Diagnosing DADA2
Approach - The diagnosis of DADA2 should be suspected in children and young adults who present with polyarteritis nodosa (PAN) like vasculitis and ischemic or hemorrhagic stroke, especially in the presence of livedo racemosa or livedo reticularis, systemic inflammation, cytopenia’s, and hypogammaglobulinemia. It is confirmed by genetic studies that identify two deleterious ADA2 mutations or by a biochemical assay that demonstrates near-absent levels of ADA2 activity in the plasma or serum. The choice of testing for DADA2 is based on urgency and availability.
One approach used by some physicians is to measure plasma ADA2 activity to rule in or rule out DADA2 and then to arrange genetic studies to confirm the diagnosis. An alternate approach is to screen with genetic panels containing multiple immune dysregulatory inborn errors of metabolism genes. Given the recessive pattern of inheritance and incomplete penetrance, in addition to reports of symptomatic carriers, screening all siblings of patients with confirmed DADA2 is recommended, as well as any other family members with clinical features of the disease.
Genetic Testing — The ADA2 gene is included in many commercially available gene sequencing panels for periodic fever syndromes, primary immunodeficiencies and bone marrow failure. Most disease-associated ADA2 mutations are captured by targeted next-generation gene sequencing or by whole-exome sequencing. However, large deletions and complex chromosomal rearrangements can be missed by standard sequencing technology, and dedicated studies to analyze copy number variants such as multiplex ligation-dependent probe amplification may be necessary to resolve these cases.
Biochemical Assays — Measurement of ADA2 enzymatic activity can rapidly diagnose DADA2 on the basis of absent or near-absent activity in patient serum or plasma. ADA2 enzyme testing is useful to identify patients with DADA2 who do not have identifiable ADA2 mutations, who have one deleterious mutation, or who carry variants (mutations) of unknown significance. Patients with DADA2 exhibit minimal or no residual activity, while persons that are carriers for a deleterious mutation exhibit intermediate levels of enzymatic activity between patients with DADA2 and control. ADA2 enzyme testing is only performed by two labs in the U.S., one of which is for research purposes.
The DADA2 Foundation is working on a device that could be used in doctor's offices to check an ADA2 enzyme level in about 30 mins. If this project is successful, it will extensively decrease the time to diagnosis for many DADA2 patients around the world.
Differential Diagnosis
Learn more about this in the Disease Mimics section of Signs & Symptoms.
Stroke or peripheral vasculitis — DADA2 presenting as stroke or peripheral vasculitis engages a differential diagnosis that includes other forms of vasculitis such as Sneddon syndrome and polyarteritis nodosa (PAN):
- Sneddon syndrome is a rare thrombotic vasculopathy characterized by ischemic strokes and livedo racemosa that affect females between 20 to 40 years of age. Several cases of DADA2 were previously diagnosed as Sneddon syndrome; low IgM levels favor the diagnosis of DADA2.
- Compared with classic PAN, patients with DADA2 typically are younger (mean age of onset four to five years versus nine years of age), more frequently have neurologic involvement, and commonly have ancillary manifestations of DADA2 such as hypogammaglobulinemia and/or cytopenias.
- Some cases have striking resemblance to Behçet syndrome, and carriers who have ADA2 mutation have been reported in a cohort of patients with Behçet disease.
- Although autoimmunity is generally uncommon in DADA2, manifestations of antiphospholipid syndrome and systemic lupus erythematous including the characteristic interferon signature seen in lupus have been described.
Immunodeficiency — Humoral immune deficiencies are conditions which cause impairment of humoral immunity, which can lead to immunodeficiency. It can be mediated by insufficient number or function of B cells. Immunodeficiency in DADA2 can resemble common variable immunodeficiency (CVID). Patients with CVID have low IgG and one other low immunoglobulin (A or M), by definition.
Bone Marrow Failure — DADA2 presenting as pure red cell aplasia or resembling Diamond-Blackfan anemia (DBA).