Background/Purpose:

The deficiency of adenosine deaminase II (DADA2), first described in 2014, is an autosomal recessive disease caused by mutations in CECR1and is characterized by intermittent fevers, early-onset lacunar strokes, livedoid rash, hepatosplenomegaly, immune deficiency and systemic vasculopathy.  An additional report by others included patients with cutaneous polyarteritis nodosa.  We now present clinical follow-up on our 5 reported patients and an additional 9 patients.

Methods:

We evaluated the 14 patients at the National Institutes of Health.  We performed whole-exome sequencing in the initial 3 patients and their unaffected parents and candidate-gene sequencing in the other 11 patients. Clinical information and radiographic and laboratory testing were obtained at each visit.

Results:

All patients had 2 mutations in CECR1.  11/14 patients reported recurrent fevers.  Ten had a history of at least one ischemic stroke. The age of onset of the first stroke ranged from 5 months to 8 years, with 8/10 before the age of 5 years.  MRI of the brain showed evidence of acute or chronic small subcortical infarcts involving the deep-brain nuclei and brain stem, consistent with small-vessel occlusions (lacunar strokes).  8/10 patients with ischemic stroke had at least one occur in the thalamus; other involved areas included the midbrain (4/10), pons (4/10), internal capsule (3/10) and basal ganglia (3/10).  One patient had an anterior thoracic-lumbar spinal cord infarct that resulted in the development of a neurogenic bladder.  Three patients had hemorrhagic strokes in addition to their ischemic strokes.  One patient developed posterior reversible encephalopathy syndrome (PRES) in relation to hypertension.  Subsequent MRI revealed complete reversal of the PRES. In 10/10 patients magnetic angiography showed no evidence of cerebral vasculitis.

All 14 patients demonstrated livedo racemosa.  Erythematous papules or nodules were seen in 11 of these patients.  Hepato-and/or splenomegaly was observed in 10/14 with 3 patients demonstrating portal hypertension.  One patient developed a perforated small bowel requiring resection. 

Hypertension was noted in 2 patients.  Prolonged QT was reported in 3 patients.  12/14 demonstrated hematologic abnormalities including anemia, leukopenia, and/or thrombocytopenia.  Elevation of acute phase reactants was reported in 13/14.  Low serum iron was noted in 8/10 patients tested.  10/13 presented with hypogammaglobulinemia, however this may reflect prior treatment with cyclophosphamide in 3 patients.

Most patients received a number of medications over the course of their disease.  It was our practice to discontinue aspirin and/or anticoagulation in all DADA2 patients.  We observed striking improvement in CRP, ESR, CBC, and serum iron in 10/12 patients receiving anti-TNF agents.

Conclusion:

We have expanded the clinical picture in patients with DADA2 to include multiple strokes, livedo racemosa, cutaneous PAN, portal hypertension, hematologic abnormalities, vascular pathology and mild immunodeficiency.  In addition, we have demonstrated both clinical and laboratory improvement following treatment with anti-TNF agents.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/deficiency-of-adenosine-deaminase-type-ii-expanding-the-clinical-spectrum/