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Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutières and Singleton-Merten syndromes

Research output: Contribution to journalArticle

  • A-C Bursztejn
  • T A Briggs
  • Y del Toro Duany
  • B H Anderson
  • J O'Sullivan
  • S G Williams
  • C Bodemer
  • S Fraitag
  • F Gebhard
  • B Leheup
  • I Lemelle
  • A Oojageer
  • E Raffo
  • E Schmitt
  • G I Rice
  • S Hur
  • Y J Crow

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)1505-13
Number of pages9
JournalBritish journal of dermatology
Issue number6
StatePublished - Dec 2015


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.

    Research areas

  • Adult, Aortic Diseases, Autoimmune Diseases of the Nervous System, Chilblains, Child, Preschool, DEAD-box RNA Helicases, Dental Enamel Hypoplasia, Heterozygote, Humans, Infant, Interferon-Induced Helicase, IFIH1, Lupus Erythematosus, Cutaneous, Male, Metacarpus, Muscular Diseases, Mutation, Nervous System Diseases, Nervous System Malformations, Odontodysplasia, Osteoporosis, Phenotype, Skin Diseases, Genetic, Tooth Loss, Vascular Calcification, Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

ID: 59199454