Deficiency of Adenosine Deaminase Type 2: A Description of Phenotype and Genotype in Fifteen Cases

Abstract

Objective. To describe the clinical features, genotype, and treatment in a series of subjects with confirmed adenosine deaminase 2 (ADA2) deficiency.Methods. All symptomatic subjects were referred for genetic testing for suspected ADA2 deficiency; relatives of index cases were also screened. Demographic, clinical, and laboratory characteristics and treatments were recorded. Genetic analyses included whole-exome sequencing in 4 subjects and Sanger sequencing of CECR1 (the gene for cat eye syndrome chromosome region candidate 1) in all subjects. Assays for ADA2 enzyme activity and quantitative polymerase chain reaction analysis of CECR1 messenger RNA (mRNA) were also performed.Results. We identified 15 subjects with ADA2 deficiency, 5 of whom were asymptomatic (relatives of index cases; ages 5-42 years). Homozygous or compound heterozygous mutations in CECR1 were identified in all subjects. Phenotypic manifestations in the patients with symptomatic ADA2 deficiency included livedo racemosa (73.3%), neurologic involvement (53.3%), and immunodeficiency (46.7%). CECR1 mRNA expression in 8 subjects, including 5 who were presymptomatic, was significantly lower than in healthy controls (P 5 0.0016). Subjects with ADA2 deficiency (with or without symptoms) also had lower ADA2 enzyme activity compared to healthy pediatric controls (P < 0.0001) and patients with sporadic (nonfamilial) childhood polyarteritis nodosa (PAN) without CECR1 mutation (P 5 0.0108). Anti2tumor necrosis factor therapy was required in 9 of the 10 symptomatic subjects.Conclusion. The clinical manifestations of ADA2 deficiency ranged in severity from limited cutaneous involvement to severe multisystemic vasculitis; one-third of our cases (5 of 15) were currently asymptomatic, and required close monitoring. We recommend CECR1 screening for unaffected siblings of index cases, cases of familial vasculitis, and cases of PAN that is resistant to standard treatment.

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

“…Patients homozygous for this mutation have variable age at presentation, intensity and spectrum of symptoms. There is another report on the variable disease penetrance in a large Iraqi family . Thus, other factors, epigenetic or environmental, may influence disease expressivity.…”

Adenosine Deaminase Two and Immunoglobulin M Accurately Differentiate Adult Sneddon’s Syndrome of Unknown Cause

“…An extremely low, or even absent, activity of ADA2 in paediatric patients with DADA2 had previously been shown in other studies [13][14][15]. These authors have previously shown a statistically significant difference between ADA2 activity in DADA2 patients in comparison to HC, but the relation with sporadic patients exhibiting a similar clinical phenotype was not tested.…”

“…Notwithstanding, these findings should be confirmed in larger multicentre studies, that would encompass both adult and paediatric DADA2 patients. As other authors have reported, ADA2 activity might be lower in adults that in children [4,14] and an age-adjusted cut-off value would probably be needed. In our study, as in the study of Schepp et al [19], there was no evidence of an influence of the position and type of mutation on ADA2 enzymatic activity.…”

“…These results are particularly relevant, since recent observational studies have reported that some drugs (anti-TNF-α with or without daily prednisolone and/or an alternative disease modifying anti-rheumatic drug) [14] seem to be effective, and hematopoietic stem cell transplantation might represent a potential definitive treatment for DADA2 [16].…”

“…Other studies have reported on ADA2 activity in CECR1 single-mutation carriers, and while some authors showed a reduction to approximately half [4,19] other reported no difference in relation to HCs [5,14]. Meanwhile, for serum IgM levels, at the best cut-off of 0.92 g/L, AUC was 0.647 (p = 0.225, 95% CI 0.386-0.908), with a sensitivity of 67.6%, and specificity of 71.4 %, which suggests that this test does not accurately identify CECR1 heterozygous.…”