Ethnic Genotype: Phenotype Correlation and Treatment of DADA2. A Single-center Cohort

Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive disorder caused by loss-of-function mutations in the ADA2 gene, with a broad phenotype spanning systemic vasculitis, hematologic, immune deficiency, and autoinflammatory manifestations.

To describe a decade of DADA2 management within a uniquely diverse population.

We conducted a single-center retrospective cohort study of genetically confirmed DADA2 patients (2014-2024). Demographics, clinical manifestations, laboratory findings, treatments, and long-term outcomes were reviewed.

Seventeen pediatric patients were included from two ethnic groups: Arab Muslim (12/17, 70%) and Georgian Jewish (5/17, 29%). The median age at symptom onset was 3.5 months and at diagnosis 4 years. Phenotypes were purely vasculitic/inflammatory (5/17), purely hematologic (3/17), mixed hematologic-inflammatory (6/17), or mixed hematologic-immunodeficiency (3/17). None had isolated immune deficiency. The purely vasculitic/inflammatory phenotype was confined to Georgian Jewish patients, all homozygous for p.Gly47Arg, presenting with cutaneous and ischemic manifestations. Twelve patients received TNF-α inhibitors: 9 achieved complete response, 1 partial, and 2 none, with no subsequent strokes. Arab patients more often presented with fever, red cell aplasia, cytopenias, and immunodeficiency at younger ages. Three patients underwent hematopoietic stem cell transplantation (HSCT). Two responded favorably, one died of infection-related complications after engraftment.

We observed a distinct, ethnicity-driven genotype-phenotype correlation: Georgian Jewish patients with homozygous p.Gly47Arg had a pure vasculitic/inflammatory phenotype responsive to TNF-α inhibitors, whereas Arab patients harbored heterogeneous variants with hematologic/ immune deficiency phenotype potentially benefiting from HSCT. Early, genetically informed diagnosis and phenotype-driven, multidisciplinary management are essential to improve outcomes.