AIM:Epidermolysis bullosa (EB) is characterised by chronic cutaneous wounds and gastrointestinal complications, including constipation. Aim to identify factors that impacted stool frequency and laxative use in paediatric patients with severe subtypes of EB. METHODS:Retrospective data collection on demographics, type of EB, total fibre intake (food, enteral formula and supplements), probiotic supplementation, laxative use, iron supplementation, opioid-based pain medication, stool consistency and frequency using the Bristol Stool Chart. RESULTS:Data collected on 37 patients. The mean total fibre intake was 16.67 g/day (10.67 SD). Twenty-seven of 37 (73%) children were on macrogol osmotic laxatives. Children who were taking fibre supplementation were also more likely to be on macrogol compared to children not taking fibre supplementation (p = 0.047). No significant association was found between total fibre intake g/day or fibre reference nutrient intake (%) on stool consistency, r = -0.04 and r = -0.3, respectively. Children taking iron supplements were more likely to take macrogol compared to children not on iron supplements. Eight of 37 patients were on regular probiotics, but there was not a significant reduction in the need for macrogol osmotic laxatives compared to children not taking probiotics (χ2 0.025, p-value 0.87). CONCLUSION:Patients who were on fibre supplementation were also more likely to take laxatives. Patients on iron supplements had a greater reliance on laxatives than those patients not taking iron supplements, further demonstrating the impact iron has within the intestines. The potential benefits of probiotics in the management of constipation may be suppressed in children with EB due to regular antibiotic administration.

Introduction:Patients with Severe Recessive Dystrophic Epidermolysis Bullosa (RDEB-S) develop hand contractures that progress over time and impact function and quality of life. The role of the Occupational Therapist includes hand assessment and interventions to help maintain function. We developed the Assessment of Hand Contractures in Epidermolysis Bullosa (ACE-EB) to facilitate sensitive and detailed assessment. The purpose of this article is to describe its development and use. Methods:We undertook a literature search of existing hand assessments and evaluated their use for children with RDEB-S. Most measure contracture recurrence post-operatively and none was sensitive enough to capture emerging contractures seen in children. We developed the ACE-EB by adapting the most relevant existing assessments, to include specific component contracture measurements, a Hand Deformity Grade and a hand surgery Patient Reported Outcome Measure. We explored the validity by surveying clinicians in the field of Epidermolysis Bullosa and we tested the inter-rater reliability. Results:We describe the development of the ACE-EB. The results of the validity survey showed most respondents agreed that the ACE-EB had sufficiently sensitive grading scales, included relevant aspects of hand assessment and was a useful clinical or research tool. Inter-rater reliability tests showed good strength of agreement. Discussion:The ACE-EB is a novel clinical tool designed for use with children with RDEB-S. It can be used to monitor changes, track natural history of hand contractures, guide practice and serve as a post-operative outcome measure in children and adults. Further testing of its validity and reliability is required.

Background Individuals with epidermolysis bullosa (EB) have complex health care needs requiring multidisciplinary team (MDT) care from a range of healthcare professionals. Understanding the detailed costs of hospital care for recessive dystrophic EB (RDEB) is essential for service planning and resource allocation and also supports more appropriate value assessment of potentially costly new therapies. Objectives To identify in detail the common procedures performed in children and adults with RDEB in two UK EB reference centres and associated costs for inpatient and outpatient care. Methods A bottom-up micro-costing was developed to identify costs of hospital care for RDEB. Using an iterative process, a panel of EB experts first identified the types of EB clinic and interventions accessed by RDEB patients. Next, for each clinic or intervention, costs for personnel and resources used were identified/calculated, and clinic capacity (patients seen and clinic frequency) identified. Finally, UK National Health Service (NHS) costs were applied to personnel time, inpatient bed stay, and other resources used to develop a cost/event for each clinic and procedure for children and adults with RDEB. Results Whilst outpatient clinic costs for milder patients were similar to NHS standard multidisciplinary clinic tariffs (c.£200), we identified a cost of c. £2,300 for more severe RDEB patients per MDT clinic. A day-case oesophageal dilatation was c.£2,000 and surgery for excision of a squamous cell carcinoma (SCC) varied from c.£8,000-£11,000. Surgery to release hand contractures requires an inpatient stay and prolonged follow-up for dressing changes, costing around £19,000-£22,000 per surgery. Conclusions This bottom-up micro-costing of hospital care for RDEB highlights the significant costs of providing MDT care for this complex group, which are probably greatly in excess of the current funding (Highly Specialised Service block contract) for EB services in England. Understanding the true costs of managing this rare disease underpins the need for appropriate resource allocation and may be applicable to similar complex, multisystem rare diseases which necessitate frequent hospital care. Importantly, the cost of care and lifelong and progressive nature of RDEB underscores the importance of considering current care costs when developing newer costly therapies for this devastating disease.

BACKGROUND/OBJECTIVES:Pediatric patients with epidermolysis bullosa (EB) experience lifelong complications, and wound healing is an important treatment goal. In the phase III EASE study (NCT03068780), Oleogel-S10 accelerated wound healing in EB. This prespecified subgroup analysis evaluated the long-term efficacy and safety of Oleogel-S10 in patients aged < 18 years from EASE. METHODS:EASE comprised a 90-day double-blind phase (DBP) and 24-month open-label phase (OLP). In the DBP, patients were randomized 1:1 to receive Oleogel-S10 or control gel; all patients could enter the OLP and receive Oleogel-S10. Endpoints in this analysis included wound healing, total body wound burden, dressing change burden, and safety. RESULTS:Overall, 156 pediatric patients were enrolled into the DBP (Oleogel-S10: n = 74; Control gel: n = 82); 147 entered the OLP. Oleogel-S10 resulted in 44.6% of pediatric patients with first complete target wound closure within 45 days, versus 25.6% with control gel (relative risk [95% CI]: 1.70 [1.11, 2.60], p = 0.012). Mean absolute body surface area percentage scores were 12.5% at DBP baseline and 5.3% at OLP Month 24 for the Oleogel-S10 group. Significantly more patients treated with Oleogel-S10 (38%) no longer required daily dressing changes versus control gel (9%) at DBP Day 90. Similar proportions of patients experienced adverse events in the Oleogel-S10 and control gel groups in the DBP, with most mild or moderate. CONCLUSIONS:These analyses of pediatric patients demonstrated accelerated wound healing, reduced frequency of dressing changes, and sustained reduction in wound burden up to 27 months. Long-term safety was consistent with the overall EASE population. TRIAL REGISTRATION:NCT03068780, EudraCT 2016-002066-32; registered 3 March 2017; https://clinicaltrials.gov/study/NCT03068780 and https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-002066-32/GB.

Qualitative accounts and studies employing disease-specific outcome measures have demonstrated that people with dystrophic epidermolysis bullosa (DEB) display impaired health-related quality of life (HRQoL) due to wound-related challenges. There is a paucity of utility data necessary to inform the health economic evaluation of emerging treatments for cutaneous open wounds. The objective was to implement a vignette study with a representative sample of the United Kingdom (UK) general population (N = 1139) and people with DEB (N = 44) to estimate utility values. Vignettes were defined by various attributes, including the number and area of wounds, pain, itch and hours spent managing wounds. Participants valued the vignettes from the perspective of a patient or a caregiver proxy using the EQ-5D-3L or EQ-5D-Y-3L, respectively. The mean utilities elicited from the patient perspective ranged from 0.491 to − 0.448 and 0.457 to − 0.462 for the general population (N = 627) and DEB (N = 31) sample, respectively. The utilities elicited from the proxy perspective ranged from 0.443 to − 0.543 and 0.079 to − 0.550 in the general population (N = 512) and DEB (N = 13) sample, respectively. The findings join a limited evidence base indicating that the symptoms associated with the wounds experienced by people with DEB have a considerable detrimental effect on their HRQoL.

Abstract Background Chronic disease, including different forms of epidermolysis bullosa (EB), may significantly impair health-related quality of life (HRQoL). To date, HRQoL in specific subtypes of recessive dystrophic EB (RDEB) has not been studied in depth. Objectives To measure HRQoL in a large cohort of individuals with different RDEB subtypes, to explore differences in physical functioning and emotional/psychosocial health scores, and to identify potential correlation with disease severity. Methods The Prospective EB Longitudinal Evaluation Study (PEBLES) is a register study of children and adults with RDEB. Reviews are repeated every 6 months (under 10 years) or annually (10 years and above) with HRQoL assessed using the Quality of Life in Epidermolysis Bullosa (QOLEB), an EB-specific questionnaire, for adult participants and the Pediatric Quality of Life Inventory (PedsQL) generic core scales, version 4.0, for child participants and their parents. Disease severity was measured with the Birmingham EB Severity score (BEBS) and the Instrument for Scoring Clinical Outcomes for EB (iscorEB). Results HRQoL was reported in 335 reviews over a maximum of seven years by 61 participants: severe RDEB (RDEB-S) n = 26, intermediate (RDEB-I) n = 21, inversa (RDEB-Inv) n = 9, pruriginosa (RDEB-Pru) n = 4 and pretibial RDEB n = 1. QOLEB demonstrated a severe impact on HRQoL for all RDEB adults (n = 47), particularly for RDEB-Pru and RDEB-S participants. Total and functioning QOLEB scores correlated with disease severity scores (iscorEB, BEBS) for all RDEB, with a statistically higher impact in RDEB-S compared to RDEB-I and RDEB-Inv. In children (n = 14), those with greater disease severity measured by iscorEB also reported worse HRQoL (PedsQL). In adults and children, physical functioning/health QoL was more severely impacted than emotions/psychosocial health, and HRQoL generally improved with age. Conclusion Our results highlight a significant impact on HRQoL in adults and children with all types of RDEB which generally correlates with disease severity. Relatively less impact on emotional functioning/psychosocial health rather than physical functioning/health scores suggests psychological adaptation from living with RDEB, a lifelong condition which typically presents at or shortly after birth. Further, a relative improvement in HRQoL with age, despite disease progression and increasing severity over time, supports ongoing adaptation throughout life.

Abstract Background Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare genetic skin condition causing fragile skin, blistering, and scarring. It leads to chronic pain, slow wound healing, and severe limitations, profoundly impacting patient and family quality of life. Umbilical cord tissue-derived mesenchymal stromal cells (UC-MSC) have shown therapeutic promise. The Mission EB trial (ISRCTN14409785; registration date 25/03/2021) assessed UC-MSC safety and effectiveness in children with RDEB in a placebo-controlled, double-blinded, crossover study. Methods This study used a qualitative research design with semi-structured interviews and thematic analysis, to explore Mission EB trial treatment impact on the quality of life of patients and parents. Parents and patients were interviewed at two time points (approximately 3- and 12-months post-randomisation). Purposive sampling included 10 parents and 6 children; 13 individuals (8 adults, 5 children) were interviewed twice (once in each study period). Interviews were transcribed verbatim, independently coded, with overall impressions agreed upon prior to unblinding. Results RDEB significantly impacted daily life, marked by pain and itch. Participants were hopeful of the trial, willing to pursue minor improvements. UC-MSC infusions led to reduced pain/itchiness, improved wound healing, and resulted in fewer self-reported dressing changes. These benefits often translated to increased energy, improved eating, and greater daily activity participation. Benefits were more pronounced with active treatment. Negative effects were minimal, primarily venous access difficulties. Blinded participants could discern active UC-MSC from placebo based on symptom changes; 10 of 13 showed clear differences aligning with treatment. All parents interviewed expressed willingness for their child to receive treatment again. Conclusions This qualitative research provides valuable insights into perceived benefits of UC-MSC treatment for children with RDEB. Interview findings regarding symptom improvement and participants’ ability to discern active treatment shed light on its perceived benefit in RDEB, especially in milder RDEB patients. The study highlights the critical importance of qualitative methodologies in adding to quantitative trial outcomes and capturing the meaningful impact of interventions on the lives of patients and families particularly where quantitative measures may not fully reflect lived experience.

Epidermolysis bullosa (EB) comprises a group of rare genetic blistering disorders with variable severity. Epidemiological studies on EB have previously often relied on data from specialist centres. However, many patients are managed outside of this setting. This national retrospective cohort study identified all cases of EB in England from April 1997 to April 2024 using International Classification of Diseases 10th Revision code Q81. Records were obtained from NHS England’s national Hospital Episode Statistics (HES) inpatient and outpatient data and data from the National Congenital Anomaly and legacy regional congenital anomaly registers. Cases were linked to primary care prescription data from the National Health Service Business Services Authority and mortality data from the Office for National Statistics. Crude counts and point prevalence per million in 2023 in England were calculated. Patient sociodemographic factors, treatments, prescriptions and mortality rates were described. In total, 3419 patients with EB were identified, of whom 2980 were alive as of June 2023, resulting in a prevalence of 51.7 per million [95% confidence interval (CI) 49.8–53.5]. The most common subtype was unspecified EB (n = 1442), with a prevalence of 25.0 per million (95% CI 23.7–26.3), followed by EB simplex (n = 765; prevalence 13.3, 95% CI 12.3–14.2), dystrophic EB (n = 512; prevalence 8.9, 95% CI 8.1–9.7), other EB (n = 235; prevalence 4.1, 95% CI 3.6–4.6) and severe junctional EB (n = 26; prevalence 0.5, 95% CI 0.3–0.7). Overall, 66% of patients identified as White ethnicity, followed by 10% as Asian ethnicity; however, 18% had missing ethnicity data. Female patients comprised 54% of cases. In total, 21% lived in areas of the lowest deprivation, compared with 16% in the quintile of the most deprived population. During the follow-up 481 of 3419 (14%) patients died, and 4.6% died before age 15 years, with severe junctional EB showing a median age at death of < 6 months. In the last 5 years of data, 123 of 160 (76.9%) patients underwent upper gastrointestinal tract procedures. Analysis of the community prescriptions dataset showed that 819 915 items (412 882 prescriptions) were issued from April 2018 to September 2024. Of these, 23.4% were dressings, followed by 14.8% central nervous system and 9.4% cardiovascular system medications, amounting to a total prescription cost of £62.2 million. The annual median cost per patient (2019–2023) was £244 (interquartile range £55.20 to £1027), which was highest in patients with dystrophic EB (median £735, interquartile range £152 to £6145). This is the first population-level study of EB and presents the largest and most comprehensive national EB dataset reporting prevalence, demographics and treatments for EB. It highlights the utility of national datasets in understanding rare conditions and supporting improvements in patient care.

Background:Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disorder characterised by extensive mucocutaneous blistering. This study aimed to generate evidence to inform commissioning decisions on umbilical cord-derived mesenchymal stromal cells, UC-MSCs, (CORDStrom™) for RDEB. Methods:In this double-blinded, randomised (1:1), placebo-controlled, two-period crossover phase 3 trial, children aged 6 months to 16 years of age with RDEB were enrolled at two UK specialist centres for epidermolysis bullosa (EB). Individuals were excluded if they had received oral or topical corticosteroids for more than 7 consecutive days within 30 days of enrolment into this study, excluding oral viscous budesonide and inhaled fluticasone used as prophylaxis to relieve oesophageal symptoms, an active infection that required treatment with oral or intravenous antibiotics within 7 days of screening, medical history or evidence of active malignancy, the presence of both positive collagen VII ELISA and a positive indirect immunofluorescence (IIF) with binding to the base of salt split skin, administration of MSCs from any source in the previous 9 months and participation in any other interventional trial within 3 months of enrolment into this study. This trial included an internal dose de-escalation (IDD) phase for safety gatekeeping. During IDD, 4 participants were randomised (3:1) to receive two infusions (2-3 × 106 cells/kg/infusion or placebo) on days 0 and 14 before the next participant begun treatment. The primary outcome was toxicity defined as a suspected unexpected serious adverse reaction (SUSAR) within 48 h of receiving an infusion. The DMEC reviewed the data and if one (or fewer) patients receiving the active treatment experienced a SUSAR, the dose would be reduced and toxicity evaluated in a further 5 patients randomised (3:2) to UC-MSCs or placebo. If there were no further toxicities, the trial progressed to the main two period crossover study. In the main crossover, patients were randomly assigned (1:1) using a web-based randomisation system SCRAM to receive two intravenous infusions (days 0 and 14), at a dose of 2-3x106 cells/kg UC-MSCs or placebo. There were 2 follow-up periods each of 6 months with a 3 month interval between periods, giving a 9 month duration between doses. Clinicians, caregivers, patients, and clinical trial personnel were fully blinded to treatment groups. Trial pharmacists and a team or independent research nurses who only performed administration of the infusion were unblinded to perform security checks of the product but were not involved in any assessments. The primary endpoint was change in disease severity as measured by Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) at three months post infusion assessed in the modified intention to treat (mITT) population (participants providing data at both period baselines and at least one 3-month follow-up). Prespecified subgroups included RDEB severity and age. Safety data were collected for all participants and safety assessment was based on all treatment emergent events in the safety population (those receiving at least one active or placebo infusion). This trial is registered with ISRCTN, ISRCTN14409785. Findings:Between OCT 06, 2021, and JUL 15, 2024, 44 participants were screened; 37 were randomised (18 UC-MSCs/placebo; 19 Placebo/UC-MSCs), with 34 receiving at least one infusion and 30 in the mITT analysis (14 UC-MSCs/placebo; 16 placebo/UC-MSCs). No toxicities were seen in the IDD phase (primary outcome). At three months no changes in favour of UC-MSCs were seen in the primary outcome EBDASI. The between arm difference in EBDASI at 3 months showed a 3.75 point difference (effect size 0.06) in favour of placebo (95% CI of -1.46, 8.96, p = 0.15) with corresponding figures for UC-MSCs/Placebo and Placebo/UC-MSCs of 5.5 (95% CI of -2.53 to 13.53, p = 0.16) and 2 (95% CI of -5.33 to 9.33, p = 0.58). No serious adverse events were associated with UC-MSCs. Interpretation:UC-MSCs infusions were safe and the primary outcome (EBDASI) did not show MSCs were beneficial. Further evaluation of the long-term efficacy of UC-MSCs is planned. The main strength is that Mission EB is the largest cell therapy study to date providing the most robust evidence on the safety and efficacy of UC-MSCs in children with RDEB. A limitation is that there are no robust validated outcome measures for RDEB. Funding:National Research Collaboration Programme, an NHS England and NIHR partnership (NIHR 127963) and Cure EB.

INTRODUCTION:Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic mucocutaneous fragility disorder characterised by chronic blistering, slow wound healing and increased risk of squamous cell carcinoma. Current management options are very limited. METHODS:This is a randomised (1:1), placebo-controlled, double-blinded crossover (A/B) trial with an internal phase I dose de-escalation (4+5 design) in the first 3 months and a 12-month continued treatment follow-on open-label study if 3-month outcome data from the crossover trial indicate safe and beneficial effects. RDEB is a rare condition, so we expect to recruit a maximum of 36 participants based on feasibility and not formal power considerations. Participants aged>6 months and <16 years will be recruited at Great Ormond Street Hospital and Birmingham Children's Hospital. They will receive 2-3×106 cells/kg intravenous infusion of umbilical cord-derived mesenchymal stem cells or placebo at the start of each crossover period (day 0) and 14 days later. The dose will be de-escalated to 1-1.5×106 cells/kg depending on observed toxicity. For the main crossover trial, the primary outcome is the change in disease severity as measured by the Epidermolysis Bullosa Disease Activity and Scarring Index at 3 months from day 0 infusion. Secondary outcomes measured at 3 and 6 months from day 0 infusion include changes in general clinical appearance of skin disease, pain and itch, and quality of life. Adverse events and serious adverse events will be monitored throughout the trial. ETHICS AND DISSEMINATION:North East-York Research Ethics Committee approved the protocol (ref: 21/NE/0016) on 16 March 2021. Findings will be published in peer-reviewed scientific journals, presented at relevant national and international conferences, and an open-access final report submitted to the funder. TRIAL REGISTRATION NUMBER:ISRCTN14409785. Protocol V. 8.0, 14 November 2022.

Epidermolysis bullosa (EB) comprises a group of rare genetic blistering disorders with variable severity. Epidemiological studies on EB have previously often relied on data from specialist centres. However, many patients are managed outside of this setting. This national retrospective cohort study identified all cases of EB in England from April 1997 to April 2024 using International Classification of Diseases 10th Revision code Q81. Records were obtained from NHS England’s national Hospital Episode Statistics (HES) inpatient and outpatient data and data from the National Congenital Anomaly and legacy regional congenital anomaly registers. Cases were linked to primary care prescription data from the National Health Service Business Services Authority and mortality data from the Office for National Statistics. Crude counts and point prevalence per million in 2023 in England were calculated. Patient sociodemographic factors, treatments, prescriptions and mortality rates were described. In total, 3419 patients with EB were identified, of whom 2980 were alive as of June 2023, resulting in a prevalence of 51.7 per million [95% confidence interval (CI) 49.8–53.5]. The most common subtype was unspecified EB (n = 1442), with a prevalence of 25.0 per million (95% CI 23.7–26.3), followed by EB simplex (n = 765; prevalence 13.3, 95% CI 12.3–14.2), dystrophic EB (n = 512; prevalence 8.9, 95% CI 8.1–9.7), other EB (n = 235; prevalence 4.1, 95% CI 3.6–4.6) and severe junctional EB (n = 26; prevalence 0.5, 95% CI 0.3–0.7). Overall, 66% of patients identified as White ethnicity, followed by 10% as Asian ethnicity; however, 18% had missing ethnicity data. Female patients comprised 54% of cases. In total, 21% lived in areas of the lowest deprivation, compared with 16% in the quintile of the most deprived population. During the follow-up 481 of 3419 (14%) patients died, and 4.6% died before age 15 years, with severe junctional EB showing a median age at death of < 6 months. In the last 5 years of data, 123 of 160 (76.9%) patients underwent upper gastrointestinal tract procedures. Analysis of the community prescriptions dataset showed that 819 915 items (412 882 prescriptions) were issued from April 2018 to September 2024. Of these, 23.4% were dressings, followed by 14.8% central nervous system and 9.4% cardiovascular system medications, amounting to a total prescription cost of £62.2 million. The annual median cost per patient (2019–2023) was £244 (interquartile range £55.2 to £1027), which was highest in patients with dystrophic EB (median £735, interquartile range £152 to £6145). This is the first population-level study of EB and presents the largest and most comprehensive national EB dataset reporting prevalence, demographics and treatments for EB. It highlights the utility of national datasets in understanding rare conditions and supporting improvements in patient care.

Infantile bullous pemphigoid (BP) can be an early manifestation of ZAP-70 deficiency, a rare combined immunodeficiency (CID) characterised by defective T-cell signalling and a propensity to multiple autoimmune manifestations.1 We describe two patients with BP subsequently diagnosed with ZAP-70 deficiency. Case 1: A female neonate presented at 14 days with severe seborrhoeic dermatitis. From 3 months she was repeatedly admitted with severe respiratory infections. Investigations revealed normal full blood count (FBC), but profoundly reduced CD8+ lymphocytes. At 7 months she developed an extensive bullous eruption. Skin biopsy with direct and indirect immunofluorescence confirmed the diagnosis of BP, which was difficult to control and required multiple systemic treatments, including methylprednisolone, dapsone, dupilumab, intravenous immunoglobulin and rituximab. She developed immune-mediated thrombocytopenia and is currently being prepared for bone marrow transplantation (BMT) due to ZAP-70 deficiency. Case 2: A female infant presented at 3 months with bullae of the face and extremities. Skin biopsy with direct and indirect immunofluorescence confirmed BP, which responded to topical corticosteroids and erythromycin. At 9 months she developed recurrent severe respiratory infections requiring ventilation. Laboratory studies showed near-absent CD8+ lymphocytes and confirmed ZAP-70 deficiency. She underwent BMT in June 2024, with no recurrence of blistering. Conclusion: Infantile BP should prompt suspicion of an underlying CID. Assessment of lymphocyte subsets is essential, as ZAP-70 deficiency is characterised by profoundly reduced CD8+ lymphocytes, which may not be apparent on a standard FBC where total lymphocyte numbers can be normal. Early ­diagnosis is essential, as BMT offers the only curative ­treatment.

Inherited epidermolysis bullosa (EB) is a group of rare and complex genetic disorders characterized by fragility of the skin and mucous membranes. Specifically, the gastrointestinal tract is commonly involved with a range of complications, one of the most disabling being oesophageal strictures (OS). OS manifest with progressive dysphagia, which in turn contributes to malnutrition, chronic anaemia and growth delay, with high impact on the quality of life of patients and their families. DEBRA International has supported the development of clinical practice guidelines (CPGs) for different aspects of EB care. The present CPG aims to provide healthcare professionals and affected individuals and their caregivers with recommendations on diagnostic procedures, preventive measures and treatment of OS. An international multidisciplinary panel comprising clinical experts and patient and public involvement (PPI) representatives developed the CPG, following an international PPI survey and literature review. The GRADE methodology was adopted to define PICO (population, intervention, comparison, outcome) questions, implement a literature appraisal process and prepare recommendations. Three recommendations are focused on OS diagnosis, and seven on preventive nonpharmacological (diet, oral care and therapeutic education) and pharmacological measures (topical corticosteroids) and treatment procedures. Treatment focuses particularly on oesophageal dilatation and how to delay and manage disease relapses. It is expected that this CPG will contribute to improving the quality and equity of care for individuals affected with EB, and will hopefully foster clinical research to increase evidence, in particular on noninvasive OS treatment to prevent complications and delay relapses.

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a severe type of epidermolysis bullosa resulting from mutations in COL7A1 gene. Patients experience various degrees of blistering following minor trauma which can over time lead to fibrosis, limb contractures and an increased risk of developing squamous cell carcinoma. The aim was to assess if repeated infusions of allogeneic umbilical cord derived mesenchymal stromal cells (UC-MSCs), CORDStromTM, were safe and could benefit children with RDEB. This was a prospective, double-blinded, randomised, placebo-controlled crossover trial with an internal dose de-escalation trial (for safety) conducted at the two National Paediatric UK EB centres in RDEB children aged >6months and <16years. Participants received IV infusions of 2–3 × 106 cells/kg of UC-MSCs or placebo at day 0 and 14 days later with a 9-month wash out period between the opposite. Main outcomes were change in disease severity as measured by the Epidermolysis Bullosa Disease Activity and Scarring index (EBDASI) and the Instrument for Scoring Clinical Outcomes of Research for Epidermolysis Bullosa (ISCOREB), wound clinical appearance, pain, itch, and quality of life at 3-months from infusion. Results will be discussed at the meeting. This is the largest study worldwide in children with RDEB. Administering cell therapy early and at regular intervals has the potential to reduce inflammation, effectively modulate disease activity, and lead to clinically meaningful and sustained improvements in disease progression and quality of life. An open-label study is planned and will help us further evaluate the long-term safety and outcomes of CORDStromTM infusions in children with RDEB.

Background In recessive dystrophic epidermolysis bullosa (RDEB), complications like oesophageal strictures, hand contractures, cardiomyopathy and cutaneous squamous cell carcinoma (SCC) may develop. These complications necessitate procedures such as oesophageal dilatation (OD), gastrostomy tube placement and hand surgery.Objectives To determine the prevalence and age of onset of milestone events by RDEB subtype, specifically dysphagia, first OD, first gastrostomy tube, first hand surgery, cardiomyopathy, first SCC and death.Methods The Prospective Epidermolysis Bullosa Longitudinal Evaluation Study (PEBLES) is a register study of individuals with RDEB that records comprehensive EB- and non-EB-related health information. Age of onset and prevalence of milestone events were analysed in the full cohort with all RDEB subtypes and by RDEB subtype.Results Dysphagia occurred in 85% of the 62 total participants, including all with the severe (RDEB-S) and inversa (RDEB-Inv) subtypes. OD was also frequent, in 69% overall (92% RDEB-S, 89% RDEB-Inv). All events were most frequent and occurred earliest in RDEB-S (except cardiomyopathy), with a median age of dysphagia, OD and gastrostomy tube placement in the first decade. Frequent and early dysphagia and OD in RDEB-Inv may suggest this subtype before characteristic flexural skin changes manifest. Of the participants with RDEB-S, 35% had a first SCC at a median age of 27.8 years. Seven participants died during the 10-year study; the median age for the six with RDEB-S was 36 years, and causes included sepsis, metastatic SCC and complications of refeeding syndrome.Conclusions Our results detail the frequency and prevalence of important milestone events by RDEB subtype, informing prognostication, increasing understanding of the natural history of RDEB to help inform study endpoints, and potentially serving as proxy control data for future clinical trials. This study reports on the Prospective Epidermolysis Bullosa Longitudinal Evaluation Study (PEBLES) for clinically important milestone events in individuals with recessive dystrophic epidermolysis bullosa (RDEB). Specifically, it describes the prevalence and age of onset of dysphagia, first oesophageal dilatation, first gastrostomy tube placement, first hand surgery, cardiomyopathy, first squamous cell carcinoma and death in a cohort of 62 child and adult participants. Data are reported by RDEB subtype, highlighting important differences in the occurrence and age of milestone events. These data will help to delineate the natural history and putative endpoints for future studies, as well as have the potential to serve as proxy control-arm data for clinical trials.

Harlequin ichthyosis is a very rare genodermatosis with a birth incidence of 1 in 300 000 births and a high mortality rate of 50% (Ahmed H, O’Toole E. Recent advances in the genetics and management of harlequin ichthyosis. Paediatr Dermatol 2014; 31: 539–46). This case highlights the need for highly specialized neonatal care. A routine 29 + 4 week antenatal ultrasound scan in a 34-year-old gravida 1 para 2 woman revealed severe hyperkeratosis and dysmorphic features. The parents were consanguineously related. Amniocentesis with Sanger sequencing confirmed homozygosity for the ABCA12 c.4419dup, p.(Lys1474Ter) pathogenic variant, consistent with harlequin ichthyosis. An urgent multidisciplinary team (MDT) meeting, involving the local team and a regional expert centre, planned optimal care with an elective caesarean at 37 weeks, but spontaneous labour at 36 weeks necessitated an emergency caesarean. At birth, respiratory distress required emergency intubation; mucocutaneous findings included hyperkeratotic skin, bilateral ectropion, eclabium and dysplastic ears. Due to compromised circulation in the extremities, bedside escharotomy-like procedures were performed. Dermatologists commenced oral acitretin at 0.5 mg kg−1 per day at 2 days of life, increasing to 1 mg kg−1 per day on day 30. Skin barrier was maintained to minimize infection risk. A humidified incubator was used to optimize temperature and hydration. Complications during the neonatal period included a 17-day ventilation requirement, sepsis caused by multidrug-resistant Klebsiella, Staphylococcus haemolyticus and Candida requiring intensive antibiotic and antifungal therapy, and anaemia of prematurity requiring multiple transfusions. Exposure keratitis was managed with amniotic membrane transplantation, but persistent corneal exposure necessitated eyelid skin grafting at another trust. Weight gain was poor due to the high caloric demands, despite nasogastric feeding with skin-protective measures. Otology and audiology managed hearing assessments and will perform ear canal debridement as needed. The Ichthyosis Support Group offered parental support. The regional expert centre provided ongoing MDT support. This case highlights the multisystemic complexity of harlequin ichthyosis. Even tertiary centres may not have sufficient expertise across all required specialties. The UK lacks a clear national referral pathway, unlike the epidermolysis bullosa highly specialized service (HSS), although discussion has been underway regarding the establishment of an HSS for ichthyosis for over 20 years. Several expert centres provide support upon request. We hope that this case will add to the impetus for a national MDT framework for congenital ichthyosis to standardize care, ensure equitable access to specialized services, establish a national register and provide dedicated nursing support to improve patient outcomes.

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 wildtype 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.

Abstract Erythrokeratodermia variabilis et progressiva (EKVP) is a clinically heterogeneous group of inherited disorders characterized by the coexistence of localized or generalized hyperkeratotic plaques and transient, stationary or migratory erythematous patches. EKPV is most often transmitted in an autosomal dominant manner. Causal pathogenic variants have been detected in the GJB3, GJB4, GJA1 KDSR and KRT83 genes encoding connexins 31, 30.3, 43, 3-ketodihydrosphingosine reductase and keratin 83, respectively. Connexins are expressed in almost all tissues and pathogenic variants in the connexin genes can cause skin diseases, cardiovascular disorders, myelin-related diseases, craniofacial disorders and hearing loss. We present a 2-year-old girl who was referred to our centre with well-demarcated hyperkeratotic plaques symmetrically distributed with a predilection for the distal extremities and buttocks as well as erythematous plaques on her cheeks. The hyperkeratotic plaques were hyperpigmented, exhibited a geographic morphology and had prominent hypertrichosis. Her trunk and upper extremities were spared and her hair, teeth and nails were normal. There was family history of mild psoriasis in her mother and mild eczema in her father. Next generation sequencing confirmed she was heterozygous for the GJB3 c.625C&gt;T p.(Leu209Phe) pathogenic variant which is associated with erythrokeratodermia variabilis et progressiva-1 (MIM 133200) and autosomal dominant deafness-2B (MIM 612644). Erythrokeratodermia variabilis is largely a skin-limited condition however GJB3 pathogenic variants can cause haring loss and neuropathy due to its expression in peripheral nerves and the cochlea. Our patient’s hearing and development have been normal to date and will be monitored.

Erythrokeratodermia variabilis et progressiva (EKVP) is a clinically heterogeneous group of inherited disorders characterized by the coexistence of localized or generalized hyperkeratotic plaques and transient, stationary or migratory erythematous patches. EKPV is most often transmitted in an autosomal dominant manner. Causal pathogenic variants have been detected in the GJB3, GJB4, GJA1 KDSR and KRT83 genes encoding connexins 31, 30.3, 43, 3-ketodihydrosphingosine reductase and keratin 83, respectively. Connexins are expressed in almost all tissues and pathogenic variants in the connexin genes can cause skin diseases, cardiovascular disorders, myelin-related diseases, craniofacial disorders and hearing loss. We present a 2-year-old girl who was referred to our centre with well-demarcated hyperkeratotic plaques symmetrically distributed with a predilection for the distal extremities and buttocks as well as erythematous plaques on her cheeks. The hyperkeratotic plaques were hyperpigmented, exhibited a geographic morphology and had prominent hypertrichosis. Her trunk and upper extremities were spared and her hair, teeth and nails were normal. There was family history of mild psoriasis in her mother and mild eczema in her father. Next generation sequencing confirmed she was heterozygous for the GJB3 c.625C>T p.(Leu209Phe) pathogenic variant which is associated with erythrokeratodermia variabilis et progressiva-1 (MIM 133200) and autosomal dominant deafness-2B (MIM 612644). Erythrokeratodermia variabilis is largely a skin-limited condition however GJB3 pathogenic variants can cause haring loss and neuropathy due to its expression in peripheral nerves and the cochlea. Our patient’s hearing and development have been normal to date and will be monitored.