Unveiling Deficiency of Adenosine Deaminase 2: An Adult Patient With Recurrent Strokes, Vasculitic Ulcers, and Bowel Perforation

To the Editor:

Here we describe the case of a 38-year-old man with a history of ischemic transient attacks and strokes from the age of 9 years, livedo reticularis, asymmetrical sensorimotor neuropathy, optic neuritis, testicular ischemia, digital ulcers, ulcerative colitis, and diastolic hypertension.

Disease course was characterized by severe disease bouts treated with high-dose intravenous (IV) glucocorticoid (GC) pulse therapy, short periods of paucisymptomatic disease, and inability to taper GCs despite the use of traditional oral and IV immunosuppressants, interferon, and plasmapheresis. In 2012, after the failure of conventional therapy, the patient was treated with infliximab and had a significant reduction in the number of flares and hospitalizations. In 2016, the patient was switched to etanercept (ETN) achieving clinical remission, normalization of the inflammatory variables, and steroid tapering. Unfortunately, in 2018, anti–tumor necrosis factor (TNF) treatment was discontinued due to severe infectious complications. After a few months, the patient was admitted to hospital for a new vasculitic pontine infarction. Laboratory findings revealed mild thrombocytopenia, lymphopenia, and fluctuating inflammatory marker levels. He was treated with high-dose IV GC pulse therapy and was referred to our Rheumatology Unit for reevaluation. Upon reviewing the clinical history, the patient apparently met most of the 1990 American College of Rheumatology criteria for the classification of polyarteritis nodosa (PAN) and skin biopsy was suggestive for medium- and small-vessel vasculitis. However, atypical features included relapsing/chronic course of the disease, spleen enlargement, thrombocytopenia, early onset, and, above all, family history. Indeed, our patient has an older brother with a similar but more severe clinical picture, characterized by a massive ischemic stroke at the age of 33 years. On the suspicion of a more recently1 discovered autoinflammatory disorder called deficiency of adenosine deaminase 2 (DADA2), we performed a genetic analysis and identified a homozygous 1078A>G mutation (Thr360Ala) in exon 6 of the cat eye syndrome critical region protein 1 (CECR) gene, confirming our hypothesis. The patient was successfully treated with ETN 25 mg every 5 days (later increased to 50 mg once a week), but after 7 months of remission, ETN was discontinued due to an infected mechanic injury on a toe. Soon after, the patient developed vasculitic ulcers on the forefoot and fingers, requiring IV antibiotic treatment, advanced wound care, IV prostanoids, and ETN.

To date, approximately 200 patients with DADA2 have been described worldwide, but the prevalence of this syndrome could be underestimated, due to undiagnosed cases or paucisymptomatic disease.2

The disorder is caused by a biallelic mutation in the CECR1 gene, encoding adenosine deaminase 2 (ADA2), an enzyme involved in endothelial homeostasis, adaptive immune response, and macrophage proliferation/differentiation.1,3 ADA2 deficiency triggers NETosis, TNF production, and myeloid cell–mediated endothelial damage.4,5

The first symptoms usually occur in childhood, and, prior to the discovery of the molecular defect, the death rate was around 8% before the age of 30 years. Two main subsets of disease have been described.3 The vasculitic phenotype is almost indistinguishable from PAN, but the differential diagnosis becomes more extensive in the presence of incomplete expression of the disease. Among rheumatologic DADA2 mimickers, we find Behçet disease, systemic lupus erythematosus, Sneddon syndrome, and antiphospholipid syndrome. Similarities and differences are shown in the Table. The hematological phenotype is characterized by immunodeficiency and severe cytopenias due to bone marrow failure.

Table.

DADA2 with vasculitic phenotype mimickers in the rheumatological setting.

The clinical suspicion can be confirmed with genetic testing or with the determination of enzyme activity in the peripheral blood. Genotype-phenotype correlations are still under investigation, but a recent paper demonstrated that patients with vasculitis predominantly carried missense mutations, with at least 3% residual enzymatic activity.6 Conversely, bone marrow failure was associated with a complete loss of function. The relevance of heterozygous mutation in hematopoiesis, inflammation, and vascular homeostasis is still to be investigated.

Rama and collegues7 proposed a preliminary decision tree for genetic testing. ADA2 mutations should be investigated if at least 1 item from each of 3 categories is present: signs of inflammation (fever and/or elevated C-reactive protein), signs of vasculitis (cutaneous and/or neurologic), and recurrent or chronic course (only for adults). Unfortunately, as highlighted by Sönmez and colleagues,8 this approach may be helpful in identifying patients with the vasculitic phenotype but may overlook those in which the prevailing features are immunodeficiency and/or bone marrow failure.

Our case report not only supports the importance of an early diagnosis of DADA2 to prevent major organ damage and disability, but also highlights how challenging the treatment of these patients can be. Indeed, as far as treatment is concerned, anti-TNF drugs seem to be very effective in preventing ischemic strokes and reducing inflammatory manifestations and hepatosplenomegaly3; however, their efficacy for nonvasculitic features, neutropenia, and immunodeficiency is less clear since drug-induced immunosuppression could raise the risk of serious infections.9 Moreover, dose and administration schedule are still not clear for this disease. Future treatments such as enzyme replacement or gene therapy will perhaps improve the outcome of this complex disease.

Copyright © 2022 by the Journal of Rheumatology

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