Unravelling drivers of cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa.

Epidermolysis bullosa (EB) is an umbrella term for a group of rare inherited skin disorders characterised by mucocutaneous fragility. Patients suffer from blisters and chronic wounds that arise spontaneously or following minor mechanical trauma, often resulting in inflammation, scarring and fibrosis due to poor healing. The recessive form of dystrophic EB (RDEB) has a particularly severe phenotype and is caused by mutations in the COL7A1 gene, encoding the collagen VII protein, which is responsible for adhering the epidermis and dermis together. One of the most feared and devastating complications of RDEB is the development of an aggressive form of cutaneous squamous cell carcinoma (cSCC), which is the main cause of mortality in this patient group. However, pathological drivers behind the development and progression of RDEB-associated cSCC (RDEB-cSCC) remain somewhat of an enigma, and the evidence to date points towards a complex process. Currently, there is no cure for RDEB-cSCC, and treatments primarily focus on prevention, symptom management and support. Therefore, there is an urgent need for a comprehensive understanding of this cancer's pathogenesis, with the aim of facilitating the discovery of drug targets. This review explores the current knowledge of RDEB-cSCC, emphasising the important role of the immune system, genetics, fibrosis, and the tumour-promoting microenvironment, all ultimately intricately interconnected.

Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin disease characterized by defects in type VII collagen leading to a range of fibrotic pathologies resulting from skin fragility, aberrant wound healing, and altered dermal fibroblast physiology. Using a novel in vitro model of fibrosis based on endogenously produced extracellular matrix, we screened an FDA-approved compound library and identified antivirals as a class of drug not previously associated with anti-fibrotic action. Preclinical validation of our lead hit, daclatasvir, in a mouse model of RDEB demonstrated significant improvement in fibrosis as well as overall quality of life with increased survival, weight gain and activity, and a decrease in pruritus-induced hair loss. Immunohistochemical assessment of daclatasvir-treated RDEB mouse skin showed a reduction in fibrotic markers, which was supported by in vitro data demonstrating TGFß pathway targeting and a reduction of total collagen retained in the extracellular matrix. Our data support the clinical development of antivirals for the treatment of patients with RDEB and potentially other fibrotic diseases.

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.

Type VII Collagen Deficiency in the Oncogenesis of Cutaneous Squamous Cell Carcinoma in Dystrophic Epidermolysis Bullosa.

Dystrophic epidermolysis bullosa is a rare genetic skin disorder caused by COL7A1 sequence variations that result in type VII collagen deficits and cutaneous and extracutaneous manifestations. One serious complication of dystrophic epidermolysis bullosa is cutaneous squamous cell carcinoma, a leading driver of morbidity and mortality, especially among patients with recessive dystrophic epidermolysis bullosa. Type VII collagen deficits alter TGFß signaling and evoke multiple other cutaneous squamous cell carcinoma progression-promoting activities within epidermal microenvironments. This review examines cutaneous squamous cell carcinoma pathophysiology in dystrophic epidermolysis bullosa with a focus on known oncogenesis pathways at play and explores the idea that therapeutic type VII collagen replacement may reduce cutaneous squamous cell carcinoma risk.

Mapping the burden of severe forms of epidermolysis bullosa - Implications for patient management.

Background: The pathophysiological processes underlying the phenotypic spectrum of severe forms of epidermolysis bullosa (EB) are complex and poorly understood. Objective: To use burden mapping to explore relationships between primary pathomechanisms and secondary clinical manifestations in severe forms of EB (junctional and dystrophic EB [JEB/DEB]) and highlight strengths and weaknesses in evidence regarding the contribution of different pathways. Methods: Literature searches were performed to identify evidence regarding the pathophysiological and clinical aspects of JEB/DEB. Identified publications and clinical experience were used to construct burden maps to visually communicate plausible connections and their relative importance by subtype. Results: Our findings suggest that most of the clinical consequences of JEB/DEB may result from an abnormal state and/or faulty skin remodeling driven by a vicious cycle of delayed wound healing, predominantly mediated through inflammation. The quantity and quality of evidence varies by individual manifestations and disease subtype. Limitations: The burden maps are provisional hypotheses requiring further validation and are limited by the published evidence base and subjectivity in clinical opinion. Conclusions: Delayed wound healing appears to be a key driver of the burden of JEB/DEB. Further studies are warranted to understand the role of inflammatory mediators and accelerated wound healing in patient management.

Prevalence of and risk factors for nutritional deficiency and food allergy in a cohort of 21 patients with Netherton syndrome.

BACKGROUND: Netherton syndrome (NS; OMIM: 256500) is a rare autosomal recessively inherited disease due to SPINK5 mutations. Hair and inflammatory skin involvement are variable along with allergies. Morbidity and mortality are high, particularly in infancy. A detailed clinical analysis of a NS patient cohort should broaden the understanding of nutritional challenges and allergic comorbidities. METHODS: In this retrospective monocentric cohort study, medical and dietetic records of pediatric NS patients, presenting between 1999 and 2018, were reviewed. The severity of skin involvement was assessed according to the extent of the body surface area (BSA) affected by erythema. RESULTS: We identified 21 patients with NS (median age 11.6 years). Within the first 6 months of life, requirements for fluid and kcals/protein were high for all patients (average 228 ml/kg/day) and infants had an average of 1.9 feed changes (range 0-4) due to food intolerance. Clinical evidence for IgE-mediated food allergy was present in 84.2% (16/19 children, 2 no data) with a range of 1-12 food allergies per patient. In 75%, more than one food had to be avoided. Specific IgE levels were falsely positive in 38.3% and 8/18 patients (44.4%). One-third (5/15; 6 no data) of patients, all with severe disease, had anaphylactic reactions following ingestion of fish (n = 2), sesame (n = 1), cow's milk (n = 1), and both peanut and egg (n = 1). CONCLUSIONS: Our data emphasize feeding difficulties in children with NS and reveal an unexpectedly higher prevalence of food allergies that gives evidence to the importance of early coordinated multidisciplinary care for overcoming these challenges in NS.

Biallelic TUFT1 variants cause woolly hair, superficial skin fragility and desmosomal defects.

BACKGROUND: Desmosomes are complex cell junction structures that connect intermediate filaments providing strong cell-to-cell adhesion in tissues exposed to mechanical stress. OBJECTIVES: To identify causal variants in individuals with woolly hair and skin fragility of unknown genetic cause. METHODS: This research was conducted using whole-genome sequencing, whole-exome sequencing, clinical phenotyping, haplotype analysis, single-cell RNA sequencing data analysis, immunofluorescence microscopy and transmission electron microscopy. RESULTS: We identified homozygous predicted loss-of-function tuftelin-1 (TUFT1) variants in nine individuals, from three families, with woolly hair and skin fragility. One donor splice-site variant, c.60+1G>A, was present in two families, while a frameshift variant, p.Gln189Asnfs*49, was found in the third family. Haplotype analysis showed the c.60+1G>A substitution to be a founder variant in the Irish population that likely arose approximately 20 generations ago. Human and mouse single-cell RNA sequencing data showed TUFT1 expression to be enriched in the hair dermal sheath and keratinocytes. TUFT1 expression was highly correlated with genes encoding desmosomal components implicated in diseases with phenotypes that overlap with the cohort presented here. Immunofluorescence showed tuftelin-1 to be mainly localized to the peripheral cell membranes of keratinocytes in normal skin. Skin samples from individuals with TUFT1 variants showed markedly reduced immunoreactivity for tuftelin-1, with a loss of the keratinocyte cell membrane labelling. Light microscopy revealed keratinocyte adhesion, mild hyperkeratosis and areas of superficial peeling. Transmission electron microscopy showed panepidermal acantholysis with widening of intercellular spaces throughout the epidermis and desmosomal detachment through the inner plaques. CONCLUSIONS: Biallelic loss-of-function TUFT1 variants cause a new autosomal recessive skin/hair disorder characterized by woolly hair texture and early-onset skin fragility. Tuftelin-1 has a role in desmosomal integrity and function.

Novel mixed-method, inclusive protocol involving global key stakeholders, including carers as experts, to co-develop relevant Caregiver-Reported Outcome Domains (CRODs) in skin disease.

INTRODUCTION: Ichthyoses comprise a heterogenous group of rare genetic skin disorders that involves the entire skin surface, often with additional syndromic features, and pose many clinical challenges. Without curative intervention, the mainstay of life-long symptom management is supportive in nature and can remain the responsibility of the caregiver. Although impact on the wider family is considered an important outcome of policies and services, there is a lack of caregiver consensus on what outcome domains to measure to fully assess the impact of ichthyosis on the patient and the caregiver. This project aims to identify a set of core outcome domains towards a core outcome set for ichthyosis that can measure all relevant concepts of ichthyosis in clinical practice, service delivery and research. METHODS AND ANALYSIS: Following the COMET (Core Outcome Measures in Effectiveness Trials) initiative, this project will employ a mixed-method study design which was developed using public and patient involvement and an international multidisciplinary expert group (clinical experts, patients and their representatives, policymakers, researchers and service providers). Experts by experience, or caregivers, will be recruited through online ichthyosis support groups. Phase one will focus on item generation and involve: (1) a systematic literature review, (2) a multimethods international qualitative study with ichthyosis caregivers and (3) co-development of items for an e-survey. Phase two, item refinement, will employ a novel four-pronged consensus approach: (1) an e-Delphi survey, (2) statistical analysis of e-Delphi survey results, (3) online qualitative feedback and (4) an online consensus discussion. All methodological considerations will be clearly linked with each Core Outcome Set-STAndards for Developing recommendation. ETHICS AND DISSEMINATION: Research Ethics Committee approval obtained from the School of Psychology, Ulster University (UK)(Ref:REC/20/0004). Results will be presented in published international peer-reviewed journals, at scientific meetings and support groups. REGISTRATION: COMET database (January 2019).

Retinoid-induced skeletal hyperostosis in disorders of keratinization.

For disorders of keratinization, topical treatment alone may be ineffective, and systemic retinoid therapy may be indicated. Treatment with systemic retinoids (acitretin, isotretinoin and alitretinoin) has been shown to be effective in reducing disease severity; however, potentially rare adverse effects (AEs) may occur, including hyperostotic skeletal changes. The true prevalence of this AE in adult patients administered life-long therapy is unknown. We identified 3 of 127 (2.4%) patients (with ichthyosis or Darier disease) who had been prescribed isotretinoin with or without acitretin, and who developed radiological signs and clinical symptoms of hyperostosis and ligamentous ossification. This clinical review highlights the significance of retinoid-induced skeletal hyperostosis in patients prescribed long-term, high-dose retinoid therapy for disorders of keratinization. Patients commencing systemic retinoid therapy, particularly women of childbearing age, should be counselled about this important and potentially serious AE, especially if long-term treatment is indicated.

Epidermolysis bullosa acquisita: a case series of three paediatric patients.

Epidermolysis bullosa acquisita is a highly uncommon condition in the paediatric population. This article describes three children with this disease, different clinical presentation and management. It also reviews the most relevant articles on this topic.

Transcriptomic profiling of recessive dystrophic epidermolysis bullosa wounded skin highlights drug repurposing opportunities to improve wound healing.

Chronic wounds present a major disease burden in people with recessive dystrophic epidermolysis bullosa (RDEB), an inherited blistering skin disorder caused by mutations in COL7A1 encoding type VII collagen, the major component of anchoring fibrils at the dermal-epidermal junction. Treatment of RDEB wounds is mostly symptomatic, and there is considerable unmet need in trying to improve and accelerate wound healing. In this study, we defined transcriptomic profiles and gene pathways in RDEB wounds and compared these to intact skin in RDEB and healthy control subjects. We then used a reverse transcriptomics approach to discover drugs or compounds, which might restore RDEB wound profiles towards intact skin. Differential expression analysis identified >2000 differences between RDEB wounds and intact skin, with RDEB wounds displaying aberrant cytokine-cytokine interactions, Toll-like receptor signalling, and JAK-STAT signalling pathways. In-silico prediction for compounds that reverse gene expression signatures highlighted methotrexate as a leading candidate. Overall, this study provides insight into the molecular profiles of RDEB wounds and underscores the possible clinical value of reverse transcriptomics data analysis in RDEB, and the potential of this approach in discovering or repurposing drugs for other diseases.

The epidemiology of epidermolysis bullosa in England and Wales: data from the national epidermolysis bullosa database.

BACKGROUND: The National Health Service (NHS) epidermolysis bullosa (EB) service, established in 2002, offers comprehensive, free care to all patients in England and Wales. OBJECTIVES: To quantify prevalence, incidence and mortality of EB in England and Wales. METHODS: Demographic data for patients in England and Wales were collected on a secure electronic database, prospectively from January 2002 to April 2021 and retrospectively for cases prior to 2002. Vital status was verified using central NHS data. RESULTS: By March 2021, 2594 individuals were registered, of whom 2361 were living, which yielded a prevalence of 34·8 per million of the population for all EB types [EB simplex (EBS) 17 per million, dystrophic EB (DEB) 10·7 per million, junctional EB (JEB) 1 per million and Kindler EB 0·3 per million]. We recorded 1200 babies with EB born since 2002. The average incidence per million live births for EBS, DEB, JEB and Kindler EB was 32·5, 26·1, 8·9 and 0·9, respectively (total incidence for all types of EB was 67·8 per million). Birth rates fell progressively over the 19-year period for JEB-severe (JEB-S) (r = -0·56) and recessive DEB-severe (r = -0·44) and also for milder types of EB. We observed longer survival in JEB-S over the 19-year period (r2 = 0·18) with a median survival of 12·7 months over the past 5 years. CONCLUSIONS: In this study, we provide the first accurate epidemiological data for EB in England and Wales. We believe the observed reduction in birth incidence of severe types of EB reflects an uptake of genetic counselling advice, whereas the reduction in milder types may be due to delayed presentation. A potential small trend towards longer survival of babies with JEB-S may reflect improved multidisciplinary care.

Gamer's nodulesBRIEF REPORT.

A 15-year-old boy presented with a two-year history of subcutaneous nodules on his feet that were painful on palpation and with footwear. The patient is an avid gamer, and his mother had noted a distinct sitting position as he sat playing his console. Skin biopsy showed features of a collagenoma, consistent with previous reports of repetitive pressure lesions associated with various sports and religious practices. It is important to be aware of these "gamer's nodules" that result from prolonged periods of fixed seating postures.