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Ann Rheum Dis. 2017 Oct;76(10):1648-1656. doi: 10.1136/annrheumdis-2016-210802. Epub 2017 May 18.

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

Author information

1
Second Division of Pediatrics, G. Gaslini Institute, Genova, Italy.
2
Division of Human Genetics, G. Gaslini Institute, Genova, Italy.
3
Division of Rheumatology, Bambino Gesù Children's Hospital, Rome, Italy.
4
DINOMGI, University of Genova, Genova, Italy.
5
Department of Pediatrics, Federico II Hospital, Napoli, Italy.
6
Department of Pediatric Rheumatology and Nephrology, Policlinico di Messina, Messina, Italy.
7
Department of Pediatrics, S. Maria delle Croci Hospital, Ravenna, Italy.
8
Department of Pediatrics, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy.
9
Department of Pediatrics, Regina Margherita Hospital, Torino, Italy.
10
Dipartimento di Patologia Umana dell'adulto e dell'età evolutiva, Università degli Studi di Messina, Messina, Italy.
11
Hospital Brotzu, Clinica Pediatrica, Talassemie e Malattie Rare, Università degli studi di Cagliari, Cagliari, Italy.
12
Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genova, Genova, Italy.
13
Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy.
14
Division of Medical Genetics, Bambino Gesù Children's Hospital, Rome, Italy.
15
Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
16
Neuroradiology Unit, G. Gaslini Institute, Genova, Italy.

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.

KEYWORDS:

Anti-TNF; Fever Syndromes; Gene Polymorphism

PMID:
28522451
DOI:
10.1136/annrheumdis-2016-210802
[Indexed for MEDLINE]

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