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.
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Contributors RC, MG: coordination of the study, interpretation of the results, elaboration of the manuscript.
FP, AO, FS: functional immunological studies.
AG, QZ: genetic analysis.
MS, CG: neuroimaging.
AS, GD: biochemical studies.
AI, MA, GC, FM, PP, AT, SM, CM, RG, RAP, FF, FG, AMo, MP: clinical characterisation of patients, interpretation of the results, critical reading of the manuscript.
AMa, AR, IA, IC: interpretation of the results and critical reading of the manuscript.
Competing interests None declared.
Patient consent Patient or guardian according to the age.
Ethics approval G. Gaslini IRCCS Ethics Board.
Provenance and peer review Not commissioned; externally peer reviewed.
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