Adenosine Deaminase 2 Deficiency

Clinical characteristics: Adenosine deaminase 2 deficiency (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 (e.g., in age of onset, frequency and severity of manifestations) can be observed; also, individuals with biallelic ADA2 pathogenic variants may remain asymptomatic until adulthood or may never develop clinical manifestations of DADA2.

Diagnosis/testing: The diagnosis of DADA2 is established in a proband with suggestive clinical and laboratory findings and biallelic loss-of-function ADA2 pathogenic variants identified by molecular testing and/or low (<5% of normal) or undetectable ADA2 catalytic activity in plasma or serum.

Management: Treatment of manifestations: Anti-tumor necrosis factor (TNF) agents (etanercept, adalimumab, golimumab, infliximab, certolizumab) are the drugs of choice for both 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.

Surveillance: Routine monitoring of clinical and laboratory aspects of DADA2.

Agents/Circumstances to avoid: Antiplatelet medications including aspirin; anticoagulants (except in the presence of atrial fibrillation); and smoking, which may exacerbate peripheral arterial disease.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those with biallelic ADA2 pathogenic variants who are currently symptomatic and would benefit from prompt initiation of treatment and those who are currently asymptomatic and would benefit from treatment with anti-TNF agents to reduce the risk of stroke.

Genetic counseling: DADA2 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier (heterozygote), and a 25% chance of being unaffected and not a carrier. Once the ADA2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.