Session Title: Pediatric Rheumatology – Pathogenesis and Genetics Poster
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Deficiency of adenosine deaminase 2 (DADA2) is a recently recognized, autosomal recessive genetic disease. Patients present with various, early-onset systemic vascular and inflammatory manifestations, and often recurrent strokes. The clinical features and histological findings of DADA2 overlap with those of early childhood onset polyarteritis nodosa (PAN), a primary “idiopathic” systemic vasculitis, characterized by necrotizing inflammatory lesions of small and medium-sized vessels. Despite similar clinical presentation, individuals with PAN and DADA2 may benefit from different therapy. While treatment of primary chronic vasculitis is usually with toxic immunosuppressive drugs, there has been clinical indication that DADA2 patients respond better to less toxic IL-6 receptor antagonists and anti-TNFα therapy. We aimed to screen patients with PAN, cutaneous PAN, unclassifiable phenotype, or chronic vasculitis of any type with onset-age less than 5 years for variants in adenosine deaminase 2 (ADA2).
Of the 493 pediatric patients included in our international, multi-ethnic cohort, ARChive (A Registry of Childhood Vasculitis), there were 99 patients who provided DNA samples, and 41 of these fulfilled screening criteria. We sequenced the coding exons of ADA2 in these 41 patients. Identified variants in ADA2 were characterized by quantifying their effect on ADA2 expression, secretion, and enzymatic activity by qPCR, standard ELISA, and kinetic colorimetric assays, respectively. RNA sequencing of whole blood was done to enable transcriptomic profiling of patients with DADA2 versus PAN and other types of chronic vasculitis.
We have identified variants in ADA2 with known and novel association with DADA2; four patients were found to be homozygous or compound heterozygous for rare (MAF < 0.01), predicted pathogenic variants. An additional two patients were found to be heterozygous for rare, missense variants; further analysis of expression and enzymatic activity may guide the identification of additional pathogenic variants that could contribute to the observed phenotype.
At present, the gold standard for direct diagnosis of vasculitis is histopathological examination of biopsy specimens from involved organs. Screening ADA2 among patients with possible early-onset chronic vasculitis or PAN phenotype may identify and diagnose patients, perhaps without requirement for biopsy. Early diagnosis of DADA2 patients may spare them treatment with toxic systemic immunosuppressive drugs, and allow more effective intervention with targeted biologic and/or gene therapy.
This work was supported by a Canadian Institutes of Health Research grant for the PedVas Initiative [TR2-119188 to DAC].
To cite this abstract in AMA style:Gibson K, Cabral D, Drogemoller B, Xhan X, Miao F, Morishita K, Gill E, Hancock REW, Ross C, Brown K. Characterization of Adenosine Deaminase 2 Variants Identified in an International Pediatric Vasculitis Cohort [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/characterization-of-adenosine-deaminase-2-variants-identified-in-an-international-pediatric-vasculitis-cohort/. Accessed September 29, 2020.
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