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

Autor:	Caorsi R; Second Division of Pediatrics, G. Gaslini Institute, Genova, Italy., Penco F; Second Division of Pediatrics, G. Gaslini Institute, Genova, Italy., Grossi A; Division of Human Genetics, G. Gaslini Institute, Genova, Italy., Insalaco A; Division of Rheumatology, Bambino Gesù Children's Hospital, Rome, Italy., Omenetti A; Second Division of Pediatrics, G. Gaslini Institute, Genova, Italy.; DINOMGI, University of Genova, Genova, Italy., Alessio M; Department of Pediatrics, Federico II Hospital, Napoli, Italy., Conti G; Department of Pediatric Rheumatology and Nephrology, Policlinico di Messina, Messina, Italy., Marchetti F; Department of Pediatrics, S. Maria delle Croci Hospital, Ravenna, Italy., Picco P; Second Division of Pediatrics, G. Gaslini Institute, Genova, Italy., Tommasini A; Department of Pediatrics, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy., Martino S; Department of Pediatrics, Regina Margherita Hospital, Torino, Italy., Malattia C; Second Division of Pediatrics, G. Gaslini Institute, Genova, Italy.; DINOMGI, University of Genova, Genova, Italy., Gallizzi R; Dipartimento di Patologia Umana dell'adulto e dell'età evolutiva, Università degli Studi di Messina, Messina, Italy., Podda RA; Hospital Brotzu, Clinica Pediatrica, Talassemie e Malattie Rare, Università degli studi di Cagliari, Cagliari, Italy., Salis A; Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genova, Genova, Italy., Falcini F; Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy., Schena F; Second Division of Pediatrics, G. Gaslini Institute, Genova, Italy., Garbarino F; Second Division of Pediatrics, G. Gaslini Institute, Genova, Italy.; DINOMGI, University of Genova, Genova, Italy., Morreale A; Second Division of Pediatrics, G. Gaslini Institute, Genova, Italy.; DINOMGI, University of Genova, Genova, Italy., Pardeo M; Division of Rheumatology, Bambino Gesù Children's Hospital, Rome, Italy., Ventrici C; Department of Pediatric Rheumatology and Nephrology, Policlinico di Messina, Messina, Italy., Passarelli C; Division of Medical Genetics, Bambino Gesù Children's Hospital, Rome, Italy., Zhou Q; Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA., Severino M; Neuroradiology Unit, G. Gaslini Institute, Genova, Italy., Gandolfo C; Neuroradiology Unit, G. Gaslini Institute, Genova, Italy., Damonte G; Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genova, Genova, Italy., Martini A; Second Division of Pediatrics, G. Gaslini Institute, Genova, Italy., Ravelli A; Second Division of Pediatrics, G. Gaslini Institute, Genova, Italy.; DINOMGI, University of Genova, Genova, Italy., Aksentijevich I; Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA., Ceccherini I; Division of Human Genetics, G. Gaslini Institute, Genova, Italy., Gattorno M; Second Division of Pediatrics, G. Gaslini Institute, Genova, Italy.
Jazyk:	angličtina
Zdroj:	Annals of the rheumatic diseases [Ann Rheum Dis] 2017 Oct; Vol. 76 (10), pp. 1648-1656. Date of Electronic Publication: 2017 May 18.
DOI:	10.1136/annrheumdis-2016-210802
Abstrakt:	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. Competing Interests: Competing interests: None declared. (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
Databáze:	MEDLINE
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