ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Issue 10 (18th May 2017)

• Record Type: Journal Article
• Authors: Caorsi, Roberta; Penco, Federica; Grossi, Alice; Insalaco, Antonella; Omenetti, Alessia; Alessio, Maria; Conti, Giovanni; Marchetti, Federico; Picco, Paolo; Tommasini, Alberto; Martino, Silvana; Malattia, Clara; Gallizi, Romina; Podda, Rosa Anna; Salis, Annalisa; Falcini, Fernanda; Schena, Francesca; Garbarino, Francesca; Morreale, Alessia; Pardeo, Manuela; Ventrici, Claudia; Passarelli, Chiara; Zhou, Qing; Severino, Mariasavina; Gandolfo, Carlo; Damonte, Gianluca; Martini, Alberto; Ravelli, Angelo; Aksentijevich, Ivona; Ceccherini, Isabella; Gattorno, Marco;
• Is Part Of: Annals of the rheumatic diseases. Volume 76:Issue 10(2017)
• Page Start: 1648
• Page End: 1656
• Publication Date: 2017-05-18
• Subjects: Anti-TNF -- Fever Syndromes -- Gene Polymorphism; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2016-210802
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Objectives: To analyse the prevalence of CECR1 mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis nodosa (PAN). Forty-eight patients from 43 families were included in the study. Methods: Direct sequencing of CECR1 was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor. Results: Biallelic homozygous or compound heterozygous CECR1 mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24 months (6 months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without CECR1 mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect. Conclusions: DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.