RESUMO
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and most often severe genetic disease characterized by recurrent blistering and erosions of the skin and mucous membranes after minor trauma, leading to major local and systemic complications. The disease is caused by loss-of-function variants in COL7A1 encoding type VII collagen (C7), the main component of anchoring fibrils, which form attachment structures stabilizing the cutaneous basement membrane zone. Alterations in C7 protein structure and/or expression lead to abnormal, rare or absent anchoring fibrils resulting in loss of dermal-epidermal adherence and skin blistering. To date, more than 1,200 distinct COL7A1 deleterious variants have been reported and 19% are splice variants. Here, we describe two RDEB patients for whom we identified two pathogenic deep intronic pathogenic variants in COL7A1. One of these variants (c.7795-97C > G) promotes the inclusion of a pseudoexon between exons 104 and 105 in the COL7A1 transcript, while the other causes partial or complete retention of intron 51. We used antisense oligonucleotide (ASO) mediated exon skipping to correct these aberrant splicing events in vitro. This led to increased normal mRNA splicing above 94% and restoration of C7 protein expression at a level (up to 56%) that should be sufficient to reverse the phenotype. This first report of exon skipping applied to counteract deep intronic variants in COL7A1 represents a promising therapeutic strategy for personalized medicine directed at patients with intronic variants at a distance of consensus splice sites.
Assuntos
Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Íntrons , Splicing de RNA , Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/patologia , Humanos , Íntrons/genética , Masculino , Feminino , Éxons/genética , Oligonucleotídeos Antissenso/genéticaRESUMO
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease caused by loss of function mutations in the gene coding for collagen VII (C7) due to deficient or absent C7 expression. This disrupts structural and functional skin architecture, leading to blistering, chronic wounds, inflammation, important systemic symptoms affecting the mouth, gastrointestinal tract, cornea, and kidney function, and an increased skin cancer risk. RDEB patients have an extremely poor quality of life and often die at an early age. A frequent class of mutations in RDEB is premature termination codons (PTC), which appear in homozygosity or compound heterozygosity with other mutations. RDEB has no cure and current therapies are mostly palliative. Using patient-derived keratinocytes and a library of 8273 small molecules and 20,160 microbial extracts evaluated in a phenotypic screening interrogating C7 levels, we identified three active chemical series. Two of these series had PTC readthrough activity, and one upregulated C7 mRNA, showing synergistic activity when combined with the reference readthrough molecule gentamicin. These compounds represent novel potential small molecule-based systemic strategies that could complement topical-based treatments for RDEB.
Assuntos
Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Humanos , Regulação para Cima/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Códon sem Sentido , Gentamicinas/farmacologiaRESUMO
INTRODUCTION: Epidermolysis Bullosa Pruriginosa (EBP) is a persistent, recurring disease that seriously affects quality of life. Fewer than 100 cases of EBP have been reported to date. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling, and inhibition of this pathway using Janus kinase (JAK) inhibitors might be a useful therapeutic strategy for these diseases. PATIENT CONCERNS: A male patient, 28 years of age, was admitted to our hospital because of recurrent papules, nodules, and intense itching on the trunk and extremities for 12 years. Repeated large and intense itching has seriously affected the patient normal life. DIAGNOSIS: The patient was diagnosed with EBP based on examination results. INTERVENTIONS: Oral baricitinib tablets (2 mg, once a day)â +â Oral desloratadine citrate disodium tablets (8.8 mg, once a day) combined with topical compound flumethasone ointment and Fucidin cream. OUTCOMES: The patient skin rashes had subsided and flattened remarkable, and his itching was markedly relieved. The visual analogue scale (VAS) itching score of the patient gradually declined from 8 to 9 points to 2 to 3 points. CONCLUSION: This study confirms that baricitinib is effective and feasible in treating EBP, especially in remarkable relieving itching, which rendered new ideas for therapeutic approaches for EBP in the future.
Assuntos
Azetidinas , Purinas , Pirazóis , Sulfonamidas , Humanos , Purinas/uso terapêutico , Masculino , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Azetidinas/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Administração OralRESUMO
We present Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a scalable platform producing autologous organotypic iPS cell-derived induced skin composite (iSC) grafts for definitive treatment. Clinical-grade manufacturing integrates CRISPR-mediated genetic correction with reprogramming into one step, accelerating derivation of COL7A1-edited iPS cells from patients. Differentiation into epidermal, dermal and melanocyte progenitors is followed by CD49f-enrichment, minimizing maturation heterogeneity. Mouse xenografting of iSCs from four patients with different mutations demonstrates disease modifying activity at 1 month. Next-generation sequencing, biodistribution and tumorigenicity assays establish a favorable safety profile at 1-9 months. Single cell transcriptomics reveals that iSCs are composed of the major skin cell lineages and include prominent holoclone stem cell-like signatures of keratinocytes, and the recently described Gibbin-dependent signature of fibroblasts. The latter correlates with enhanced graftability of iSCs. In conclusion, DEBCT overcomes manufacturing and safety roadblocks and establishes a reproducible, safe, and cGMP-compatible therapeutic approach to heal lesions of DEB patients.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Células-Tronco Pluripotentes Induzidas , Humanos , Epidermólise Bolhosa Distrófica/terapia , Epidermólise Bolhosa Distrófica/genética , Animais , Células-Tronco Pluripotentes Induzidas/transplante , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Camundongos , Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Terapia Baseada em Transplante de Células e Tecidos/métodos , Fibroblastos/metabolismo , Diferenciação Celular , Queratinócitos/metabolismo , Queratinócitos/transplante , Pele/metabolismo , Transplante Autólogo , Masculino , Mutação , Feminino , Transplante de Pele/métodos , Edição de Genes/métodos , Sistemas CRISPR-CasRESUMO
Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience numerous complications, which are exacerbated by inflammatory dysregulation and infection. Understanding the immunological mechanisms is crucial for selecting medications that balance inflammation control and immunocompetence. In this cross-sectional study, aiming to identify potential immunotherapeutic targets and inflammatory biomarkers, we delved into the interrelationship between clinical severity and systemic inflammatory parameters in a representative RDEB cohort. Encompassing 84 patients aged 1-67 and spanning all three Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) severity categories, we analysed the interrelationship of infection history, standard inflammatory markers, systemic cytokines and Ig levels to elucidate their roles in RDEB pathophysiology. Our findings identify C-reactive protein as an excellent biomarker for disease severity in RDEB. A type 2 inflammatory profile prevails among moderate and severe RDEB patients, correlating with dysregulated circulating IgA and IgG. These results underscore the IL4/IL13 pathways as potential evidence-based therapeutic targets. Moreover, the complete inflammatory scenario aligns with Staphylococcus aureus virulence mechanisms. Concurrently, abnormalities in IgG, IgE and IgM levels suggest an immunodeficiency state in a substantial number of the cohort's patients. Our results provide new insights into the interplay of infection and immunological factors in the pathogenesis of RDEB.
Assuntos
Biomarcadores , Proteína C-Reativa , Epidermólise Bolhosa Distrófica , Interleucina-13 , Interleucina-4 , Índice de Gravidade de Doença , Humanos , Estudos Transversais , Biomarcadores/sangue , Criança , Pré-Escolar , Interleucina-4/sangue , Adolescente , Proteína C-Reativa/metabolismo , Adulto , Adulto Jovem , Feminino , Masculino , Lactente , Pessoa de Meia-Idade , Interleucina-13/sangue , Interleucina-13/metabolismo , IdosoRESUMO
Epidermolysis bullosa (EB) encompasses a range of rare genetic dermatological conditions characterized by mucocutaneous fragility and a predisposition to blister formation, often triggered by minimal trauma. Blisters in the pharynx and esophagus are well-documented, particularly in dystrophic EB (DEB). However, there have been few reports of mucocutaneous squamous cell carcinoma (SCC) in the head and neck region, for which surgery is usually avoided. This report presents the first case of free jejunal flap reconstruction after total pharyngolaryngoesophagectomy for hypopharyngeal cancer in a 57-year-old patient with DEB. The patient with a known diagnosis of DEB had a history of SCC of the left hand and esophageal dilatation for esophageal stricture. PET-CT imaging during examination of systemic metastases associated with the left-hand SCC revealed abnormal accumulation in the hypopharynx, which was confirmed as SCC by biopsy. Total pharyngolaryngoesophagectomy was performed, followed by reconstruction of the defect using a free jejunal flap. A segment of the jejunum, approximately 15 cm in length, was transplanted with multiple vascular pedicles. The patient made an uneventful recovery postoperatively and was able to continue oral intake 15 months later with no complications and no recurrence of SCC in the head and neck region. While cutaneous SCC is common in DEB, extracutaneous SCC is relatively rare. In most previous cases, non-surgical approaches with radiotherapy and chemotherapy were chosen due to skin fragility and multimorbidity. In the present case, vascular fragility and mucosal damage of the intestinal tract were not observed, and routine vascular and enteric anastomoses could be performed, with an uneventful postoperative course. Our findings suggest that highly invasive surgery, including free tissue transplantation such as with a free jejunal flap, can be performed in patients with DEB.
Assuntos
Carcinoma de Células Escamosas , Epidermólise Bolhosa Distrófica , Retalhos de Tecido Biológico , Neoplasias Hipofaríngeas , Jejuno , Procedimentos de Cirurgia Plástica , Humanos , Neoplasias Hipofaríngeas/cirurgia , Neoplasias Hipofaríngeas/complicações , Pessoa de Meia-Idade , Retalhos de Tecido Biológico/transplante , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa Distrófica/cirurgia , Jejuno/transplante , Jejuno/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Masculino , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/complicações , Faringectomia/métodos , Esofagectomia/métodos , Laringectomia/métodosRESUMO
BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by mutations in the COL7A1 gene, which encodes type VII collagen (COL7), the main constituent of anchoring fibrils for attaching the epidermis to the dermis. Persistent skin erosions frequently result in intractable ulcers in RDEB patients. Adipose-derived mesenchymal stromal cells (AD-MSCs) are easily harvested in large quantities and have low immunogenicity. Therefore, they are suitable for clinical use, including applications involving allogeneic cell transplantation. Keratinocyte-like cells transdifferentiated from AD-MSCs (KC-AD-MSCs) express more COL7 than undifferentiated AD-MSCs and facilitate skin wound healing with less contracture. Therefore, these cells can be used for skin ulcer treatment in RDEB patients. OBJECTIVE: We investigated whether KC-AD-MSCs transplantation ameliorated the RDEB phenotype severity in the grafted skin of a RDEB mouse model (col7a1-null) on the back of the immunodeficient mouse. METHODS: KC-AD-MSCs were intradermally injected into the region surrounding the skin grafts, and this procedure was repeated after 7 days. After a further 7-day interval, the skin grafts were harvested. RESULTS: Neodeposition of COL7 and generation of anchoring fibrils at the dermal-epidermal junction were observed, although experiments were based on qualitative. CONCLUSION: KC-AD-MSCs may correct the COL7 insufficiency, repair defective/reduced anchoring fibrils, and improve skin integrity in RDEB patients.
Assuntos
Colágeno Tipo VII , Modelos Animais de Doenças , Epidermólise Bolhosa Distrófica , Queratinócitos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Transplante de Pele , Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Epidermólise Bolhosa Distrófica/terapia , Epidermólise Bolhosa Distrófica/patologia , Epidermólise Bolhosa Distrófica/genética , Animais , Humanos , Queratinócitos/transplante , Queratinócitos/metabolismo , Camundongos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Transplante de Pele/métodos , Pele/patologia , Pele/citologia , Tecido Adiposo/citologia , Diferenciação Celular , Células Cultivadas , Cicatrização , Camundongos KnockoutRESUMO
BACKGROUND: Invasive cutaneous squamous cell carcinomas (cSCC) are a leading cause of death in recessive dystrophic epidermolysis bullosa (RDEB), a rare blistering genodermatosis. Outcomes of RDEB-cSCC therapies have primarily been described in case reports. Systematic studies are scarce. This systematic review aims to assess the pathophysiology, clinical characteristics, and outcomes of RDEB-cSCCs, with a focus on results and mechanisms of recent immunotherapies and anti-EGFR treatments. RESULTS: A systematic literature search of epidermolysis bullosa and cSCC was performed in February 2024, using PubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and EudraCT databases. Cases with administration of systematic therapies and unpublished outcomes regarding death were tracked with corresponding authors. Data extraction and risk of bias assessment was performed by two independent reviewers. Of 1132 references in the original search, 163 relevant articles were identified, representing 59 case reports, 7 cohort studies, 49 abstracts, 47 in-vitro/in-vivo experiments, and 1 bioinformatic study. From these, 157 cases of RDEB-cSCCs were included. The majority of RDEB-cSCCs were well-differentiated (64.1%), ulcerated (59.6%), and at least 2 cm in size (77.6%), with a median age at diagnosis of 30 years old (range 6-68.4). Surgery was the primary form of treatment (n = 128), followed by chemotherapy and radiotherapy. Anti-EGFR therapy and immunotherapy was also reported beginning in 2009 and 2019, respectively. Survival time from first cSCC diagnosis to death was available in 50 cases. When stratified by their treatment regimen, median survival time was 1.85 years (surgery + chemotherapy, n = 6), 2 years (surgery only, n = 19), 4.0 years (+ anti-EFGR therapy, n = 10), 4 years (surgery + radiotherapy, n = 9), 4.6 years (+ immunotherapy, n = 4), and 9.5 years (surgery + chemotherapy + radiotherapy; n = 2). Treatment-related adverse events were primarily limited to impaired wound healing for immunotherapies and nausea and fatigue for anti-EGFR therapies. CONCLUSIONS: Despite the challenges of a limited sample size in a rare disease, this systematic review provides an overview of treatment options for cSCCs in RDEB. When surgical treatment options have been exhausted, the addition of immunotherapy and/or anti-EGFR therapies may extend patient survival. However, it is difficult to attribute extended survival to any single treatment, as multiple therapeutic modalities are often used to treat RDEB-cSCCs.
Assuntos
Carcinoma de Células Escamosas , Epidermólise Bolhosa Distrófica , Neoplasias Cutâneas , Humanos , Epidermólise Bolhosa Distrófica/terapia , Epidermólise Bolhosa Distrófica/patologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patologia , ImunoterapiaRESUMO
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.
Assuntos
Carcinoma de Células Escamosas , Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Neoplasias Cutâneas , Humanos , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/etiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/imunologia , Colágeno Tipo VII/genética , Mutação , Animais , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Fibrose , Genes RecessivosRESUMO
BACKGROUND/PURPOSE: Dystrophic epidermolysis bullosa (DEB), a rare genetic skin disease caused by loss-of-function mutations in COL7A1, the gene encoding type VII collagen (COL7), is characterized by skin blistering, scarring, and extracutaneous manifestations that markedly reduce patient quality-of-life. Beremagene geperpavec-svdt ('B-VEC') is a gene therapy employing a non-integrating, replication-defective herpes simplex virus type 1 (HSV-1)-based vector encoding two copies of full-length human COL7A1 to restore COL7 protein after topical administration to DEB wounds. B-VEC was approved in the United States in 2023 as the first topical gene therapy and the first approved treatment for DEB. However, few providers have experience with use of this gene therapy. METHODS: Data was obtained through literature review and the experience of providers who participated in the B-VEC clinical study or initiated treatment after B-VEC approval. RESULTS: This review discusses the burden of disease, describes the clinical trial outcomes of B-VEC, and provides physician and patient/caregiver recommendations as a practical guide for the real-world use of B-VEC, which can be administered in-office or at the patient's home. CONCLUSIONS: By continuing to optimize the practical aspects of B-VEC administration, the focus will continue to shift to patient-centric considerations and improved patient outcomes.
Assuntos
Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Terapia Genética , Humanos , Epidermólise Bolhosa Distrófica/terapia , Epidermólise Bolhosa Distrófica/genética , Colágeno Tipo VII/genética , Vetores Genéticos , Herpesvirus Humano 1/genética , Resultado do Tratamento , Qualidade de VidaRESUMO
Recessive dystrophic epidermolysis bullosa is a rare genodermatosis caused by a mutation of the Col7a1 gene. The Col7a1 gene codes for collagen type VII protein, a major component of anchoring fibrils. Mutations of the Col7a1 gene can cause aberrant collagen type VII formation, causing an associated lack or absence of anchoring fibrils. This presents clinically as chronic blistering, scarring, and fibrosis, often leading to the development of cutaneous squamous cell carcinoma. Patients also experience persistent pain and pruritus. Pain management and supportive bandaging remain the primary treatment options. The pathology of recessive dystrophic epidermolysis bullosa was first described in the 1980s, and there has since been a multitude of encouraging treatment options developed. However, in vivo research has been hindered by inadequate models of the disease. The various mouse models in existence possess longevity and surface area constraints, or do not adequately model a normal human disease state. In this paper, we describe a novel rat model of recessive dystrophic epidermolysis bullosa that offers an alternative to previous murine models. An 8-base pair deletion was induced in the Col7a1 gene of Lewis rats, which was subsequently found to cause a premature stop codon downstream. Homozygous mutants presented with a fragile and chronically blistered phenotype postnatally. Further histological analysis revealed subepidermal clefting and the absence of anchoring fibrils. The generation of this novel model offers researchers an easily maintained organism that possesses a larger surface area for experimental topical and transfused therapies to be tested, which may provide great utility in the future study of this debilitating disease.
Assuntos
Colágeno Tipo VII , Modelos Animais de Doenças , Epidermólise Bolhosa Distrófica , Mutação da Fase de Leitura , Fenótipo , Colágeno Tipo VII/genética , Animais , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/patologia , Ratos , Genes Recessivos , Ratos Endogâmicos Lew , Vesícula/genética , Vesícula/patologia , Pele/patologia , MasculinoRESUMO
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin disease caused by mutations in the type VII collagen gene (COL7A1; 3p21.31). Mutations in this gene lead to an alteration in function or reduced amounts of collagen VII. This alteration of collagen VII leads to skin fragility and lesions at minor injuries with difficult healing. Cutaneous squamous cell carcinoma (cSCC) is more frequent in patients with RDEB than in the general population because of chronic wound formation; it constitutes a major cause of morbidity and is often cited as a cause of death for these patients. There is little experience with the treatment of cSCC in patients with RDEB. We report the case of a 19-year-old female patient with RDBE and inoperable locally advanced cSCC of the left arm. Because of the lack of therapy options, therapy with cemiplimab was started at a dose of 350 mg administered intravenously every 3 weeks. A confirmed clinical response was observed after the second cycle of treatment with no toxicity. During follow-up, the patient had a notable clinical response with no auto-immune adverse reactions. This shows that cemiplimab has a good safety profile for cSCC in patients with RDEB and is a valuable therapy option.
Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma de Células Escamosas , Epidermólise Bolhosa Distrófica , Neoplasias Cutâneas , Humanos , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Epidermólise Bolhosa Distrófica/complicações , Feminino , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Adulto Jovem , Resultado do Tratamento , Antineoplásicos Imunológicos/uso terapêuticoRESUMO
BACKGROUND: Genotype-phenotype associations in recessive dystrophic epidermolysis bullosa (RDEB) have been difficult to elucidate. OBJECTIVE: To investigate RDEB genotype-phenotype associations and explore a functional approach to genotype classification. METHODS: Clinical examination and genetic testing of RDEB subjects, including assessment of clinical disease by RDEB subtype and extent of blistering. Genotypes were evaluated according to each variant's effect on type VII collagen function per updated literature and subsequently categorized by degree of impact on VII collagen function as low-impact (splice/missense, missense/missense), medium-impact (premature termination codon [PTC]/missense, splice/splice), and high-impact (PTC/PTC, PTC/splice). Genotype-phenotype associations were investigated using Kruskal-Wallis and Fisher's exact tests, and age-adjusted regressions. RESULTS: Eighty-three participants were included. High-impact variants were associated with worse RDEB subtype and clinical disease, including increased prevalence of generalized blistering (55.6% for low-impact vs 72.7% medium-impact vs 90.4% high-impact variants, P = .002). In age-adjusted regressions, participants with high-impact variants had 40.8-fold greater odds of squamous cell carcinoma compared to low-impact variants (P = .02), and 5.7-fold greater odds of death compared to medium-impact variants (P = .05). LIMITATIONS: Cross-sectional design. CONCLUSION: Functional genotype categories may stratify RDEB severity; high-impact variants correlated with worse clinical outcomes. Further validation in larger cohorts is needed.
Assuntos
Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Estudos de Associação Genética , Humanos , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/patologia , Masculino , Feminino , Colágeno Tipo VII/genética , Adulto , Criança , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Pré-Escolar , Fenótipo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Genótipo , Índice de Gravidade de Doença , Genes RecessivosRESUMO
EPIDERMOLYSIS: Bullosa is a rare hereditary skin condition that causes blisters. Genes encoding structural proteins at or near the dermal-epidermal junction are mutated recessively or dominantly, and this is the primary cause of EB. Herein, two Chinese boys were diagnosed with the condition, each with a different variant in a gene that serves as a reference for EB genetic counseling. Skincare significantly impacted their prognosis and quality of life. CASE PRESENTATION: Two Chinese boys, with phenotypically normal parents, have been diagnosed with distinct blister symptoms, one with Dominant Dystrophic Epidermolysis Bullosa and the other with a severe form of Epidermolysis Bullosa Simplex. The first patient had a G-to-A variant in the COL7A1 allele, at nucleotide position 6163 which was named "G2055A". The proband is heterozygous for Dystrophic Epidermolysis Bullosa due to a COL7A1 allele with a glycine substitution at the triple helix domain. A similar variant has been discovered in his mother, indicating its potential transmission to future generations. Another patient had severe Epidermolysis Bullosa Simplex with a rare c.377T > A variant resulting in substitution of amino acid p.Leu126Arg (NM_000526.5 (c.377T > G, p.Leu126Arg) in the Keratin 14 gene. In prior literature, Keratin 14 has been associated with an excellent prognosis. However, our patient with this infrequent variant tragically died from sepsis at 21 days old. There has been a reported occurrence of the variant only once. CONCLUSION: Our study reveals that Epidermolysis Bullosa patients with COL7A1 c.6163G > A and KRT14 c.377T>A variants have different clinical presentations, with dominant forms of Dystrophic EB having milder phenotypes than recessive ones. Thus, the better prognosis in the c.6163G > A patient. Furthermore, c.377T>A patient was more prone to infection than the patient with c.6163G>A gene variant. Genetic testing is crucial for identifying the specific variant responsible and improving treatment options.
Assuntos
Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa Simples , Epidermólise Bolhosa , Humanos , Masculino , Colágeno , Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Epidermólise Bolhosa/genética , Epidermólise Bolhosa Distrófica/diagnóstico , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/metabolismo , Queratina-14/genética , Mutação , Qualidade de VidaRESUMO
The effect of persistent skin inflammation on extracutaneous organs and blood is not well studied. Patients with recessive dystrophic epidermolysis bullosa (RDEB), a severe form of the inherited blistering skin disorder, have widespread and persistent skin ulcers, and they develop various complications including anaemia, hyperglobulinaemia, hypoalbuminaemia and secondary amyloidosis. These complications are associated with the bioactivities of IL-6, and the development of secondary amyloidosis requires the persistent elevation of serum amyloid A (SAA) level. We found that patients with RDEB had significantly higher serum levels of IL-6 and SAA compared to healthy volunteers and patients with psoriasis or atopic dermatitis. Both IL-6 and SAA were highly expressed in epidermal keratinocytes and dermal fibroblasts of the skin ulcer lesions. Keratinocytes and fibroblasts surrounding the ulcer lesions are continuously exposed to Toll-like receptor (TLR) ligands, pathogen-associated and damage-associated molecular pattern molecules. In vitro, TLR ligands induced IL-6 expression via NF-κB in normal human epidermal keratinocytes (NHEKs) and dermal fibroblasts (NHDFs). SAA further induced the expression of IL-6 via TLR1/2 and NF-κB in NHEKs and NHDFs. The limitation of this study is that NHEKs and NHDFs were not derived from RDEB patients. These observations suggest that TLR-mediated persistent skin inflammation might increase the risk of IL-6-related systemic complications, including RDEB.
Assuntos
Amiloidose , Epidermólise Bolhosa Distrófica , Interleucina-6 , Humanos , Amiloidose/metabolismo , Amiloidose/patologia , Colágeno Tipo VII/metabolismo , Epidermólise Bolhosa Distrófica/metabolismo , Epidermólise Bolhosa Distrófica/patologia , Fibroblastos/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Queratinócitos/metabolismo , NF-kappa B/metabolismo , Proteína Amiloide A Sérica/metabolismo , Receptores Toll-Like/metabolismoRESUMO
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.
Assuntos
Carbamatos , Epidermólise Bolhosa Distrófica , Imidazóis , Pirrolidinas , Valina/análogos & derivados , Humanos , Animais , Camundongos , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Epidermólise Bolhosa Distrófica/patologia , Qualidade de Vida , Colágeno Tipo VII/metabolismo , Colágeno Tipo VII/uso terapêutico , Fibrose , Antivirais/farmacologia , Antivirais/uso terapêutico , Pele/metabolismo , Pele/patologiaRESUMO
Preweaning mortality is a widespread problem in laboratory mouse breeding, particularly in the case of fragile mouse models. While numerous studies explore alternative care methods to increase the survivability of common mouse strains, there remains a paucity of research into the care of mice with fragile health conditions that result from induced or natural genetic mutations. In this study, standard husbandry practices were enhanced by the addition of a softened diet, a nutritionally fortified dietary supplement, soft bedding, gentle handling techniques, decreased handling, lengthened weaning age, and dam productivity tracking. This alternative care plan was shown to increase the survival of a fragile recessive dystrophic epidermolysis bullosa mouse model, and some aspects could be used in developing a care plan for other fragile mouse strains.