Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: Aicardi-Goutières-Singleton-Merten overlapping syndrome.

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Abstract

BACKGROUND: Cutaneous lesions described as chilblain lupus occur in the context of familial chilblain lupus or Aicardi-Goutières syndrome. To date, seven Aicardi-Goutières 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-Goutières 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-Goutières syndrome and Singleton-Merten syndrome. This article is protected by copyright. All rights reserved.

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