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TNFRSF1A-pR92Q variant identifies a subset of patients more similar to systemic undifferentiated recurrent fever than TNF receptor-associated periodic syndrome

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16


  1. Department of Paediatrics, Wilhelmina Children’s Hospital, Utrecht, The Netherlands.
  2. IRCCS Istituto Giannina Gaslini, UOC Reumatologia e Malattie Autoinfiammatorie, Genova, and Paediatric Unit, University “Magna Graecia” of Catanzaro, Italy.
  3. Rheumatology Unit, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Italy.
  4. Paediatrics Clinic, University of Brescia and Spedali Civili of Brescia, Italy.
  5. National Amyloidosis Centre, Royal Free Hospital, London, UK.
  6. Department of Paediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt - Universität zu Berlin; German Rheumatism Research Centre, Berlin, Germany.
  7. Department of Paediatric Rheumatology and Immunology, Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
  8. Stem Cells, Cellular Plasticity, Regenerative Medicine and Immunotherapies, INSERM, University of Montpellier, Department of Medical Genetics, Rare Diseases and Personalized Medicine, National Referral Centre of Auto-Inflammatory Diseases and Inflammatory Amyloidosis, CEREMAIA CHU Montpellier, France.
  9. IRCCS Istituto Giannina Gaslini, UOC Reumatologia e Malattie Autoinfiammatorie, Genova, Italy.
  10. Division of Paediatric Rheumatology, Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues de Llobregat, Barcelona, Spain.
  11. Department of Paediatric Medicine, Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
  12. Paediatric Rheumatology Unit, Hospital Universitari Vall d’Hebron, Barcelona, Spain.
  13. Department of Paediatric Rheumatology, Hospital Universitari Parc Taulí, Autonomous University of Barcelona, Sabadell, Barcelona, Spain.
  14. IRCCS Istituto Giannina Gaslini, UOC Servizio di Sperimentazioni Cliniche Pediatriche, PRINTO, Genova, Italy.
  15. Department of Paediatrics, Wilhelmina Children’s Hospital, Utrecht, The Netherlands.
  16. IRCCS Istituto Giannina Gaslini, UOC Reumatologia e Malattie Autoinfiammatorie, Genova, Italy.

for Eurofever/Eurotraps projects and Paediatric Rheumatology International Trials Organisation (PRINTO)

2023 Vol.41, N°10
PI 1998, PF 2007
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PMID: 37470237 [PubMed]

Received: 16/06/2022
Accepted : 22/12/2022
In Press: 11/07/2023
Published: 30/10/2023


To describe the clinical phenotype and response to treatment of autoinflammatory disease (AID) patients with the TNFRSF1A-pR92Q variant compared to patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) due to pathogenic mutations in the same gene and patients diagnosed with other recurrent fever syndromes including periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) and syndrome of undefined recurrent fever (SURF).
Clinical data from pR92Q variant associated AID, classical TRAPS, PFAPA and SURF patients were obtained from the Eurofever registry, an international, multicentre registry enabling retrospective collection of data on AID patients.
In this study, 361 patients were enrolled, including 77 pR92Q variant, 72 classical TRAPS, 152 PFAPA and 60 SURF patients. pR92Q carriers had an older age of disease onset than classical TRAPS and PFAPA patients. Compared to pR92Q variant patients, classical TRAPS patients had more relatives affected and were more likely to have migratory rash and AA-amyloidosis. Despite several differences in disease characteristics and symptoms between pR92Q variant and PFAPA patients, part of the pR92Q variant patients experienced PFAPA-like symptoms. pR92Q variant and SURF patients showed a comparable clinical phenotype. No major differences were observed in response to treatment between the four patient groups. Steroids were most often prescribed and effective in the majority of patients.
Patients with AID carrying the TNFRSF1A-pR92Q variant behave more like SURF patients and differ from patients diagnosed with classical TRAPS and PFAPA in clinical phenotype. Hence, they should no longer be diagnosed as having TRAPS and management should differ accordingly.


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