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This article discusses the use of xenografts and single-cell RNA sequencing (scRNA-seq) in the study of genetic skin diseases. Xenografts, which involve transplanting human skin cells onto immunocompromised mice, provide a valuable model for studying genetic skin diseases. However, performing scRNA-seq on xenografts presents challenges due to the hybrid nature of the tissue. The article provides recommendations for optimizing the scRNA-seq process using human skin xenografts and highlights the importance of independently piloting each step of the protocol. The authors suggest additional quality control steps to verify the presence of information of interest in the sample. The study was sponsored by various organizations and the authors declare no conflict of interest. The data supporting the findings are available upon request. [Extracted from the article]

Background: Paraneoplastic pemphigus (PNP) is an extremely rare life‐threatening blistering autoimmune disease that is associated with an underlying neoplasm. There is a set diagnostic criterion for PNP, which is primarily based on a severe stomatitis and the detection of specific antibodies against envoplakin, periplakin and alpha‐2‐macroglobulin‐like protein 1. However, it has become increasingly evident that there are patients with PNP that do not meet all the diagnostic criteria requirements. Objectives: The aim of this study was to analyse our cohort of Dutch patients and to define the atypical cases that did not meet the diagnostic criteria. Methods: A retrospective case study of all known Dutch PNP patients of the past 25 years. Patients' clinical and immunological variables were thoroughly analysed and described. Results: Twenty‐four patients were included in this study. The results revealed several atypical patient cases that did not completely meet the set diagnostic criteria. Of the 24 patients, two patients presented without stomatitis, in three patients an underlying neoplasm could not be detected, and in two patients the presence of specific autoantibodies could not be demonstrated, although all other criteria for PNP were met. Finally, three of the 24 patients survived the disease. Conclusion: Although our findings showed similarities to previous studies and most of the patients met the criteria, there were a few atypical patient cases; highlighting the importance of not strictly adhering to the set criteria when making a diagnosis, as this can lead to a missed or late diagnosis. Thus, it is of crucial importance to combine clinical and elaborate laboratory results to confirm the diagnosis of PNP in suspected patients. Although PNP harbours an unfavourable prognosis in most cases, it might be resolved by timely treatment of the underlying cause. [ABSTRACT FROM AUTHOR]

Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types. The subtype and severity of EB is linked to the gene involved and the specific variants in that gene, which also determine its mode of inheritance. Current treatment is mainly focused on symptomatic relief such as wound care and blister prevention, because truly curative treatment options are still at the preclinical stage. Given the current level of understanding, the broad spectrum of genes and variants underlying EB makes it impossible to develop a single treatment strategy for all patients. It is likely that many different variant-specific treatment strategies will be needed to ultimately treat all patients. Antisense-oligonucleotide (ASO)-mediated exon skipping aims to counteract pathogenic sequence variants by restoring the open reading frame through the removal of the mutant exon from the pre-messenger RNA. This should lead to the restored production of the protein absent in the affected skin and, consequently, improvement of the phenotype. Several preclinical studies have demonstrated that exon skipping can restore protein production in vitro, in skin equivalents, and in skin grafts derived from EB-patient skin cells, indicating that ASO-mediated exon skipping could be a viable strategy as a topical or systemic treatment. The potential value of exon skipping for EB is supported by a study showing reduced phenotypic severity in patients who carry variants that result in natural exon skipping. In this article, we review the substantial progress made on exon skipping for EB in the past 15 years and highlight the opportunities and current challenges of this RNA-based therapy approach. In addition, we present a prioritization strategy for the development of exon skipping based on genomic information of all EB-involved genes. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Hailey–Hailey disease (HHD) is a rare genetic therapy‐resistant blistering disease with great disease burden. Treatment is currently focused on symptomatic relief. Er:YAG ablative laser therapy is a therapeutic modality with promising results, though evidence is currently scarce.To analyse the effect of Er:YAG ablative laser therapy on clinical remission of erosive plaques in HHD and on patient's quality of life (QoL).In this observational study eight patients were included and 77 erosive plaques were treated once only by Er:YAG laser and assessed for clinical remission. QoL was evaluated by obtaining Skindex‐29 and DLQI questionnaires before laser therapy, 6 weeks and 3 years after laser therapy. Skin biopsies were taken to evaluate the depth of laser ablation. The intercellular distance between keratinocytes, the number of desmosomes and intermediate filament distribution were studied by electron microscopy before and after laser therapy and in clinically uninvolved skin and were compared to subjects without HHD.One single Er:YAG laser ablation to mid‐dermis resulted in complete remission of 97.4% of HHD plaques (75/77) after median 38 months (range 7–63 months) and significantly improved QoL. Laser therapy restored the number of desmosomes, decreased intercellular distance and diminished perinuclear retraction of keratin filaments to a level comparable to the patient's clinically uninvolved skin. After laser ablation, the skin showed significantly fewer ultrastructural aberrations compared to the patient's clinically uninvolved skin and rather resembled the skin of healthy control individuals.One single Er:YAG laser treatment resulted in long‐term remission of HHD and significantly improved QoL. Our findings support a greater role for ablative laser surgery in the management of this recalcitrant disorder. [ABSTRACT FROM AUTHOR]

Introduction: Itch is one of the most burdensome symptoms in epidermolysis bullosa (EB), indicating a hitherto unmet therapeutic need. This review leverages existing data on efficacy of itch treatment in EB to support sound decision making., Methods: A systematic literature search was performed on 29 March 2022. Studies written later than 1991 and reporting outcomes in patients with EB treated for itch were considered., Results: Of the 3,099 articles screened, 21 studies met eligibility criteria, comprising 353 patients (65.9%) diagnosed for recessive dystrophic EB. Only two studies (9.5%) evaluated itch as primary endpoint, of which solely one revealed a significant relief of self-reported itch upon topical skin care. In those studies assessing itch as secondary endpoint (19/21, 90.5%), only 36.8% studies ( n  = 7/19) revealed a statistically significant itch reduction of up to 42%. Methodological limitations (heterogeneity of outcomes, inconsistent data assessment) in addition to limited superiority over control were implicated to account for low treatment efficacy observed in most studies., Conclusion: Current data quality impairs comparative efficacy analyses of itch treatments in EB. Large scale randomized clinical trials and more personalized approaches applying validated measurement instruments for core outcomes are needed to substantiate evidence-based treatment approaches for EB-associated itch.