Genotype and Phenotype of Adenosine Deaminase 2 Deficiency: The Experience From Saudi Arabia

Abstract PurposeDADA2 is a rare and potentially fatal systemic autoinflammatory disease characterized by reduced or absence of ADA2 enzyme activity resulting from mutations in the ADA2 gene. Symptoms of DADA2 are variable and include vasculitis, immune dysregulation, and cytopenia. Scattered Saudi cases of DADA2 have been reported. We describe clinical, molecular, and outcome characterization of Saudi cases focused on phenotypic variability of DADA2.Methods To summarize the clinical features of Saudi patients with DADA2, we conducted a retrospective observational study in the seven major tertiary medical centers. Analysis of clinical characteristics, diagnostic findings, and treatment outcomes was obtained.ResultsWe identified 21 individuals with DADA2 from 14 families. At the time of the study, the patient's age was between 4 and 26 years (median age of 11.3 years). 20 patients presented during childhood. Homozygous c1447-1451del of ADA2 was the most frequently observed mutation in 38%, followed by c882-2A: G in 29%. Absent ADA2 activity was identified in all tested patients with homozygous mutations. Phenotypic manifestations included vasculopathy (stroke or cutaneous lesion) in 48%, cytopenia in 95%, autoinflammatory features such as intermittent fever, transaminases, and hepatosplenomegaly, and or immunodeficiency in 71% of the patients. 4 patients presented with Hodgkin lymphoma and one patient presented with clinical features mimic transverse myelitis, adding to the clinical spectrum of DADA2. Anti-tumor necrosis factor (anti-TNF) is the main treatment. However, regular blood transfusion, splenectomy, cyclosporine, and hematopoietic stem cell transplant (HSCT) were initiated in other patients because of anti-TNF failure. Morality was reported in 3 patients due to fulminant hepatitis and septic multi-organ failure.ConclusionOur cohort expands the variability of molecular and clinical characteristics of DADA2. Hematological phenotype predominates in the patients. Consensus diagnostic criteria are required to facilitate early diagnosis and initiation of prompt therapy. Evaluation of the rare disease complications such as cancer needs large prospective studies or disease registries