Recessive dystrophic epidermolysis bullosa (RDEB) is a rare monogenic blistering disorder with wide clinical heterogeneity, ranging from localized skin fragility to life-limiting systemic complications. Understanding genotype-phenotype correlations in COL7A1, the causative gene, is critical for clinical prognostication, genetic counseling, and the rational design of emerging molecular therapies. To determine the frequency of genotypic and phenotypic subtypes, and to assess whether variant type or location can predict phenotypic severity and extracutaneous complications in patients with RDEB carrying homozygous variants. This was a systematic review of all RDEB genotypes and phenotypes reported to the International Dystrophic Epidermolysis Bullosa Patient Registry (DEB Registry) and eligible studies published in English from May 1993 to September 2025. PubMed, Cochrane Library, and Web of Science were searched and eligible studies were reviewed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020) guidelines. Included studies reported bi-allelic COL7A1 variants and clinical phenotypes. Data from the DEB Registry were cross-checked to supplement the published cases. Descriptive statistics were used for data analyses, and Fisher exact and χ2 methods were used to test additional genotype-phenotype correlations in patients with RDEB carrying homozygous variants. A total of 1802 patients with RDEB comprising 1002 pathogenic variants within COL7A1 were identified from 217 articles. Among the 706 patients with homozygous variants (mean [SD; range] age, 12.2 [13.0; 0-72] years), 533 (75.5%) had severe RDEB, most frequently associated with frameshift and nonsense variants (388 [72.8%] premature termination codons [PTCs]). In contrast, intermediate and milder subtypes were associated with missense or non-PTC variants. Variant location also influenced phenotype: homozygous variants affecting the noncollagenous 1 domain were associated with severe RDEB in 74 of 83 unique variants (89.2%). Extracutaneous involvement clustered in homozygous PTC carriers and was observed almost exclusively in severe RDEB, with occasional cases in the intermediate subtype and rare instances in the inversa, localized, and self-improving subtypes. Recurrent and population-specific variants suggested founder effects. Splice site and missense variants showed phenotypic variability, with augmented intelligence-based predictions correlating with severity. In this systematic review, the type and site of pathogenic variants in COL7A1 correlated with the severity of RDEB phenotype across different nationalities, races, and ethnicities. These findings may provide improved patient prognosis, genetic counseling, and personalized therapeutics.

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. 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. 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. 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. 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.

Pain is common in the genetic skin fragility disorder epidermolysis bullosa (EB), from skin and mucosal injury and inflammation as well as extra-mucocutaneous sites. Individuals living with EB have identified pain as a priority for better treatments. The Prospective EB Longitudinal Evaluation Study (PEBLES) is a prospective register study exploring the natural history of RDEB across all ages from birth to death. Here, we investigated the characteristics and treatment of pain in different RDEB subtypes. Information was collected from individuals with different RDEB subtypes over an 8-year period. Data included visual analogue scale (VAS) ratings of background and procedural pain, its location, intensity and impact on sleep, as well as pain medication. Disease severity scores and quality of life measures were correlated to pain scores. Sixty-one participants (13 children, 48 adults) completed a total of 361 reviews. Pain was common, experienced by 93% of participants at index review, with 80% suffering both background and procedural pain. Across all RDEB patients, the median VAS for background pain was 40 (out of 100) [interquartile range 20,60] and for those having regular dressing changes, median procedural pain was 52 [40,80]. Severe (RDEB-S) and pruriginosa (RDEB-Pru) groups had the greatest increase in procedural compared to background pain of 20 and 22 VAS points, respectively. Correlations between disease severity and quality of life impairment were observed across most groups, particularly RDEB-S. Over half of those studied experienced pain frequently or constantly, and in one third pain disturbed sleep at least 4 nights per week. Skin was the commonest source of pain in all subtypes except inversa RDEB where the mouth was the main site. Despite frequent and severe pain, one third of participants used no medication for pain and, in those that did, pain levels remained high suggesting ineffectiveness of current pain management approaches and a significant unmet need in RDEB. The frequency, severity, and impact of pain in all RDEB patients is significant, particularly in RDEB-S and RDEB-Pru. Our findings highlight that current RDEB pain management is poorly effective and that further research is needed to address this symptom.

Itch is common and distressing in epidermolysis bullosa (EB) but has not previously been studied in depth in different recessive dystrophic EB (RDEB) subtypes. 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. 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. 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. 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.