European Journal of Dermatology最新文献

Kindler epidermolysis bullosa (KEB), a rare genodermatosis caused by loss-of-function mutations in the FERMT1 gene (encoding kindlin-1), is clinically characterized by congenital blistering, skin atrophy, poikiloderma, photosensitivity, and an increased predisposition to cutaneous squamous cell carcinoma (cSCC). Hearing loss, a common sensory impairment with multifactorial origins, often stems from genetic or environmental factors. Here, we report a unique familial case in which one sibling has KEB complicated by cSCC, and the other has congenital autosomal recessive non-syndromic hearing loss (ARNSHL). To describe the co-occurrence of KEB and ARNSHL in a single family and emphasize the utility of next-generation sequencing (NGS) for precise genetic diagnosis. NGS-based approaches (gene panel and whole-exome sequencing) were used to screen for pathogenic variants in two affected siblings. Sanger sequencing validated variant segregation with disease phenotypes and was used to assessed pathogenicity in family members. Genetic analysis identified a novel homozygous nonsense mutation, c.T240A (p.Y80X), in FERMT1 in the KEB patient, consistent with molecular characteristics of loss-of-function. The ARNSHL-affected sibling carried a novel homozygous missense mutation, c.T4469C (p.F1490S), in MYO15A, a gene critical for auditory hair cell function. Both variants followed autosomal recessive inheritance and were absent in population databases. This study highlights the power of NGS in diagnosing genetically distinct disorders without shared pathogenic mechanisms within a single family. Our findings underscore the clinical value of comprehensive genomic sequencing for unravelling complex hereditary conditions, especially when multiple rare disorders segregate independently in kindreds.

Immune dysregulation is implicated in fibrotic skin pathogenesis. However, causal inflammatory cytokines remain inadequately characterized. To identify inflammatory cytokines with potential causal roles in fibrotic skin disorders using integrative genetic and experimental approaches. Two-sample Mendelian randomization (MR) analysis was conducted utilizing summary statistics from genome-wide association studies (GWAS) for 41 inflammatory cytokines and four fibrotic skin diseases. Differences in selected inflammatory cytokine levels in tissues, sera and cells between hypertrophic scar (HS) patients and healthy volunteers were investigated. In addition, primary human HS fibroblasts were stimulated using recombinant proteins of selected inflammatory cytokines. The effects of recombinant proteins on proliferation, apoptosis, migration and collagen deposition of fibroblasts were examined by EdU (5-ethynyl-2'-deoxyuridine), annexin V-FITC/PI double staining, Transwell migration and western blot assay, respectively. The levels of stem cell growth factor beta (SCGF-β) were significantly associated with all four fibrotic skin diseases, with OR=1.24 (p=0.016) for HS, OR=0.77 (p=0.048) for keloid, OR=1.20 (p=0.022) for lichen sclerosus, and OR=1.40 (p=0.021) for systemic sclerosis. Moreover, SCGF-β levels in HS tissues and sera were elevated. Fibroblasts cultured with recombinant proteins of SCGF-β showed enhanced proliferation and collagen production, reduced apoptosis (p<0.05), and no significant effect on migration (p>0.05). This study establishes SCGF-β as a putative causal mediator of fibrotic skin diseases, with experimental validation for HS, demonstrating its pro-fibrotic activity.