Deficiency of adenosine deaminase type 2 (DADA2): A description of phenotype and genotype in 15 cases

OBJECTIVES: To describe the clinical features, genotype, and treatment of a series of subjects with confirmed Deficiency of Adenosine Deaminase 2 (DADA2) referred to Great Ormond Street Hospital NHS Foundation Trust (GOSH), London. Methods All symptomatic subjects were referred for genetic testing for suspected DADA2; relatives of index cases were also screened. The demographic, clinical, laboratory characteristics and treatments were recorded. Genetic analyses performed included whole-exome sequencing in 4 patients; and Sanger sequencing of Cat Eye Syndrome Chromosome Region Candidate 1 (CECR1) in all subjects. ADA2 enzyme activity assay, and quantitative PCR of CECR1 mRNA were also performed. Results We identified 15 subjects with DADA2; 5 subjects were asymptomatic (relatives of index cases; age 5-42 years). Homozygous or compound heterozygous mutations in CECR1 were identified in all subjects. The phenotypic manifestations of the symptomatic DADA2 patients included livedo racemosa (73.3%); neurologic involvement (53.3%); and immune deficiency (46.6%). CECR1 mRNA expression in 8 subjects, including five pre-symptomatic subjects was significantly lower than healthy controls (p=0.0016). DADA2 subjects (with or without symptoms) also had lower ADA2 enzyme activity compared to healthy paediatric controls (p<0.0001), and sporadic cases of childhood polyarteritis nodosa without CECR1 mutation (p=0.0108). Nine/10 symptomatic patients required anti-TNF-α therapy. Conclusion The clinical severity of DADA2 ranged from limited cutaneous to severe multi-systemic vasculitis; one third (5/15) of our cases were currently asymptomatic, and required close monitoring. We recommend CECR1 screening for: unaffected siblings of index cases; cases of familial vasculitis; and patients with polyarteritis nodosa recalcitrant to standard treatment. This article is protected by copyright. All rights reserved.