Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation

Abstract

Background: Loss-of-function CECR1 mutations cause polyarteritis nodosa (PAN) with childhood onset, an autoinflammatory disorder without significant signs of autoimmunity. Herein we describe the unusual presentation of an autoimmune phenotype with constitutive type I interferon activation in siblings with adenosine deaminase 2 (ADA2) deficiency.

Case presentation: We describe two siblings with early-onset recurrent strokes, arthritis, oral ulcers, discoid rash, peripheral vascular occlusive disease and high antinuclear antibody titers. Assessment of interferon signatures in blood revealed constitutive type I interferon activation. Aicardi-Goutières syndrome (AGS) was suspected, but no mutation in the known AGS genes were detected. Whole exome sequencing identified compound heterozygosity for a known and a novel mutation in the CECR1 gene. Functional consequences of the mutations were demonstrated by marked reduction in ADA2 catalytic activity.

Conclusions: Our findings demonstrate that ADA2 deficiency can cause an unusual autoimmune phenotype extending the phenotypic spectrum of PAN. Constitutive interferon I activation in patient blood suggests a possible role of type I interferon in disease pathogenesis which may have therapeutic implications.

Keywords: Adenosine deaminase 2; Antinuclear antibodies; CECR1; Hypergammaglobulinaemia; Interferon signature; Systemic lupus erythematosus.

Fig. 1

Clinical findings of the patients. a Livedo reticularis of patient 1. b, c, d Erythematous skin lesions of patient 2, which appear as discoid plaques or annular papules. e T2-weighted magnetic resonance image of the brain of patient 2 showing a recent ischemic lesion in the right thalamus and an older lesion in the left thalamus. f Blue finger syndrome due to vascular occlusion in patient 2

Fig. 2

Genetic and molecular findings. a Pedigree of the family with ADA2 deficiency. Solid symbols indicate affected persons, open symbols unaffected relatives, squares male persons, circles female persons. The amino acid changes are indicated next to the symbols. b The upper panel shows electropherograms with the two heterozygous CECR1 mutations, c.139G>C (p.Gly47Arg) and c.1223G>A (p-Cys408Tyr), identified in both siblings. The lower panels show alignments of ADA2 protein sequences from different species. The positions of the altered amino acid residues Gly47 and Cys408 are marked by arrows. Highly conserved regions are marked in red and less conserved regions are indicated in blue. c, d Expression of interferon-stimulated genes, IFI27, IFI44, IFI44L, IFIT1, ISG15, RSAD2 and SIGLEC1 in peripheral blood. Shown is the fold-change of the respective mRNA relative to the mean expression of 10 healthy controls