Of note, these criteria may not apply to individuals who present with hematologic manifestations only. Among those with DADA2, more than 80% had a combination of a biomarker of inflammation (fever, elevated CRP), evidence of vasculitis (cutaneous, neurologic), and more than one clinical flare. Among 66 individuals who were clinically suspected of having DADA2 and underwent genetic analysis at a French referral center for autoinflammatory disorders, 13 individuals from 11 families (20%) were found to have biallelic ADA2 pathogenic variants. When the phenotypic and laboratory findings suggest the diagnosis of DADA2 molecular genetic testing approaches can include single- gene testing or use of a multigene panel. Because the phenotype of DADA2 is broad, individuals with some of the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of DADA2 has not been considered are more likely to be diagnosed using genomic testing (see Option 2). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing ( exome sequencing, exome array, genome sequencing) depending on the phenotype. Note: While both tests are diagnostic, molecular genetic testing is more widely available. The diagnosis of DADA2 is established in a proband with suggestive findings by identification of biallelic loss-of-function ADA2 pathogenic variants on molecular testing ( Table 1) and/or low (<5% of normal) or undetectable plasma ADA2 catalytic activity. Surveillance: Routine monitoring of clinical and laboratory aspects of DADA2.ДЄgents/Circumstances to avoid: Antiplatelet medications including aspirin anticoagulants (except in the presence of atrial fibrillation) and smoking, which may exacerbate peripheral arterial disease.Д®valuation 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. 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. They prevent and eliminate manifestations of autoinflammatory disease / vasculitis, reduce the risk of ischemic stroke, reduce inflammatory burden, and relieve immunodeficiency, hepatosplenomegaly, and neutropenia. 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. 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. Hematologic disorders may begin early in life or in late adulthood, and can include lymphopenia, neutropenia, pure red cell aplasia, thrombocytopenia, or pancytopenia. 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.

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. Hypertension and hepatosplenomegaly are often found. 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. Inflammatory features include intermittent fevers, rash (often livedo racemosa/reticularis), and musculoskeletal involvement (myalgia/arthralgia, arthritis, myositis). Adenosine deaminase 2 deficiency (DADA2) is a complex systemic autoinflammatory disorder in which vasculopathy/vasculitis, dysregulated immune function, and/or hematologic abnormalities may predominate.

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