Name: Adenosine deaminase 2 deficiency | Acronym: DADA2
Alt. names: Deficiency of ADA2 | Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome

Gene: ADA2 | MOI: Autosomal recessive | Mechanism of action: Loss of Function

No. of cases in DB: 108 | First reported in: 2014

Last updated on: 2024-07-28 22:31:35 by Xiao P. Peng

OMIM: 615688

Orphanet: 404553

MONDO: 0014306

DOID: -

ClinGen:

DADA2 is a complex systemic autoinflammatory disorder in which vasculopathy/vasculitis, dysregulated immune function, and/or hematologic abnormalities may predominate. Inflammatory features include intermittent fevers, rash (often livedo racemosa/reticularis), and musculoskeletal involvement (myalgia/arthralgia, arthritis, myositis). Vasculitis, which usually begins before age ten years, may manifest as early-onset ischemic (lacunar) and/or hemorrhagic strokes, or as cutaneous or systemic polyarteritis nodosa. Hypertension and hepatosplenomegaly are often found. More severe involvement may lead to progressive central neurologic deficits (dysarthria, ataxia, cranial nerve palsies, cognitive impairment) or to ischemic injury to the kidney, intestine, and/or digits. Dysregulation of immune function can lead to immunodeficiency or autoimmunity of varying severity; lymphadenopathy may be present and some affected individuals have had lymphoproliferative disease. Hematologic disorders may begin early in life or in late adulthood, and can include lymphopenia, neutropenia, pure red cell aplasia, thrombocytopenia, or pancytopenia. Of note, both interfamilial and intrafamilial phenotypic variability can be observed and some individuals may remain asymptomatic until adulthood or may never develop clinical manifestations of DADA2. Labs are notable for upregulation of several key pro-inflammatory cytokines, prominently TNF-α, whose secretion is thought to arise from pro-inflammatory macrophages and chronically activated neutrophils, which may explain the efficacy of TNF-α inhibition in DADA2 patients, especially those with vasculitic and hematologic complications (PMID: 30995379, 32845415). However, patients also show increased type I IFN production along with upregulation of type I ISGs, as well as elevated levels of IL-6, IL-8, and IL-10, while immunophenotyping may show reduced memory B cells, as well as NK, NKT, and CD16-positive monocytes (PMID: 32845415, 34657246).

Anti-TNF agents (etanercept, adalimumab, golimumab, infliximab, certolizumab) are firstline choice for symptomatic and asymptomatic individuals with biallelic ADA2 pathogenic variants. They prevent and eliminate manifestations of autoinflammatory disease / vasculitis, reduce the risk of ischemic stroke, reduce inflammatory burden, and relieve immunodeficiency, hepatosplenomegaly, and neutropenia. Anti-TNF agents also improve growth and development in affected children, and red blood cell and platelet counts; however, anti-TNF agents appear to have little effect in rescuing severe bone marrow abnormalities, which may require hematopoietic stem cell transplant (HSCT). HSCT can be curative in individuals in whom bone marrow failure and/or immune dysregulation predominate, and who fail to respond to TNF inhibitor treatment. Successful HSCT returns plasma ADA2 activity to normal levels. In one study the hematologic and immunologic phenotype resolved post HSCT in all 14 patients with bone marrow dysfunction or immunodeficiency (6 of whom also had vasculitis); however, acute and moderate chronic autoimmunity and graft-versus-host disease were reported (PMID: 28974505).