The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
John A. Mcgrath - One of the best experts on this subject based on the ideXlab platform.
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Ectodermal dysplasia-Skin Fragility syndrome: Two new cases and review of this desmosomal genodermatosis.
Experimental dermatology, 2020Co-Authors: Brent J. Doolan, Jemima E. Mellerio, Lu Liu, Nesrin S. Gomaa, Mohamed M. Fawzy, Noha N. Dogheim, Alexandros Onoufriadis, John A. McgrathAbstract:BACKGROUND Desmosomes are intercellular cadherin-mediated adhesion complexes that anchor intermediate filaments to the cell membrane and are required for strong adhesion for tissues under mechanical stress. One specific component of desmosomes is plakophilin 1 (PKP1), which is mainly expressed in the spinous layer of the epidermis. Loss-of-function autosomal recessive mutations in PKP1 result in ectodermal dysplasia-Skin Fragility (EDSF) syndrome, the initial inherited Mendelian disorder of desmosomes first reported in 1997. METHODS To investigate two new cases of EDSF syndrome and to perform a literature review of pathogenic PKP1 mutations from 1997 to 2019. RESULTS Sanger sequencing of PKP1 identified two new homozygous frameshift mutations: c.409_410insAC (p.Thr137Thrfs*61) and c.1213delA (p.Arg411Glufs*22). Comprehensive analyses were performed for the 18 cases with confirmed bi-allelic PKP1 gene mutations, but not for one mosaic case or 6 additional cases that lacked gene mutation studies. All pathogenic germline mutations were loss-of-function (splice site, frameshift, nonsense) with mutations in the intron 1 consensus acceptor splice site (c.203-1>A or G>T) representing recurrent findings. Skin Fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases). Further observations in some individuals included pruritus, failure to thrive with low height/weight centiles, follicular hyperkeratosis, hypohidrosis, walking difficulties, dysplastic dentition and recurrent chest infections. CONCLUSION These data expand the molecular basis of EDSF syndrome and help define the spectrum of both the prototypic and variable manifestations of this desmosomal genodermatosis.
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ultrastructure of desmosomes as a diagnostic clue in a case of congenital Skin Fragility syndrome
Journal of Investigative Dermatology, 2014Co-Authors: Anders Vahlquist, John A. Mcgrath, Marie Virtanen, Maritta Hellstrompigg, Anca Dragomir, K Ryberg, Neil J Wilson, F J D SmithAbstract:Ultrastructure of desmosomes as a diagnostic clue in a case of congenital Skin Fragility syndrome
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a scandinavian case of Skin Fragility alopecia and cardiomyopathy caused by dsp mutations
Clinical and Experimental Dermatology, 2014Co-Authors: Anders Vahlquist, John A. Mcgrath, Marie Virtanen, Maritta Hellstrompigg, Anca Dragomir, K Ryberg, Neil J Wilson, I Ostmansmith, F J D SmithAbstract:Congenital Skin Fragility is a heterogeneous disorder with epidermolysis bullosa and various Skin infections as the leading causes. However, even rare diseases must be considered in the differential diagnosis of neonatal Skin blistering, including some genetic syndromes with extracutaneous involvement. One such syndrome is ectodermal dysplasia due to deficiency of desmoplakin, a desmosomal protein essential for cellular cohesion in both epithelia and cardiac tissues. Desmoplakin is encoded by the DSP gene, which is localized on chromosome 6p24. Both dominant and recessive mutations in this gene have been reported to cause Skin Fragility and keratinization defects. We report a child born with a fragile epidermis, alopecia, thick nails, and focal hyperkeratoses on the digits and knees. She was found to have a deficiency of desmoplakin caused by compound heterozygous DSP mutations. She has gradually developed signs of a left ventricular cardiomyopathy.
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mutations in exph5 result in autosomal recessive inherited Skin Fragility
British Journal of Dermatology, 2014Co-Authors: L Liu, J E Mellerio, A E Martinez, James R Mcmillan, Sophia Aristodemou, Madeline Parsons, John A. McgrathAbstract:Several different genes have been implicated in the pathophysiology of inherited blistering Skin diseases. Recently, autosomal recessive loss-of-function mutations in EXPH5 (encoding exophilin-5, also known as Slac2-b, a protein involved in intracellular vesicle transport) were identified in a new mechanobullous disease resembling a form of epidermolysis bullosa simplex (EBS). Here, we searched for mutations in EXPH5 in a 4-year-old white boy with EBS in whom initial Sanger sequencing of known genes implicated in intraepidermal Skin Fragility failed to identify pathogenic mutations. Transmission electron microscopy of rubbed nonlesional patient Skin revealed disruption of keratinocytes in the lower epidermis with cytolysis and acantholysis, keratin filament clumping and prominent perinuclear cytoplasmic vesicles, and provided the clue to the candidate gene pathology. Sanger sequencing of genomic DNA showed compound heterozygosity for two new mutations in EXPH5, c.1947dupC (p.Pro649fsPro*11) and c.2249C>A (p.Ser750*). Immunofluorescence microscopy of patient Skin showed a complete absence of exophilin-5 labelling. This case represents the third pedigree with EXPH5 mutations resulting in inherited Skin Fragility. The clinical and molecular data expand genotype-phenotype correlation in this new form of EBS and demonstrate the important role of exophilin-5 in keratinocyte cell biology.
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germline mutation in exph5 implicates the rab27b effector protein slac2 b in inherited Skin Fragility
American Journal of Human Genetics, 2012Co-Authors: John A. Mcgrath, James R Mcmillan, Kristina L Stone, Rumena Begum, Michael A Simpson, Patricia J C Doppinghepenstal, Lu Liu, Andrew P South, Celine PourreyronAbstract:The Rab GTPase Rab27B and one of its effector proteins, Slac2-b (also known as EXPH5, exophilin-5), have putative roles in intracellular vesicle trafficking but their relevance to human disease is not known. By using whole-exome sequencing, we identified a homozygous frameshift mutation in EXPH5 in three siblings with inherited Skin Fragility born to consanguineous Iraqi parents. All three individuals harbor the mutation c.5786delC (p.Pro1929Leufs∗8) in EXPH5, which truncates the 1,989 amino acid Slac2-b protein by 52 residues. The clinical features comprised generalized scale-crusts and occasional blisters, mostly induced by trauma, as well as mild diffuse pigmentary mottling on the trunk and proximal limbs. There was no increased bleeding tendency, no neurologic abnormalities, and no increased incidence of infection. Analysis of an affected person's Skin showed loss of Slac2-b immunostaining (C-terminal antibody), disruption of keratinocyte adhesion within the lower epidermis, and an increased number of perinuclear vesicles. A role for Slac2-b in keratinocyte biology was supported by findings of cytoskeletal disruption (mainly keratin intermediate filaments) and decreased keratinocyte adhesion in both keratinocytes from an affected subject and after shRNA knockdown of Slac2-b in normal keratinocytes. Slac2-b was also shown to colocalize with Rab27B and β4 integrin to early adhesion initiation sites in spreading normal keratinocytes. Collectively, our findings identify an unexpected role for Slac2-b in inherited Skin Fragility and expand the clinical spectrum of human disorders of GTPase effector proteins.
David T Woodley - One of the best experts on this subject based on the ideXlab platform.
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De Novo Anti-Type VII Collagen Antibodies in Patients With Recessive
2016Co-Authors: Dystrophic Epidermolysis Bullosa, David T Woodley, Jon Cogan, Xinyi Wang, Cyrus Haghighian, Yingping Hou, Kudo Douglas R. KeeneAbstract:The two main layers of human Skin are held together by structures at the dermal-epidermal junction (DEJ) called anchoring fibrils (AFs). Without properly functioning AFs, the adherence between the epidermis and dermis is compromised. Clinically, this translates into Skin Fragility and Skin bullae. AFs are composed of type VII collagen (C7) that has a central triple helical domain (TH) flanked by a 145-kDa non-collagenous amino-terminal domain (NC1) and a 30-kDa carboxyl-terminal domain (NC2) (Burgeson et al., 1993). AFs and C7 are perturbed in recessive dystrophic epidermolysis bullosa (RDEB), a disease characterized clinically by Skin Fragility, Skin bullae, scarring, and nail loss (Fine et al., 2008). RDEB is caused by mutations in the COL7A1 gene encoding C7. Over 700 mutations have been identified in DEB patients (Wertheim-Tysarowska et al., 2012). According to a recent consensus report, RDEB is classified as RDEB, severe, generalized (RDEB-sev, gen), RDEB, generalized, other (RDEB-O) and RDEB inversa (RDEB-I) (Fine et al., 2008). There is also an acquired type of EB called epidermolysis bullosa acquisita (EBA). EBA patients are born with normal Skin and then during middle age, they inappropriately generate IgG antibodies against their C7 and AFs (Yaoita et al., 1981, Woodley et al., 1984;) leadin
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de novo anti type vii collagen antibodies in patients with recessive dystrophic epidermolysis bullosa
Journal of Investigative Dermatology, 2014Co-Authors: David T Woodley, Jon Cogan, Xinyi Wang, Cyrus Haghighian, Gail Kudo, Douglas R Keene, Mei ChenAbstract:The two main layers of human Skin are held together by structures at the dermal-epidermal junction (DEJ) called anchoring fibrils (AFs). Without properly functioning AFs, the adherence between the epidermis and dermis is compromised. Clinically, this translates into Skin Fragility and Skin bullae. AFs are composed of type VII collagen (C7) that has a central triple helical domain (TH) flanked by a 145-kDa non-collagenous amino-terminal domain (NC1) and a 30-kDa carboxyl-terminal domain (NC2) (Burgeson et al., 1993). AFs and C7 are perturbed in recessive dystrophic epidermolysis bullosa (RDEB), a disease characterized clinically by Skin Fragility, Skin bullae, scarring, and nail loss (Fine et al., 2008). RDEB is caused by mutations in the COL7A1 gene encoding C7. Over 700 mutations have been identified in DEB patients (Wertheim -Tysarowska et al., 2012). According to a recent consensus report, RDEB is classified as RDEB, severe, generalized (RDEB-sev, gen), RDEB, generalized, other (RDEB-O) and RDEB inversa (RDEB-I) (Fine et al., 2008).
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epidermolysis bullosa acquisita
The New England Journal of Medicine, 2013Co-Authors: Mei Chen, Dafna Hallelhalevy, David T WoodleyAbstract:EBA is a clinically heterogeneous acquired, subepidermal bullous disease. In its classical form, it is a mechanobullous disease with Skin Fragility and trauma-induced blisters that have minimal inflammation and heal with scarring and milia — features that are highly reminiscent of hereditary dystrophic forms of epidermolysis bullosa. A hallmark of EBA are IgG autoantibodies targeted against the type VII collagen within anchoring fibrils. Anchoring fibrils are structures that anchor the epidermis and its underlying BMZ onto the dermis. However, it has also become evident that EBA may present with clinical manifestations reminiscent of bullous pemphigoid (BP), cicatricial pemphigoid (CP), and Brunsting-Perry pemphigoid. The diagnostic criteria for EBA are: (1) spontaneous or trauma-induced blisters resembling hereditary DEB, (2) adult onset, (3) a negative family history for EB, and (4) the exclusion of all other bullous diseases. Due to the pronounced Skin Fragility caused by the autoantibody-induced paucity of anchoring fibrils, EBA is difficult to treat. The BP-like inflammatory variants of EBA respond well to systemic corticosteroids and immunosuppressive adjuvants while the mechanobullous variant and the MMP-like variants do to a much lesser extent. Novel therapeutic strategies such as immunoadsorption and the anti-CD20 monoclonal antibody, rituximab, had beneficial effects in small case series.
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injection of recombinant human type vii collagen corrects the disease phenotype in a murine model of dystrophic epidermolysis bullosa
Molecular Therapy, 2009Co-Authors: Jennifer Remington, Jouni Uitto, Xinyi Wang, Douglas R Keene, Yingpin Hou, Hui Zhou, Julie Burnett, Trevor Muirhead, David T WoodleyAbstract:Patients with recessive dystrophic epidermolysis bullosa (RDEB) have incurable Skin Fragility, blistering, and scarring due to mutations in the gene that encodes for type VII collagen (C7) that mediates dermal–epidermal adherence in human Skin. We showed previously that intradermal injection of recombinant C7 into transplanted human DEB Skin equivalents stably restored C7 expression at the basement membrane zone (BMZ) and reversed the RDEB disease features. In this study, we evaluated the feasibility of protein therapy in a C7 null mouse (Col7a1–/–) which recapitulates the features of human RDEB. We intradermally injected purified human C7 into DEB mice and found that the injected human C7 stably incorporated into the mouse BMZ, formed anchoring fibrils, and corrected the DEB murine phenotype, as demonstrated by decreased Skin Fragility, reduced new blister formation, and markedly prolonged survival. After 4 weeks, treated DEB mice developed circulating anti-human C7 antibodies. Most surprisingly, these anti-C7 antibodies neither bound directly to the mouse's BMZ nor prevented the incorporation of newly injected human C7 into the BMZ. Anti-C7 antibody production was prevented by treating the mice with an anti-CD40L monoclonal antibody, MR1. We conclude that protein therapy may be feasible for the treatment of human patients with RDEB.
Cristina Has - One of the best experts on this subject based on the ideXlab platform.
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consensus reclassification of inherited epidermolysis bullosa and other disorders with Skin Fragility
British Journal of Dermatology, 2020Co-Authors: Cristina Has, Leena Brucknertuderman, Christine Bodemer, Maria C Bolling, Johann W Bauer, Anja Diem, Jodavid Fine, Adrian Heagerty, Alain Hovnanian, M P MarinkovichAbstract:Background: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). Objectives: We sought to reclassify disorders with Skin Fragility, with a focus on EB, based on new clinical and molecular data. Methods: This was a consensus expert review. Results: In this latest consensus report, we introduce the concept of genetic disorders with Skin Fragility, of which classical EB represents the prototype. Other disorders with Skin Fragility, where blisters are a minor part of the clinical picture or are not seen because Skin cleavage is very superficial, are classified as separate categories. These include peeling Skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with Skin Fragility. Because of the common manifestation of Skin Fragility, these ‘EB-related’ disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Conclusions: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic?. Epidermolysis bullosa (EB) is a group of genetic disorders with Skin blistering. The last updated recommendations on diagnosis and classification were published in 2014. What does this study add?. We introduce the concept of genetic disorders with Skin Fragility, of which classical EB represents the prototype. Clinical and genetic aspects, genotype–phenotype correlations, disease-modifying factors and natural history of EB are reviewed. Other disorders with Skin Fragility, e.g. peeling Skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with Skin Fragility are classified as separate categories; these ‘EB-related’ disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Linked Comment: Pope. Br J Dermatol 2020; 183:603.
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withdrawn Skin Fragility caused by biallelic krt10 mutations an intriguing form of self improving epidermolytic ichthyosis
British Journal of Dermatology, 2020Co-Authors: L Frommherz, J Kusel, Andreas Zimmer, Judith Fischer, Cristina HasAbstract:Autosomal recessive epidermolytic ichthyosis is a rare Skin condition associated with KRT10 loss-of-function mutations. It presents with severe life-threatening clinical manifestations. Here we describe a case of autosomal recessive epidermolytic ichthyosis with an unusually mild, spontaneously improving phenotype. Erythroderma and superficial blistering were present at birth, but the Skin recovered and remained almost intact at the age of 1 year. Mild scaling on the neck and Skin Fragility manifesting as superficial erosions after scratching were the only clinical features as the child grew. As a cause, previously unreported compound heterozygous KRT10 pathogenic variants were found: a nonsense mutation leads to mRNA decay, while the other synonymous variant induces a leaky splice site, explaining the residual keratin 10 expression and mild clinical phenotype. What's already known about this topic? Autosomal recessive epidermolytic ichthyosis is a rare Skin condition caused by loss-of-function KRT10 mutations. The clinical phenotype is severe with superficial Skin blistering, scaling and hyperkeratosis. What does this study add? Here we extend the mutational and phenotypic spectrum of autosomal recessive epidermolytic ichthyosis. Our case presented with erythroderma and superficial blistering at birth, but the Skin recovered and was almost intact at the age of 1 year. The only disease manifestations were mild scaling on the neck and Skin Fragility appearing as superficial erosions after scratching. The causative factors were found to be one nonsense mutation in KRT10 that leads to mRNA decay, and one synonymous variant that affects the donor splice site of exon 3. We hypothesize that this leaky splice site explains the residual keratin 10 expression and self-improving clinical phenotype.
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syndromes with Skin Fragility
Hautarzt, 2019Co-Authors: Antonia Reimer, Cristina HasAbstract:Syndrome mit Hautfragilitat gehoren zu verschiedenen Gruppen von Genodermatosen: Epidermolysis bullosa, Ehlers-Danlos-Syndromen und Porphyrien. Dabei sind auser dem Integument auch extrakutane Organe oder Systeme primar beteiligt: Herz, Skelettmuskeln, Darm, Nieren, Leber, Gefase oder das Skelett. Pathogenetisch sind diese Syndrome auf Verlust oder Dysfunktion von Strukturproteinen, die die mechanische Stabilitat der Gewebe gewahrleisten, zuruckzufuhren. Vom betroffenen Protein abhangig kann die Hautfragilitat zu oberflachlichen Erosionen, Blasenbildung, Wunden, Wundheilungsstorungen oder Vernarbung fuhren. Im Rahmen der Epidermolysis bullosa gibt es einige syndromale Subtypen, z. B. Hautfragilitat mit: 1) Kardiomyopathie, bei Mutationen in den Genen fur Desmoplakin, Plakoglobin oder Kelch-like-Protein 24; 2) Muskeldystrophie bei Mutationen im Plektin-Gen; 3) Pylorusatresie bei Verlust von Integrin α6β4 oder Plektin; 4) primare Nierenbeteiligung in Form eines nephrotischen Syndroms oder Malformationen bei CD151 oder Integrin-α3-Mutationen. Mutationen im Gen fur Lysylhydroxylase 3 storen die posttranslationale Modifikation von Kollagenen und verursachen eine komplexe systemische Erkrankung, die der dystrophen Epidermolysis bullosa ahnlich ist. Defekte der Kollagene im Bindegewebe inklusive der Dermis fuhren zu verschiedenen Formen der Ehlers-Danlos-Syndrome mit Gefas- und Gelenkbeteiligung. Schlieslich sind die Porphyrien eine Gruppe komplexer metabolischer Erkrankungen mit Hautfragilitat, Photosensitivitat sowie auch neurologischer oder hepatischer Beteiligung. Vermutlich beruht die Pathogenese auf der Akkumulation von Ham-Vorstufen. In der Praxis sind diese Erkrankungen sehr selten. Allerdings ist es wichtig, an die mogliche syndromale Konstellation zu denken, um den Weg zur Diagnose zu verkurzen und mogliche Komplikationen fruhzeitig zu erkennen.
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advances in understanding the molecular basis of Skin Fragility
F1000Research, 2018Co-Authors: Cristina HasAbstract:Skin Fragility refers to a large group of conditions in which the ability of the Skin to provide protection against trivial mechanical trauma is diminished, resulting in the formation of blisters, erosions, wounds, or scars. Acquired and physiological Skin Fragility is common; genetic disorders are rare but give insight into the molecular mechanisms ensuring Skin stability. The paradigm is represented by inherited epidermolysis bullosa. This review is focused on recent advances in understanding the molecular basis of genetic Skin Fragility, including emerging concepts, controversies, unanswered questions, and opinions of the author. In spite of the advanced knowledge on the genetic causes of Skin Fragility, the molecular pathology is still expanding. Open questions in understanding the molecular basis of genetic Skin Fragility are the following: what are the causes of phenotypes which remain genetically unsolved, and what are the molecular modifiers which might explain phenotypic differences among individuals with similar mutations? New mutational mechanisms and new genes have recently been discovered and are briefly described here. Comprehensive next-generation sequencing-based genetic testing improved mutation detection and facilitated the identification of the genetic basis of unclear and new phenotypes. Characterization of the biochemical and cell biological consequences of the genetic variants is challenging and laborious but may represent the basis for personalized therapeutic approaches. Molecular modifiers of Skin Fragility have been uncovered in particular animal and genetic models but not in larger cohorts of patients. This scientific progress is the basis for revisions of the epidermolysis bullosa classification and for innovative therapeutic approaches designed for this intractable condition.
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focal adhesions in the Skin lessons learned from Skin Fragility disorders
European Journal of Dermatology, 2017Co-Authors: Cristina HasAbstract:Focal adhesions are large multiprotein cell-matrix adhesion complexes, which regulate multiple cellular functions, such as adhesion and migration. Their biological significance in Skin is underscored by two genetic disorders, the Kindler syndrome and the interstitial lung disease, nephrotic syndrome and epidermolysis bullosa, in which mutations affect focal adhesion proteins, kindlin-1 and the integrin α3 subunit, respectively. Here we provide an overview of what we learned from the study of the molecular mechanisms of these diseases. Emphasis is put on the point of view of the clinician dermatologist.
Leena Brucknertuderman - One of the best experts on this subject based on the ideXlab platform.
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consensus reclassification of inherited epidermolysis bullosa and other disorders with Skin Fragility
British Journal of Dermatology, 2020Co-Authors: Cristina Has, Leena Brucknertuderman, Christine Bodemer, Maria C Bolling, Johann W Bauer, Anja Diem, Jodavid Fine, Adrian Heagerty, Alain Hovnanian, M P MarinkovichAbstract:Background: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). Objectives: We sought to reclassify disorders with Skin Fragility, with a focus on EB, based on new clinical and molecular data. Methods: This was a consensus expert review. Results: In this latest consensus report, we introduce the concept of genetic disorders with Skin Fragility, of which classical EB represents the prototype. Other disorders with Skin Fragility, where blisters are a minor part of the clinical picture or are not seen because Skin cleavage is very superficial, are classified as separate categories. These include peeling Skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with Skin Fragility. Because of the common manifestation of Skin Fragility, these ‘EB-related’ disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Conclusions: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic?. Epidermolysis bullosa (EB) is a group of genetic disorders with Skin blistering. The last updated recommendations on diagnosis and classification were published in 2014. What does this study add?. We introduce the concept of genetic disorders with Skin Fragility, of which classical EB represents the prototype. Clinical and genetic aspects, genotype–phenotype correlations, disease-modifying factors and natural history of EB are reviewed. Other disorders with Skin Fragility, e.g. peeling Skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with Skin Fragility are classified as separate categories; these ‘EB-related’ disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Linked Comment: Pope. Br J Dermatol 2020; 183:603.
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consensus reclassification of inherited epidermolysis bullosa and other disorders with Skin Fragility
British Journal of Dermatology, 2020Co-Authors: Johann W Bauer, Leena Brucknertuderman, Anja Diem, Jodavid Fine, Adrian Heagerty, Alain Hovnanian, M P Marinkovich, C Bodemer, M C Bolling, A E MartinezAbstract:BACKGROUND: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). OBJECTIVES: We sought to reclassify disorders with Skin Fragility, with a focus on EB, based on new clinical and molecular data. METHODS: This was a consensus expert review. RESULTS: In this latest consensus report, we introduce the concept of genetic disorders with Skin Fragility, of which classical EB represents the prototype. Other disorders with Skin Fragility, where blisters are a minor part of the clinical picture or are not seen because Skin cleavage is very superficial, are classified as separate categories. These include peeling Skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with Skin Fragility. Because of the common manifestation of Skin Fragility, these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. CONCLUSION: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB.
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Skin Fragility perspectives on evidence based therapies
Acta Dermato-venereologica, 2020Co-Authors: Leena BrucknertudermanAbstract:The term Skin Fragility disorders describes a group of conditions in which the structural integrity of the Skin is compromised and its resistance to external shear forces diminished. Skin Fragility can have different causes, ranging from genetic variations to inflammatory or physical phenomena. The genetic Skin Fragility disorders, collectively called epidermolysis bullosa, serve as a paradigm for the study of causes and mechanisms of Skin Fragility. Recent biomedical research has revealed substantial genetic heterogeneity of the epidermolysis bullosa group, delivered ample new knowledge on its pathophysiology, and facilitated the design of evidence-based therapeutic strategies. The therapy development process extends from in vitro testing to preclinical validation in animal models, and clinical trials. This article reviews different approaches to curative and symptom-relief therapies, and appraises their status and perspectives for clinical implementation.
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small molecule therapies for genetic Skin Fragility
Molecular Therapy, 2014Co-Authors: Leena BrucknertudermanAbstract:Of the known genetic Skin diseases, dystrophic epidermolysis bullosa (DEB) is a prime target for therapy development. It is a monogenic, strongly disabling disorder with high unmet medical need. Lifelong generalized Skin blistering as a consequence of minor mechanical friction, chronic wounds, excessive scarring, and progressive soft-tissue fibrosis are clinical hallmarks. Joint contractures and mitten deformities of the extremities cause severe disability, and the fibrosis of the Skin increases tissue stiffness and favors development of aggressive squamous cell carcinoma, a feared complication of the disease.1 For obvious reasons, many investigators have pursued curative gene-, cell-, and protein-based therapy approaches for DEB, but these have turned out to be much more challenging than anticipated and have shown very limited benefit in pilot clinical trials.2 In the recent past, it has become clear that alternative approaches are urgently needed to improve the health and quality of life of severely affected patients. In line with this, Cogan et al.3 report in this issue on the use of aminoglycosides to induce readthrough of premature termination codons (PTCs) and to restore functional protein production in DEB keratinocytes and fibroblasts in vitro.
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the genetics of Skin Fragility
Annual Review of Genomics and Human Genetics, 2014Co-Authors: Cristina Has, Leena BrucknertudermanAbstract:Genetic Skin Fragility manifests with diminished resistance of the Skin and mucous membranes to external mechanical forces and with Skin blistering, erosions, and painful wounds as clinical features. Skin Fragility disorders, collectively called epidermolysis bullosa, are caused by mutations in 18 distinct genes that encode proteins involved in epidermal integrity and dermal-epidermal adhesion. The genetic spectrum, along with environmental and genetic modifiers, creates a large number of clinical phenotypes, spanning from minor localized lesions to severe generalized blistering, secondary Skin cancer, or early demise resulting from extensive loss of the epidermis. Laboratory investigations of Skin Fragility have greatly augmented our understanding of genotype-phenotype correlations in epidermolysis bullosa and have also advanced Skin biology in general. Current translational research concentrates on the development of biologically valid treatments with therapeutic genes, cells, proteins, or small-molecule compounds in preclinical settings or human pilot trials.
Mei Chen - One of the best experts on this subject based on the ideXlab platform.
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de novo anti type vii collagen antibodies in patients with recessive dystrophic epidermolysis bullosa
Journal of Investigative Dermatology, 2014Co-Authors: David T Woodley, Jon Cogan, Xinyi Wang, Cyrus Haghighian, Gail Kudo, Douglas R Keene, Mei ChenAbstract:The two main layers of human Skin are held together by structures at the dermal-epidermal junction (DEJ) called anchoring fibrils (AFs). Without properly functioning AFs, the adherence between the epidermis and dermis is compromised. Clinically, this translates into Skin Fragility and Skin bullae. AFs are composed of type VII collagen (C7) that has a central triple helical domain (TH) flanked by a 145-kDa non-collagenous amino-terminal domain (NC1) and a 30-kDa carboxyl-terminal domain (NC2) (Burgeson et al., 1993). AFs and C7 are perturbed in recessive dystrophic epidermolysis bullosa (RDEB), a disease characterized clinically by Skin Fragility, Skin bullae, scarring, and nail loss (Fine et al., 2008). RDEB is caused by mutations in the COL7A1 gene encoding C7. Over 700 mutations have been identified in DEB patients (Wertheim -Tysarowska et al., 2012). According to a recent consensus report, RDEB is classified as RDEB, severe, generalized (RDEB-sev, gen), RDEB, generalized, other (RDEB-O) and RDEB inversa (RDEB-I) (Fine et al., 2008).
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epidermolysis bullosa acquisita
The New England Journal of Medicine, 2013Co-Authors: Mei Chen, Dafna Hallelhalevy, David T WoodleyAbstract:EBA is a clinically heterogeneous acquired, subepidermal bullous disease. In its classical form, it is a mechanobullous disease with Skin Fragility and trauma-induced blisters that have minimal inflammation and heal with scarring and milia — features that are highly reminiscent of hereditary dystrophic forms of epidermolysis bullosa. A hallmark of EBA are IgG autoantibodies targeted against the type VII collagen within anchoring fibrils. Anchoring fibrils are structures that anchor the epidermis and its underlying BMZ onto the dermis. However, it has also become evident that EBA may present with clinical manifestations reminiscent of bullous pemphigoid (BP), cicatricial pemphigoid (CP), and Brunsting-Perry pemphigoid. The diagnostic criteria for EBA are: (1) spontaneous or trauma-induced blisters resembling hereditary DEB, (2) adult onset, (3) a negative family history for EB, and (4) the exclusion of all other bullous diseases. Due to the pronounced Skin Fragility caused by the autoantibody-induced paucity of anchoring fibrils, EBA is difficult to treat. The BP-like inflammatory variants of EBA respond well to systemic corticosteroids and immunosuppressive adjuvants while the mechanobullous variant and the MMP-like variants do to a much lesser extent. Novel therapeutic strategies such as immunoadsorption and the anti-CD20 monoclonal antibody, rituximab, had beneficial effects in small case series.
