Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutières and Singleton-Merten syndromes.
Cutaneous lesions described as chilblain lupus occur in the context of familial chilblain lupus or Aicardi-Goutières syndrome. To date, seven genes related to Aicardi-Goutières 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-Goutières 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-Goutières syndrome and Singleton-Merten syndrome.
Dermatology Department, CHU Nancy, 5 Allée du Morvan, 54500 Vandoeuvre les Nancy, France.
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Bursztejn
Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, U.K.
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TA
Briggs
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, U.S.A.
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del Toro Duany
Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, U.K.
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Anderson
Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, U.K.
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O'Sullivan
Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, U.K.
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Williams
Dermatology Department, Imagine Institute, APHP, Université Sorbonne-Paris Cité - Hôpital Necker-Enfants Malades, 149 Rue de Sèvres, 75743 Paris, France.
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Bodemer
Pathology Department, Hôpital Necker-Enfants Malades, APHP, Université Paris-Descartes, 149 Rue de Sèvres, 75743 Paris, France.
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Fraitag
Medical Office, 150 Rue de Nancy, 54390 Frouard, France.
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Gebhard
Paediatric and Clinical Genetic Department, CHU Nancy, 5 Allée du Morvan, 54500 Vandoeuvre les Nancy, France.
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Leheup
Paediatric Onco-Haematology Department, CHU Nancy, 5 Allée du Morvan, 54500 Vandoeuvre les Nancy, France.
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Lemelle
Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, U.K.
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Oojageer
Paediatric and Clinical Genetic Department, CHU Nancy, 5 Allée du Morvan, 54500 Vandoeuvre les Nancy, France.
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Raffo
Neuroradiology Department, CHU Nancy, 29 Avenue du Maréchal de Lattre de Tassigny, 54000 Nancy, France.
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Schmitt
Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, U.K.
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Rice
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, U.S.A.
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Hur
Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, U.K.|Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, 24 Boulevard du Montparnasse, 75015 Paris, France.
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Crow
D000328:Adult; D001018:Aortic Diseases / Q000235:genetics* / Q000473:pathology; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics* / Q000473:pathology; D002647:Chilblains / Q000235:genetics; D002675:Child, Preschool; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D003744:Dental Enamel Hypoplasia / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D007223:Infant; D000072640:Interferon-Induced Helicase, IFIH1; D008178:Lupus Erythematosus, Cutaneous / Q000235:genetics; D008297:Male; D008663:Metacarpus / Q000002:abnormalities* / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009422:Nervous System Diseases / Q000235:genetics; D009421:Nervous System Malformations / Q000235:genetics* / Q000473:pathology; D018126:Odontodysplasia / Q000235:genetics* / Q000473:pathology; D010024:Osteoporosis / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D012873:Skin Diseases, Genetic / Q000235:genetics* / Q000473:pathology; D016388:Tooth Loss / Q000235:genetics; D061205:Vascular Calcification / Q000235:genetics* / Q000473:pathology
C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1