ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study

作者：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

来源：Annals of the Rheumatic Diseases, 2017, 76(10): 1648-1656.

DOI：10.1136/annrheumdis-2016-210802

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.

• 出版日期2017-10