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ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study
  1. Roberta Caorsi1,
  2. Federica Penco1,
  3. Alice Grossi2,
  4. Antonella Insalaco3,
  5. Alessia Omenetti1,4,
  6. Maria Alessio5,
  7. Giovanni Conti6,
  8. Federico Marchetti7,
  9. Paolo Picco1,
  10. Alberto Tommasini8,
  11. Silvana Martino9,
  12. Clara Malattia1,4,
  13. Romina Gallizi10,
  14. Rosa Anna Podda11,
  15. Annalisa Salis12,
  16. Fernanda Falcini13,
  17. Francesca Schena1,
  18. Francesca Garbarino1,4,
  19. Alessia Morreale1,4,
  20. Manuela Pardeo3,
  21. Claudia Ventrici6,
  22. Chiara Passarelli14,
  23. Qing Zhou15,
  24. Mariasavina Severino16,
  25. Carlo Gandolfo16,
  26. Gianluca Damonte12,
  27. Alberto Martini1,
  28. Angelo Ravelli1,4,
  29. Ivona Aksentijevich15,
  30. Isabella Ceccherini2,
  31. Marco Gattorno1
  1. 1Second Division of Pediatrics, G. Gaslini Institute, Genova, Italy
  2. 2Division of Human Genetics, G. Gaslini Institute, Genova, Italy
  3. 3Division of Rheumatology, Bambino Gesù Children's Hospital, Rome, Italy
  4. 4DINOMGI, University of Genova, Genova, Italy
  5. 5Department of Pediatrics, Federico II Hospital, Napoli, Italy
  6. 6Department of Pediatric Rheumatology and Nephrology, Policlinico di Messina, Messina, Italy
  7. 7Department of Pediatrics, S. Maria delle Croci Hospital, Ravenna, Italy
  8. 8Department of Pediatrics, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
  9. 9Department of Pediatrics, Regina Margherita Hospital, Torino, Italy
  10. 10Dipartimento di Patologia Umana dell'adulto e dell'età evolutiva, Università degli Studi di Messina, Messina, Italy
  11. 11Hospital Brotzu, Clinica Pediatrica, Talassemie e Malattie Rare, Università degli studi di Cagliari, Cagliari, Italy
  12. 12Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genova, Genova, Italy
  13. 13Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy
  14. 14Division of Medical Genetics, Bambino Gesù Children's Hospital, Rome, Italy
  15. 15Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA
  16. 16Neuroradiology Unit, G. Gaslini Institute, Genova, Italy
  1. Correspondence to Dr Marco Gattorno, UO Pediatria 2, Istituto G. Gaslini, Via G. Gaslini 5, Genoa 16147, Italy; marcogattorno{at}gaslini.org

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.

  • Anti-TNF
  • Fever Syndromes
  • Gene Polymorphism

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Footnotes

  • 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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