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B Leheup - One of the best experts on this subject based on the ideXlab platform.
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unusual cutaneous features associated with a heterozygous gain of function mutation in ifih1 overlap between aicardi goutieres and singleton merten syndromes
British Journal of Dermatology, 2015Co-Authors: Ac Bursztejn, Tracy A Briggs, Y Del Toro Duany, Beverley Anderson, James Osullivan, Simon G Williams, C Bodemer, S Fraitag, F Gebhard, B LeheupAbstract:Cutaneous lesions described as Chilblain lupus occur in the context of familial Chilblain lupus or Aicardi-Goutieres syndrome. To date, seven genes related to Aicardi-Goutieres syndrome have been described. The most recently described encodes the cytosolic double-stranded RNA receptor IFIH1 (also known as MDA5), a key component of the antiviral type I interferon-mediated innate immune response. Enhanced type I interferon signalling secondary to gain-of-function mutations in IFIH1 can result in a range of neuroinflammatory phenotypes including classical Aicardi-Goutieres syndrome. It is of note that none of the patients with a neurological phenotype so far described with mutations in this gene was reported to demonstrate cutaneous involvement. We present a family segregating a heterozygous pathogenic mutation in IFIH1 showing dermatological involvement as a prominent feature, variably associated with neurological disturbance and premature tooth loss. All three affected individuals exhibited increased expression of interferon-stimulated genes in whole blood, and the mutant protein resulted in enhanced interferon signalling in vitro, both in the basal state and following ligand stimulation. Our results further extend the phenotypic spectrum associated with mutations in IFIH1, indicating that the disease can be confined predominantly to the skin, while also highlighting phenotypic overlap with both Aicardi-Goutieres syndrome and Singleton-Merten syndrome.
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unusual cutaneous features associated with a heterozygous gain of function mutation in ifih1 overlap between aicardi goutieres and singleton merten syndromes
British Journal of Dermatology, 2015Co-Authors: Ac Bursztejn, Tracy A Briggs, Beverley Anderson, James Osullivan, Simon G Williams, C Bodemer, S Fraitag, F Gebhard, Y Del Toro Duany, B LeheupAbstract:BACKGROUND: Cutaneous lesions described as Chilblain lupus occur in the context of familial Chilblain lupus or Aicardi-Gouti�res syndrome. To date, seven Aicardi-Gouti�res syndrome-related genes have been described. The most recently described encodes the cytosolic double-stranded RNA receptor IFIH1 (MDA5), a key component of the antiviral type I interferon-mediated innate immune response. Enhanced type I interferon signalling secondary to gain-of-function mutations in IFIH1 can result in a range of neuroinflammatory phenotypes including classical Aicardi-Gouti�res syndrome. It is of note that none of the patients with a neurological phenotype so-far described with mutations in this gene were reported to demonstrate cutaneous involvement. OBSERVATIONS: We present a family segregating a heterozygous pathogenic mutation in IFIH1 showing dermatological involvement as a prominent feature, variably associated with neurological disturbance and premature tooth loss. All three affected individuals exhibited increased expression of interferon stimulated genes in whole blood, and the mutant protein resulted in enhanced interferon signalling in vitro, both in the basal state and following ligand stimulation. CONCLUSIONS AND RELEVANCE: Our results further extend the phenotypic spectrum associated with mutations in IFIH1, indicating that the disease can be predominantly confined to the skin, whilst also highlighting phenotypic overlap with both Aicardi-Gouti�res syndrome and Singleton-Merten syndrome. This article is protected by copyright. All rights reserved.
Claudia Gunther - One of the best experts on this subject based on the ideXlab platform.
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Type I Interferon Signature in Chilblain-Like Lesions Associated with the COVID-19 Pandemic.
Dermatopathology (Basel Switzerland), 2020Co-Authors: Roland Aschoff, Nick Zimmermann, Stefan Beissert, Claudia GuntherAbstract:Contemporarily to the new SARS-CoV-2 mediated COVID-19 pandemic, a rise in patients with acral Chilblain lesions has been described. They manifest late after mild disease or asymptomatic exposure to SARS-CoV-2. Their pathogenic evolution is currently unknown. In biopsies from three patients with acral partially ulcerating Chilblain lesions that occurred associated to the COVID-19 pandemic, we analysed the expression of type I interferon induced proteins and signal transduction kinases. Histology demonstrated perivascular and periadnexal lymphohistiocytic infiltrates and endothelial dominated MxA-staining, as well as pJAK1 activation. Our findings demonstrate induction of the type I IFN pathway in lesional sections of COVID-19-associated Chilblain-like lesions. This may indicate a local antiviral immune activation status associated with preceding exposure to SARS-CoV-2.
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assessment of clinical response to janus kinase inhibition in patients with familial Chilblain lupus and trex1 mutation
JAMA Dermatology, 2019Co-Authors: Nick Zimmermann, Christine Wolf, Min Ae Leekirsch, Kerstin Engel, Reiner Schwenke, Anne Luth, Franziska Schmidt, Claudia GuntherAbstract:Importance Familial Chilblain lupus is a monogenic autosomal dominant form of cutaneous lupus erythematosus that in most cases is caused by mutations in the 3 prime repair exonuclease 1 (TREX1). Familial Chilblain lupus presents in early childhood with cold-induced painful erythematous infiltrates leading to mutilation and is associated with systemic involvement illustrated by an elevated type I interferon (IFN) signature in the skin and blood. Effective treatment is currently not available. Objectives To evaluate the clinical response to the Janus kinase inhibitor baricitinib in familial Chilblain lupus and assess the effect of cold on patient fibroblasts. Design, Setting, and Participants In this case series, 3 patients with familial Chilblain lupus due toTREX1mutation underwent treatment with baricitinib for 3 months. Interventions Doses of baricitinib, 4 mg, were administered daily for 3 months. Main Outcomes and Measures Reduction of cutaneous lupus lesions was measured by the revised cutaneous lupus area and severity index, pain due to skin and joint involvement was assessed by visual analog scale, type I IFN signature in blood was determined by polymerase chain reaction, and the in vitro response of fibroblasts to cold exposure was analyzed. Results All 3 patients (2 women and 1 man; mean [SD] age, 51 [24] years) showed a significant improvement of cutaneous lupus lesions with suppression of systemic type I IFN activation. One patient had a complete remission regarding pain and, in 2 patients, pain associated with joint inflammation was partially reduced. No severe adverse reactions were reported. Exposure of patient fibroblasts to cold induced a stress response and enhanced senescence along with induction of IFN-stimulated gene in vitro. Conclusions and Relevance These findings demonstrate the therapeutic efficacy of Janus kinase inhibition in a monogenic form of lupus among 3 patients and provide mechanistic insight into the process of disease exacerbation by cold inTREX1-deficient cells. This finding may be relevant to other type I IFN–mediated disorders and implicates Janus kinase inhibition as a potential therapeutic option also for multifactorial cutaneous lupus erythematosus.
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familial Chilblain lupus due to a novel mutation in the exonuclease iii domain of 3 repair exonuclease 1 trex1
JAMA Dermatology, 2015Co-Authors: Claudia Gunther, Nicole Berndt, Christine Wolf, Min Ae LeekirschAbstract:Importance Familial Chilblain lupus is a rare, autosomal dominant form of lupus erythematosus characterized by cold-induced inflammatory lesions at acral locations presenting in early childhood. Familial Chilblain lupus is usually caused by a mutation inTREX1(3′ repair exonuclease 1). Observations We report on a family with dominant Chilblain lupus segregating a novelTREX1mutation (c.585C>G; H195Q) within the highly conserved exonuclease (Exo) III domain. Affected family members experienced cold-induced Chilblain lesions of varying degrees, ranging from bluish-red infiltrations to mutilating necrotic ulcerations. In addition, all patients showed signs of systemic disease, such as arthritis, lymphopenia, or antinuclear antibodies. An increased expression of myxovirus resistance protein A in the skin and induction of interferon-stimulated genes in peripheral blood cells demonstrated activation of type I interferon. Conclusions and Relevance This case further implicates type I interferon–dependent innate immune activation in the pathogenesis ofTREX1-associated familial Chilblain lupus. Unlike previously reportedTREX1mutations, which affect the Exo I or Exo II domains, the mutation presented here alters the Exo III domain, suggesting a particular role of mutations within the catalytic Exo domains in the pathogenesis of familial Chilblain lupus. The high prevalence of extracutaneous manifestations, along with activation of type I interferon, underlines the systemic nature of familial Chilblain lupus.
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Familial Chilblain lupus--a monogenic form of cutaneous lupus erythematosus due to a heterozygous mutation in TREX1.
Dermatology (Basel Switzerland), 2009Co-Authors: Claudia Gunther, Michael Meurer, A. Stein, A. Viehweg, Min Ae Lee-kirschAbstract:Chilblain lupus erythematosus is a rare form of cutaneous lupus erythematosus characterized by bluish red infiltrates in acral locations of the body mostly affecting middle-aged women. We recently described a familial form of Chilblain lupus manifesting in early childhood caused by a heterozygous mutation in the TREX1 gene, which encodes a 3'-5' DNA exonuclease. Thus, familial Chilblain lupus represents the first monogenic form of cutaneous lupus erythematosus. Here we describe the unusual clinical course of this newly defined genodermatosis in an 18-year-old female member of the family in which familial Chilblain lupus was originally described.
Min Ae Leekirsch - One of the best experts on this subject based on the ideXlab platform.
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assessment of clinical response to janus kinase inhibition in patients with familial Chilblain lupus and trex1 mutation
JAMA Dermatology, 2019Co-Authors: Nick Zimmermann, Christine Wolf, Min Ae Leekirsch, Kerstin Engel, Reiner Schwenke, Anne Luth, Franziska Schmidt, Claudia GuntherAbstract:Importance Familial Chilblain lupus is a monogenic autosomal dominant form of cutaneous lupus erythematosus that in most cases is caused by mutations in the 3 prime repair exonuclease 1 (TREX1). Familial Chilblain lupus presents in early childhood with cold-induced painful erythematous infiltrates leading to mutilation and is associated with systemic involvement illustrated by an elevated type I interferon (IFN) signature in the skin and blood. Effective treatment is currently not available. Objectives To evaluate the clinical response to the Janus kinase inhibitor baricitinib in familial Chilblain lupus and assess the effect of cold on patient fibroblasts. Design, Setting, and Participants In this case series, 3 patients with familial Chilblain lupus due toTREX1mutation underwent treatment with baricitinib for 3 months. Interventions Doses of baricitinib, 4 mg, were administered daily for 3 months. Main Outcomes and Measures Reduction of cutaneous lupus lesions was measured by the revised cutaneous lupus area and severity index, pain due to skin and joint involvement was assessed by visual analog scale, type I IFN signature in blood was determined by polymerase chain reaction, and the in vitro response of fibroblasts to cold exposure was analyzed. Results All 3 patients (2 women and 1 man; mean [SD] age, 51 [24] years) showed a significant improvement of cutaneous lupus lesions with suppression of systemic type I IFN activation. One patient had a complete remission regarding pain and, in 2 patients, pain associated with joint inflammation was partially reduced. No severe adverse reactions were reported. Exposure of patient fibroblasts to cold induced a stress response and enhanced senescence along with induction of IFN-stimulated gene in vitro. Conclusions and Relevance These findings demonstrate the therapeutic efficacy of Janus kinase inhibition in a monogenic form of lupus among 3 patients and provide mechanistic insight into the process of disease exacerbation by cold inTREX1-deficient cells. This finding may be relevant to other type I IFN–mediated disorders and implicates Janus kinase inhibition as a potential therapeutic option also for multifactorial cutaneous lupus erythematosus.
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familial Chilblain lupus due to a novel mutation in the exonuclease iii domain of 3 repair exonuclease 1 trex1
JAMA Dermatology, 2015Co-Authors: Claudia Gunther, Nicole Berndt, Christine Wolf, Min Ae LeekirschAbstract:Importance Familial Chilblain lupus is a rare, autosomal dominant form of lupus erythematosus characterized by cold-induced inflammatory lesions at acral locations presenting in early childhood. Familial Chilblain lupus is usually caused by a mutation inTREX1(3′ repair exonuclease 1). Observations We report on a family with dominant Chilblain lupus segregating a novelTREX1mutation (c.585C>G; H195Q) within the highly conserved exonuclease (Exo) III domain. Affected family members experienced cold-induced Chilblain lesions of varying degrees, ranging from bluish-red infiltrations to mutilating necrotic ulcerations. In addition, all patients showed signs of systemic disease, such as arthritis, lymphopenia, or antinuclear antibodies. An increased expression of myxovirus resistance protein A in the skin and induction of interferon-stimulated genes in peripheral blood cells demonstrated activation of type I interferon. Conclusions and Relevance This case further implicates type I interferon–dependent innate immune activation in the pathogenesis ofTREX1-associated familial Chilblain lupus. Unlike previously reportedTREX1mutations, which affect the Exo I or Exo II domains, the mutation presented here alters the Exo III domain, suggesting a particular role of mutations within the catalytic Exo domains in the pathogenesis of familial Chilblain lupus. The high prevalence of extracutaneous manifestations, along with activation of type I interferon, underlines the systemic nature of familial Chilblain lupus.
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Chilblain lupus erythematosus a review of literature
Clinical Rheumatology, 2008Co-Authors: Christian M Hedrich, Min Ae Leekirsch, Christiane Pfeiffer, B Fiebig, Fabian Hauck, S Sallmann, G Hahn, G Heubner, M. GahrAbstract:Chilblain lupus erythematosus (CHLE) is a rare, chronic form of cutaneous lupus erythematosus. Sporadic cases and two families with autosomal dominant-inherited CHLE have been reported. In familial CHLE, two missense mutations in TREX1 encoding the 3'-5' repair exonuclease 1 were described in affected individuals. The pathogenesis of sporadic CHLE remains unknown. Up to 20% of patients develop systemic lupus erythematosus (SLE). An association with anorexia is discussed. In many cases, there is good response to symptomatic therapy. SLE therapeutics have good effects on SLE-typical symptoms but not on Chilblains themselves. This article reviews the clinical presentation, pathogenesis, diagnosis and treatment of CHLE. As an index patient with unique features, we report a 13-year-old boy developing CHLE after anorexia nervosa. Sequencing of TREX1 was normal. With psychotherapeutic support for anorexia and after antibiotic therapy, topical steroids, physical warming and calcium channel blockers, the patient experienced significant relief. Improvement of phalangeal perfusion was demonstrated by angio-MRI.
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mutations in the gene encoding the 3 5 dna exonuclease trex1 are associated with systemic lupus erythematosus
Nature Genetics, 2007Co-Authors: Min Ae Leekirsch, Dipanjan Chowdhury, Lydia Senenko, Kerstin Engel, Maolian Gong, Youngae Lee, Udesh De Silva, Suzanna L Bailey, Torsten WitteAbstract:TREX1 acts in concert with the SET complex in granzyme A–mediated apoptosis, and mutations in TREX1 cause Aicardi-Goutieres syndrome and familial Chilblain lupus. Here, we report monoallelic frameshift or missense mutations and one 3′ UTR variant of TREX1 present in 9/417 individuals with systemic lupus erythematosus but absent in 1,712 controls (P = 4.1 × 10−7). We demonstrate that two mutant TREX1 alleles alter subcellular targeting. Our findings implicate TREX1 in the pathogenesis of SLE.
Ac Bursztejn - One of the best experts on this subject based on the ideXlab platform.
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unusual cutaneous features associated with a heterozygous gain of function mutation in ifih1 overlap between aicardi goutieres and singleton merten syndromes
British Journal of Dermatology, 2015Co-Authors: Ac Bursztejn, Tracy A Briggs, Y Del Toro Duany, Beverley Anderson, James Osullivan, Simon G Williams, C Bodemer, S Fraitag, F Gebhard, B LeheupAbstract:Cutaneous lesions described as Chilblain lupus occur in the context of familial Chilblain lupus or Aicardi-Goutieres syndrome. To date, seven genes related to Aicardi-Goutieres syndrome have been described. The most recently described encodes the cytosolic double-stranded RNA receptor IFIH1 (also known as MDA5), a key component of the antiviral type I interferon-mediated innate immune response. Enhanced type I interferon signalling secondary to gain-of-function mutations in IFIH1 can result in a range of neuroinflammatory phenotypes including classical Aicardi-Goutieres syndrome. It is of note that none of the patients with a neurological phenotype so far described with mutations in this gene was reported to demonstrate cutaneous involvement. We present a family segregating a heterozygous pathogenic mutation in IFIH1 showing dermatological involvement as a prominent feature, variably associated with neurological disturbance and premature tooth loss. All three affected individuals exhibited increased expression of interferon-stimulated genes in whole blood, and the mutant protein resulted in enhanced interferon signalling in vitro, both in the basal state and following ligand stimulation. Our results further extend the phenotypic spectrum associated with mutations in IFIH1, indicating that the disease can be confined predominantly to the skin, while also highlighting phenotypic overlap with both Aicardi-Goutieres syndrome and Singleton-Merten syndrome.
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unusual cutaneous features associated with a heterozygous gain of function mutation in ifih1 overlap between aicardi goutieres and singleton merten syndromes
British Journal of Dermatology, 2015Co-Authors: Ac Bursztejn, Tracy A Briggs, Beverley Anderson, James Osullivan, Simon G Williams, C Bodemer, S Fraitag, F Gebhard, Y Del Toro Duany, B LeheupAbstract:BACKGROUND: Cutaneous lesions described as Chilblain lupus occur in the context of familial Chilblain lupus or Aicardi-Gouti�res syndrome. To date, seven Aicardi-Gouti�res syndrome-related genes have been described. The most recently described encodes the cytosolic double-stranded RNA receptor IFIH1 (MDA5), a key component of the antiviral type I interferon-mediated innate immune response. Enhanced type I interferon signalling secondary to gain-of-function mutations in IFIH1 can result in a range of neuroinflammatory phenotypes including classical Aicardi-Gouti�res syndrome. It is of note that none of the patients with a neurological phenotype so-far described with mutations in this gene were reported to demonstrate cutaneous involvement. OBSERVATIONS: We present a family segregating a heterozygous pathogenic mutation in IFIH1 showing dermatological involvement as a prominent feature, variably associated with neurological disturbance and premature tooth loss. All three affected individuals exhibited increased expression of interferon stimulated genes in whole blood, and the mutant protein resulted in enhanced interferon signalling in vitro, both in the basal state and following ligand stimulation. CONCLUSIONS AND RELEVANCE: Our results further extend the phenotypic spectrum associated with mutations in IFIH1, indicating that the disease can be predominantly confined to the skin, whilst also highlighting phenotypic overlap with both Aicardi-Gouti�res syndrome and Singleton-Merten syndrome. This article is protected by copyright. All rights reserved.
Gillian I. Rice - One of the best experts on this subject based on the ideXlab platform.
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human disease phenotypes associated with mutations in trex1
Journal of Clinical Immunology, 2015Co-Authors: Gillian I. Rice, Yanick J Crow, Mathieu P RoderoAbstract:Considering that it is a single exon gene encoding a 314 amino acid protein, the genotype-phenotype landscape of TREX1 is remarkably complex. Here we briefly describe the human diseases so-far associated with mutations in TREX1, which include Aicardi-Goutieres syndrome, familial Chilblain lupus, systemic lupus erythematosus and retinal vasculopathy with cerebral leukodystrophy.
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Chilblains as a diagnostic sign of aicardi-goutières syndrome.
Neuropediatrics, 2010Co-Authors: Ghada M.h. Abdel-salam, G. Y. El-kamah, Gillian I. Rice, M. El-darouti, Hannah Gornall, Marcin Szynkiewicz, F. Aymard, Maha S. Zaki, A. K. Abdel-aleem, Pierre LebonAbstract:Aicardi-Goutieres syndrome (AGS) is a genetically heterogeneous disorder showing variability in age of onset and clinical features. Chilblain lesions have been described in AGS patients and recent papers have discussed the clinical, molecular and cutaneous histopathological overlap with Chilblain lupus. Here we report on 2 unrelated children with AGS and Chilblain lesions, whose clinical histories and examination findings well illustrate the wide phenotypic variability that can be seen in this pleiotropic disorder. Although both patients show remarkable similarity in the histopathology of their associated skin lesions, with thrombi formation, fat necrosis and hyalinization of the subcutaneous tissue, we note that the histopathology reported in other AGS cases with Chilblains does not necessarily demonstrate this same uniformity. Our findings highlight the significant role of the characteristic Chilblain skin lesions in the diagnosis of AGS, and variability in the associated histopathology which may relate to the stage and severity of the disease.
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Cutaneous histopathological findings of Aicardi-Goutières syndrome, overlap with Chilblain lupus.
Journal of cutaneous pathology, 2008Co-Authors: Athanassios Kolivras, Gillian I. Rice, Yanick J Crow, Alec Aeby, Ursula Sass, Josette AndréAbstract:We report a 2-year-old girl with developmental delay who, from the age of 1 year, developed perniotic lesions of the hands and feet initially diagnosed as Chilblain lupus. Histological examination showed features of epidermal necrosis with intraepidermal bulla formation, interface dermatitis, lymphocytic vasculitis with fibrinoid necrosis and thrombi formation, both superficial and deep dermal lymphocytic infiltrate, lymphocytic eccrine hidradenitis and absence of marked dermal edema. Subsequent investigations suggested a clinical diagnosis of Aicardi-Goutieres syndrome (AGS), a rare genetic leukoencephalopathy. Recently, both AGS and familial Chilblain lupus, an autosomal dominant form of systemic lupus erythematosus (SLE), have been shown to be allelic thus suggesting a common pathogenic basis. In addition, a phenotypic overlap is apparent between SLE and AGS. To our knowledge, this is the first comprehensive dermatopathological report of the cutaneous lesions seen in AGS, and our paper highlights the importance of considering AGS in the differential diagnosis of perniosis and Chilblain lupus.
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heterozygous mutations in trex1 cause familial Chilblain lupus and dominant aicardi goutieres syndrome
American Journal of Human Genetics, 2007Co-Authors: Gillian I. Rice, Thomas Hollis, Scott Harvey, William G Newman, John Dean, Teresa Patrick, Rekha Parmar, Kim Flintoff, Peter Robins, Ann OharaAbstract:TREX1 constitutes the major 3′→5′ DNA exonuclease activity measured in mammalian cells. Recently, biallelic mutations in TREX1 have been shown to cause Aicardi-Goutieres syndrome at the AGS1 locus. Interestingly, Aicardi-Goutieres syndrome shows overlap with systemic lupus erythematosus at both clinical and pathological levels. Here, we report a heterozygous TREX1 mutation causing familial Chilblain lupus. Additionally, we describe a de novo heterozygous mutation, affecting a critical catalytic residue in TREX1, that results in typical Aicardi-Goutieres syndrome.