%0 Journal Article %J Ann Rheum Dis %D 2017 %T ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. %A Caorsi, Roberta %A Penco, Federica %A Grossi, Alice %A Insalaco, Antonella %A Omenetti, Alessia %A Alessio, Maria %A Conti, Giovanni %A Marchetti, Federico %A Picco, Paolo %A Tommasini, Alberto %A Martino, Silvana %A Malattia, Clara %A Gallizi, Romina %A Podda, Rosa Anna %A Salis, Annalisa %A Falcini, Fernanda %A Schena, Francesca %A Garbarino, Francesca %A Morreale, Alessia %A Pardeo, Manuela %A Ventrici, Claudia %A Passarelli, Chiara %A Zhou, Qing %A Severino, Mariasavina %A Gandolfo, Carlo %A Damonte, Gianluca %A Martini, Alberto %A Ravelli, Angelo %A Aksentijevich, Ivona %A Ceccherini, Isabella %A Gattorno, Marco %K Adenosine Deaminase %K Adolescent %K Age of Onset %K Case-Control Studies %K Child %K Child, Preschool %K DNA Mutational Analysis %K Female %K Heterozygote %K Homozygote %K Humans %K Immunoglobulins %K Immunosuppressive Agents %K Infant %K Intercellular Signaling Peptides and Proteins %K Italy %K Livedo Reticularis %K Male %K Pedigree %K Polyarteritis Nodosa %K Stroke %K Thalidomide %K Tumor Necrosis Factor-alpha %K Young Adult %X

OBJECTIVES: To analyse the prevalence of 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 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 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 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.

%B Ann Rheum Dis %V 76 %P 1648-1656 %8 2017 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/28522451?dopt=Abstract %R 10.1136/annrheumdis-2016-210802