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.

Osteoporosis and bone health in pediatric patients with epidermolysis bullosa: A scoping review.

Nutritional compromise, low levels of vitamin D, chronic inflammation, abnormal growth, and physical inactivity affect bone metabolism and compromise long-term bone health in individuals with epidermolysis bullosa (EB). The result is a high risk for osteopenia, osteoporosis, and pathologic fractures, but this important consequence of EB has been the focus of few investigations. Our scoping review found 21 publications that assessed the current understanding and clinical practices for monitoring of osteoporosis and its treatment in EB. Recommendations summarized from 13 of these publications include early nutritional and weight assessments before 2 years of age; bloodwork every 6-12 months starting at birth; Tanner stage assessments every 6 months to detect any pubertal delay; DEXA scans starting at age 6 years with repeated scans every 1-2 years, except in mild cases; and vitamin D supplementation of 80-320 IU daily for children 0-7 years and 720 IU for patients >8 years.

Oleogel-S10 in Dystrophic Epidermolysis Bullosa: A Case Series Evaluating the Impact on Wound Burden Over Two Years.

Epidermolysis bullosa (EB) is a group of rare, difficult-to-treat, inherited multisystem diseases affecting epithelial integrity. Impaired wound healing is central and can lead to serious clinical complications, deformities, and symptoms with a devastating impact on quality of life (QoL). Dressing changes and wound care are central to the management of EB. Recently Oleogel-S10 (also known as birch bark extract or birch triterpenes) was approved in Europe and the UK for treating EB wounds. This approval was based on data from the EASE phase 3 study, which demonstrated Oleogel-S10 accelerated wound healing, reduced total wound burden, and decreased the frequency of dressing changes in patients with EB. A retrospective analysis of medical records was conducted for up to 24 months in 13 patients with EB treated with Oleogel-S10 through an early access programme in Colombia. Effectiveness was assessed by measuring body surface area percentage (BSAP) and total body wound burden (EBDASI). Tolerability and safety were monitored throughout. This is the first report to evaluate the effectiveness of Oleogel-S10 in clinical practice. The results showed a reduction in percentage of BSA affected, from a mean of 27.3% at baseline to 10.4% at 24-month follow-up, despite treatment interruptions. A reduction in EBDASI skin activity score of - 16.2 (24 months) together with a reduced skin damage index score of - 15.4 (18 months) was also observed. Physicians, patients, and caregivers perceived faster wound closure. Adherence with therapy by patients was good, and patients expressed satisfaction with treatment and reported improvements in self-esteem, productivity, and social interaction. Oleogel-S10 was well tolerated; however, two patients reported worsening wounds related to gauze adherence. Two deaths during treatment interruption were reported and was not considered related to Oleogel-S10. This study supports the effectiveness of Oleogel-S10 in a real-world scenario in a country with scarce resources for the treatment of EB.

Metformin shows anti-neoplastic properties by inhibition of oxidative phosphorylation and glycolysis in epidermolysis bullosa-associated aggressive cutaneous squamous cell carcinoma.

BACKGROUND: While most cutaneous squamous cell carcinomas (cSCCs) are treatable, certain high-risk cSCCs, such as those in recessive dystrophic epidermolysis bullosa (RDEB) patients, are particularly aggressive. Owing to repeated wounding, inflammation and unproductive healing, RDEB patients have a 68% cumulative risk of developing life-threatening cSCCs by the age of 35, and a 70% risk of death by the age of 45. Despite aggressive treatment, cSCC represents the leading cause of premature mortality in these patients, highlighting an unmet clinical need. Increasing evidence points to a role of altered metabolism in the initiation and maintenance of cSCC, making metabolism a potential therapeutic target. OBJECTIVES: We sought to determine the feasibility of targeting tumour cell energetics as a strategy to selectively hinder the growth advantage of aggressive cSCC. METHODS: We evaluated the cell energetics profiles of RDEB-SCC cells by analysing available gene expression data against multiple gene signatures and single-gene targets linked to metabolic reprogramming. Additionally, we employed real-time metabolic profiling to measure glycolysis and respiration in these cells. Furthermore, we investigated the anti-neoplastic properties of the metformin against human and murine high-risk cSCCs in vitro and in vivo. RESULTS: Gene expression analyses highlighted a divergence in cell energetics profiles between RDEB-SCC and non-malignant RDEB keratinocytes, with tumour cells demonstrating enhanced respiration and glycolysis scores. Real-time metabolic profiling supported these data and additionally highlighted a metabolic plasticity of RDEB-SCC cells. Against this background, metformin exerted an anti-neoplastic potential by hampering both respiration and glycolysis, and by inhibiting proliferation in vitro. Metformin treatment in an analogous model of fast-growing murine cSCC resulted in delayed tumour onset and slower tumour growth, translating to a 29% increase in median overall survival. CONCLUSIONS: Our data indicate that metformin exerts anti-neoplastic properties in aggressive cSCCs that exhibit high-risk features by interfering with respiration and glycolytic processes.

Gross motor development in children with epidermolysis bullosa.

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare, congenital skin disorders, characterized by skin fragility and formation of blisters. The gross motor outcomes of children with EB are not known. OBJECTIVES: The primary objective of the study was to measure the proportion of gross motor delay in children with EB. The secondary objectives were to measure the difference in gross motor outcomes between EB sub-types and change in gross motor outcomes over time. METHODS: Children with EB, aged between one month and five and a half years of age, attending the Sydney Children's Hospital, Epidermolysis Bullosa Clinic, were eligible. Carers completed Ages and Stages Questionnaires, Third Edition, on behalf of their children. Questionnaires were scored, and outcomes were compared to age-expected norms. RESULTS: There were 24 participants to complete a questionnaire. Eleven participants completed additional questionnaires over the 24 month study duration. The proportion of children with EB with gross motor delay was greater than age-expected norms (29.17% vs. 2.5%). The delay occurred in children with recessive dystrophic (80%) and epidermolysis bullosa simplex (33.33%) sub-types, but not dominant dystrophic (0%). No children with Junctional EB or Kindler EB joined this study. CONCLUSIONS: This study demonstrates a difference in gross motor outcomes in children with EB. Children with recessive dystrophic and epidermolysis bullosa simplex should be prioritized for monitoring of, and intervention for, gross motor outcomes through multidisciplinary care. Further research investigating long-term outcomes for children with EB and the effectiveness of interventions would be beneficial.

[Hereditary epidermolysis bullosa in children]. / L'épidermolyse bulleuse héréditaire chez les enfants.

Hereditary epidermolysis bullosa (HES) is a heterogeneous group of rare genetic disorders characterized by localized or generalized fragility of the skin and/or mucous membranes, varying greatly in severity from one form to another and even within a subgroup. Skin wounds can be a source of pain, pruritus and discomfort from birth. Progression varies from patient to patient and from form to form. Specific care must be provided from the neonatal period onwards, and throughout life, to aid healing and limit complications. Nurses are at the heart of skin care for HES patients, and must be familiar with the main principles, while adapting to the individual.

Clinical and molecular features in a cohort of Middle Eastern patients with epidermolysis bullosa.

BACKGROUND: Epidermolysis bullosa (EB) features skin and mucosal fragility due to pathogenic variants in genes encoding components of the cutaneous basement membrane. Based on the level of separation within the dermal-epidermal junction, EB is sub-classified into four major types including EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler EB (KEB) with 16 EB-associated genes reported to date. METHODS: We ascertained a cohort of 151 EB patients of various Middle Eastern ethnic backgrounds. RESULTS: The cohort was comprised of EBS (64%, 97/151), DEB (21%, 31/151), JEB (12%, 18/151), and KEB (3%, 5/151). KRT14 and KRT5 variants were most common among EBS patients with 43% (42/97) and 46% (45/97) of EBS patients carrying mutations in either of these two genes, respectively. Truncal involvement was more common in KRT14-associated EBS as compared to EBS due to KRT5 mutations (p < .05). Mutations in COL17A1 and laminin 332-encoding genes were identified in 55% (10/18) and 45% (8/18) of JEB patients. Scarring alopecia, caries, and EB nevi were most common among JEB patients carrying COL17A1 mutations as compared to laminin 332-associated JEB (p < .05). Abnormal nails were evident in most DEB and JEB patients while poikiloderma was exclusively observed in KEB (p < .001). CONCLUSIONS: EB patients of Middle Eastern origin were found to feature specific phenotype-genotype correlations of relevance to the diagnosis and genetic counseling of patients in this region.

Treatment With Ataluren for Wound Healing and Health Complications in a Patient With Junctional Epidermolysis Bullosa.

This case report describes an 11-year-old boy with widespread chronic wounds, frequent corneal erosions, dental caries, a tracheostomy, and failure to thrive.

Itch in recessive dystrophic epidermolysis bullosa: findings of PEBLES, a prospective register study.

BACKGROUND: Itch is common and distressing in epidermolysis bullosa (EB) but has not previously been studied in depth in different recessive dystrophic EB (RDEB) subtypes. OBJECTIVES: As part of a prospective register study of the natural history of RDEB we explored features of itch, medications used, and correlation with disease severity and quality of life. METHODS: Fifty individuals with RDEB aged 8 years and above completed the Leuven Itch Scale (LIS) (total 243 reviews over a 7-year period). Data included itch frequency, severity, duration, distress, circumstances, consequences, itch surface area and medications for itch. The iscorEB disease severity score and the validated EB quality of life tool, QOLEB, were compared to LIS domains and analysed by RDEB subtype. RESULTS: Itch was frequent, present in the preceding month in 93% of reviews. Itch severity and distress were significantly greater in severe (RDEB-S) and pruriginosa (RDEB-Pru) subtypes compared to intermediate RDEB (RDEB-I). Itch medications were reported in just over half of reviews including emollients, topical corticosteroids and antihistamines; the proportion of participants not using medication despite frequent pruritus suggests limited efficacy. In inversa RDEB (RDEB-Inv) and RDEB-I, LIS domains correlated with iscorEB and QOLEB. In contrast to previous studies, correlations were lacking in RDEB-S suggesting that global disease burden relatively reduces the contribution of itch. CONCLUSIONS: This comprehensive study of RDEB-associated itch highlights differences between RDEB subtypes, suggests an unmet need for effective treatments and could serve as control data for future clinical trials incorporating itch as an endpoint.

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.

Characterization of wound microbes in epidermolysis bullosa: A focus on Pseudomonas aeruginosa.

The most common bacteria isolated from wound cultures in patients recorded in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database (EBCCOD) are Staphylococcus aureus and Pseudomonas aeruginosa. Given the prevalence of P. aeruginosa in this patient population and prior research implicating P. aeruginosa's potential role in carcinogenesis, we sought to further analyze patients with recorded wound cultures positive for Pseudomonas aeruginosa in the EBCCOD. We provide a descriptive analysis of this subset of patients and highlight potential avenues for future longitudinal studies that may have significant implications in our wound care management for patients with epidermolysis bullosa.

Type II Congenital Pyloric Atresia with Desquamative Enteropathy Diagnosed Postoperatively: A Case Report.

Congenital pyloric atresia (CPA) is a rare condition that presents as gastric outlet obstruction in the first few weeks of life. Isolated CPA typically carries a good prognosis but when associated with other conditions such as multiple intestinal atresia or epidermolysis bullosa (EB), the outcomes are generally poor. This report describes a four-day-old infant who presented with nonbilious emesis and weight loss in whom an upper gastrointestinal contrast study revealed gastric outlet obstruction determined to be consistent with pyloric atresia. The patient underwent operative repair via Heineke-Mikulicz pyloroplasty. Postoperatively, the patient continued to have severe diarrhea and was found to have desquamative enteropathy though had no skin findings consistent with EB. This report emphasizes consideration of CPA as a differential diagnosis for neonates presenting with nonbilious emesis and demonstrates the association between CPA and desquamative enteropathy without EB.

IgA nephropathy in adults with epidermolysis bullosa.

Epidermolysis bullosa (EB) is a devastating genetic condition caused by mutations in genes that give rise to aberrant proteins. There are 16 different such proteins implicated in EB that are important in maintaining the integrity of the dermoepidermal junction. It is classified into four major subtypes: (i) EB simplex; (ii) junctional EB (JEB); (iii) dystrophic EB (DEB); and (iv) Kindler EB. Renal disease is a recognized complication of EB and the aetiology is complex. We describe our experience of managing five patients with EB and IgA nephropathy. We recommend that patients with recessive DEB and JEB routinely have the following monitored: renal function, urinary albumin/creatinine ratio, urine analysis, serum albumin levels and immunoglobulins; specifically serum IgA. Management of IgA nephropathy in the context of EB should be tailored to the individual and be carried out within a specialist multidisciplinary team. Our case series provides important insights into the treatment of IgA nephropathy in patients with EB and will help inform treatment in this rare genetic disease. Case series and reports like ours are key in gaining real-life data to quantify the actual risk of morbidity and mortality from each of the treatment modalities discussed.

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.