Background/Purpose: The deficiency of adenosine deaminase 2 (DADA2) was initially described in 2014 in 2 reports: one emphasizing early-onset lacunar strokes, livedoid rash and intermittent fevers; the second focusing on patients with early-onset polyarteritis nodosa. Since then, there have been reports of antibody deficiency, pure red cell aplasia and cytopenias. We now present clinical follow-up on 38 patients evaluated at the National Institutes of Health (NIH).

Patients and Methods: All 38 patients were enrolled in an IRB approved study at the NIH. Sequencing of ADA2 (formerly known as CECR1), the gene encoding ADA2 (adenosine deaminase 2), was obtained on all patients. Clinical, laboratory, and radiographic testing were obtained at each visit.

Results: 35 patients had germline biallelic mutations in ADA2. In 3 symptomatic siblings with low ADA2 serum levels, only one mutation has been found thus far. Serum ADA2 levels were obtained in 32 patients. The mean level was 45.4% of age-matched controls (range 36.7-61.6%). 25/36 patients reported recurrent fevers. 24 (66%) patients had a history of at least one stroke, with 18 having ischemic strokes in small vessel distribution, 1 having only hemorrhagic strokes and 5 having both. The average age at the time of the first stroke was 6.2 years (range 5 months-24 years). The average number of strokes was 3 (range 1-11). Skin manifestations were found in 32 (84%) of patients and included livedo in 28, cutaneous polyarteritis nodosa in 22, and Raynaud’s in 8. Abdominal ultrasound revealed hepatomegaly in 18 patients (74%) and splenomegaly in 22 patients (58%). Portal hypertension was observed in 7 patients (18%). Abdominal MRA was abnormal in 7 patients, revealing arteritis and aneurysms. Significant peripheral vasculopathy was seen in 3 patients, one requiring amputation of gangrenous digits. Systemic hypertension was observed in 10 patients (26%), with one patient developing posterior reversible encephalopathy syndrome (PRES) in relation to hypertension. Prolonged QT was noted in 5 patients (13%).

Laboratory evaluation revealed hypogammaglobulinemia, especially IgM, in 27 patients (71%). Specific antibody response to vaccines were inadequate in 5 of 16 patients tested. Lymphocyte phenotyping revealed arrested B cell class switching in 22 of 26 patients (85%) tested. 25/38 (66%) demonstrated hematologic abnormalities including anemia, leukopenia, lymphopenia and/or thrombocytopenia with 7 patients developing pancytopenia and 1 patient with pure red cell aplasia. Three patients had bone marrow failure and underwent bone marrow transplantation, with two patients requiring a second transplant.

Conclusion: The spectrum of DADA2 continues to expand to include ischemic and hemorrhagic strokes, skin findings, portal and systemic hypertension, hematologic abnormalities, vascular pathology, immune deficiency and bone marrow failure. As the phenotypic presentation is likely to continue to expand, it is important to investigate any new complaints. In addition, it is important to monitor patients closely as their phenotypic presentation can change with time.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-expanding-clinical-spectrum-of-patients-with-deficiency-of-adenosine-deaminase-2-dada2/