BACKGROUND: Systemic autoinflammatory disorders (SAIDs) represent a growing spectrum of diseases characterized by dysregulation of the innate immune system. The most common pediatric autoinflammatory fever syndrome, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA), has well defined clinical diagnostic criteria, but there is a subset of patients who do not meet these criteria and are classified as undefined autoinflammatory diseases (uAID). This project, endorsed by PRES, supported by the EMERGE fellowship program, aimed to analyze the evolution of symptoms in recurrent fevers without molecular diagnosis in the context of undifferentiated AIDs, focusing on PFAPA and syndrome of undifferentiated recurrent fever (SURF), using data from European AID registries. METHODS: Data of patients with PFAPA, SURF and uSAID were collected from 3 registries including detailed epidemiological, demographic and clinical data, results of the genetic testing and additional laboratory investigations with retrospective application of the modified Marshall and PRINTO/Eurofever classification criteria on the cohort of PFAPA patients and preliminary SURF criteria on uSAID/SURF patients. RESULTS: Clinical presentation of PFAPA is variable and some patients did not fit the conventional PFAPA criteria and exhibit different symptoms. Some patients did not meet the criteria for either PFAPA or SURF, highlighting the heterogeneity within these groups. The study also explored potential overlaps between PFAPA and SURF/uAID, revealing that some patients exhibited symptoms characteristic of both conditions, emphasizing the need for more precise classification criteria. CONCLUSIONS: Patients with recurrent fevers without molecular diagnoses represent a clinically heterogeneous group. Improved classification criteria are needed for both PFAPA and SURF/uAID to accurately identify and manage these patients, ultimately improving clinical outcomes.

Centre for Autoinflammatory Diseases and Immunodeficiencies IRCCS Istituto Giannina Gaslini Genoa Italy

CEREMAIA Kremlin Bicêtre France

Department for Pediatrics National Referral Centre of Auto Inflammatory Diseases and Inflammatory Amyloidosis CEREMAIA Versailles Hospital Le Chesnay France

Department of General Paediatrics Paediatric Infectious Disease and Internal Medicine Assistance Publique Hôpitaux de Paris Robert Debré University Hospital Université de Paris Paris France

Department of Internal Medicine Sorbonne University Tenon Hospital Paris France

Department of Paediatrics and Inherited Metabolic Disorders Centre for Paediatric Rheumatology and Autoinflammatory Diseases 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Peadiatrics and Adolescent Medicine Jesenius Faculty of Medicine in Martin Comenius University University Hospital Martin Martin Slovakia

Department of Pediatric Immunology and Rheumatology Wilhelmina Kinderziekenhuis Utrecht Netherlands

Department of Pediatric Rheumatology and Immunology University Hospital Munster Munster Germany

Department of Pediatric Rheumatology Hospital Sant Joan de Déu Universitat de Barcelona Institut de Recerca Sant Joan de Deu Barcelona Spain

Department of Pediatric Rheumatology National Referral Centre of Auto Inflammatory Diseases and Inflammatory Amyloidosis CEREMAIA CHU de Biĉetre APHP University of Paris Sud Le Kremlin Biĉetre France

Department of Pediatric Rheumatology University Children's Hospital Essen Essen Germany

Department of Pediatrics Asklepios Clinic Sankt Augustin GmbH Sankt Augustin Germany

Department of Pediatrics Centre Hospitalier Universitaire Vaudois Lausanne Switzerland

Department of Pediatrics Jaslok Hospital Mumbai India

Department of Pediatrics Pediatric Rheumatology Medical University Innsbruck Innsbruck and Danube Private University Krems Innsbruck Austria

Department of Pediatrics Ruhr University of Bochum Bochum Germany

Department of Pediatrics School of Medicine Faculty of Health Sciences Papageorgiou General Hospital 4th Aristotle University of Thessaloniki Thessaloniki Greece

Dipartimento Della Donna del Bambino E Di Chirurgia Generale E Specialistica Università Degli Studi Della Campania L Vanvitelli Naples Italy

Division of Pediatric Rheumatology and Immunology Dr Von Hauner Children's Hospital University Hospital Munich Munich Germany

German Center for Paediatric and Adolescent Rheumatology Garmisch Partenkirchen Germany

German Rheumatism Research Center Leibniz Institute Berlin Charité Universitätsmedizin Berlin Paediatric Pneumology Immunology and Critical Care Medicine and SPZ Berlin Germany

Hospital Parc Taulí de Sabadell Reumatologia Pediàtrica Servei de Medicina Pediàtrica Barcelona Spain

Marien Children's Hospital Landshut Germany

National Pirogov Memorial Medical University Vinnytsya Ukraine

Pediatrics and Immunology CHU Pellegrin Bordeaux France

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