alternative approach for restoring the COL7A1 open reading frame. To this end, we employed an exon skipping strategy using dual single guide RNA (sgRNA)/Cas9 ribonucleoproteins (RNPs) targeted at three novel COL7A1 exons (31, 68, and 109) containing pathogenic heterozygous mutations, and achieved exon deletion rates of up to 95%. Deletion of exon 31 in both primary human RDEB keratinocytes and fibroblasts resulted in the restoration of type VII collagen (C7), leading to increased cellular adhesion in vitro and accurate C7 deposition at the dermal-epidermal junction in a 3D skin model. Taken together, we extend the list of COL7A1 exons amenable to therapeutic deletion. As an incidental finding, we find that long-read Nanopore sequencing detected large on-target structural variants comprised of deletions up to >5 kb at a frequency of ~10%. Although this frequency may be acceptable given the high rates of intended editing outcomes, our data demonstrate that standard short-read sequencing may underestimate the full range of unexpected Cas9-mediated editing events.

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Dystrophic epidermolysis bullosa (DEB) is a rare, but severe, subtype of epidermolysis bullosa. It is characterized mainly by blisters and miliary rashes of the skin, while oral mucosa-dominated cases are extremely rare. Here, we report the characteristics of oral mucosa lesions in a Chinese familial case of DEB with a novel compound heterozygous COL7A1 mutation. We further analyzed the genetic and molecular features of the proband and the two related mutation carriers. Our study further elucidates the genetic and phenotypic heterogeneity of DEB.

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BACKGROUND: Junctional epidermolysis bullosa (JEB) is one of the four major types of EB caused by genetic variants in the genes coding the proteins of the lamina lucida. All patients with this major type of EB present syndromic hypoplastic amelogenesis imperfecta (AI), with either a pits and fissures or generalized hypoplastic phenotype. Severe forms of AI are associated with compromised oral health-related quality of life (QoL) mostly due to poor dental aesthetics, dentofacial anomalies, and oral pain. AIM: To present the comprehensive dental treatment of a patient with JEB and AI from the age of 20 months until the age of 18 years, including complex orthodontics and digital oral rehabilitation. MATERIALS AND METHODS: A male patient with intermediate JEB (homozygous c.3228+1G>A LAMB3 variant) has been under the care of the special care dentistry clinic of the University of Chile since the age of 20 months. His complex dental needs include structural enamel abnormalities in primary and permanent dentition (hypoplastic generalized AI), severe dental crowding with maxillary compression, Class III skeletal pattern, agenesia (#45), and gingivitis. RESULTS: Pediatric dental care included oral hygiene education and preventive strategies (prophylaxis and fluoride applications), maintaining the dentition free of caries. Due to AI, severe tooth sensitivity hindered proper oral hygiene and required early rehabilitation with temporary polycarbonate and metallic crowns. At the age of 16, the patient began orthodontic treatment. A maxillary expansion was performed with two consecutive mini-implant assisted rapid palate expansion (MARPE) bonded to four mini-implants in the palate. After finishing orthodontic treatment metallic multibrackets (duration 19 months), a definitive oral rehabilitation based on digital smile design with feldspathic crowns of all anterior teeth and premolars was performed. CONCLUSION: Patients with severe generalized hypoplastic syndromic AI associated with JEB benefit from long-term preventive oral care. Complex orthodontic techniques, such as MARPE, and multibrackets can be successfully. Digital smile design provides a definitive oral rehabilitation technique improving oral function, aesthetics, and QoL.