A case series of ten plus one deficiency of adenosine deaminase 2 (DADA2) patients in Iran

Background: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disease caused by mutations in the ADA2 gene. DADA2 has a broad spectrum of clinical presentations. Apart from systemic manifestations, we can categorize most of the signs and symptoms of DADA2 into the three groups of vasculitis, hematologic abnormalities, and immunologic dysregulations. The most dominant vasculitis features are skin manifestations, mostly in the form of livedo racemosa/reticularis, and early onset ischemic or hemorrhagic strokes. Hypogammaglobulinemia that is found in many cases of DADA2 brings immunodeficiencies into the differential diagnosis. Cytopenia, pure red cell aplasia (PRCA), and bone marrow failure (BMF) are the hematologic abnormalities commonly found in DADA.

Case presentation: We introduce eleven patients with DADA2 diagnosis, including two brothers and sisters, one set of twin sisters, and one father and his daughter and son. Ten patients (91%) had consanguineous parents. All the patients manifested livedo racemose/reticularis. Ten patients (91%) reported febrile episodes, and seven (64%) had experienced strokes. Only one patient had hypertension. Two of the patients (11%) presented decreased immunoglobulin levels. One of the patients presented with PRCA. Except for the PRCA patient with G321E mutation, all of our patients delivered G47R mutation, the most common mutation in DADA2 patients. Except for one patient who unfortunately passed away before the diagnosis was made and proper treatment was initiated, the other patients' symptoms are currently controlled; two of the patients presented with mild symptoms and are now being treated with colchicine, and the eight others responded well to anti-TNFs. The PRCA patient still suffers from hematologic abnormalities and is a candidate for a bone marrow transplant.

Conclusions: Considering the manifestations and the differential diagnoses, DADA2 is not merely a rheumatologic disease, and introducing this disease to hematologists, neurologists, and immunologists is mandatory to initiate prompt and proper treatment. The efficacy of anti-TNFs in resolving the symptoms of DADA2 patients have been proven, but not for those with hematologic manifestations. Similarly, they were effective in controlling the symptoms of our cohort of patients, except for the one patient with cytopenia.