title: The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.
abstract: OBJECTIVE
  To evaluate the genetic findings, demographic features and clinical presentation of tumour necrosis factor receptor-associated autoinflammatory syndrome (TRAPS) in patients from the Eurofever/EUROTRAPS international registry.
  
  
  METHODS
  A web-based registry collected retrospective data on patients with TNFRSF1A sequence variants and inflammatory symptoms. Participating hospitals included paediatric rheumatology centres and adult centres with a specific interest in autoinflammatory diseases. Cases were independently validated by experts in the disease.
  
  
  RESULTS
  Complete information on 158 validated patients was available. The most common TNFRSF1A variant was R92Q (34% of cases), followed by T50M (10%). Cysteine residues were disrupted in 27% of cases, accounting for 39% of sequence variants. A family history was present in 19% of patients with R92Q and 64% of those with other variants. The median age at which symptoms began was 4.3 years but 9.1% of patients presented after 30 years of age. Attacks were recurrent in 88% and the commonest features associated with the pathogenic variants were fever (88%), limb pain (85%), abdominal pain (74%), rash (63%) and eye manifestations (45%). Disease associated with R92Q presented slightly later at a median of 5.7 years with significantly less rash or eye signs and more headaches. Children were more likely than adults to present with lymphadenopathy, periorbital oedema and abdominal pains. AA amyloidosis has developed in 16 (10%) patients at a median age of 43 years.
  
  
  CONCLUSIONS
  In this, the largest reported case series to date, the genetic heterogeneity of TRAPS is accompanied by a variable phenotype at presentation. Patients had a median 70 symptomatic days a year, with fever, limb and abdominal pain and rash the commonest symptoms. Overall, there is little evidence of a significant effect of age or genotype on disease features at presentation.
authors: National Amyloidosis Centre, Royal Free Campus, University College Medical School, London, UK.
authors: H J
authors: HJ
authors: Lachmann
authors: Pediatria II, Istituto Giannina Gaslini, Genova, Italy.
authors: R
authors: R
authors: Papa
authors: Pediatric Pneumology and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: K
authors: K
authors: Gerhold
authors: Biotechnology Research Laboratories, Amyloid Centre, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors: L
authors: L
authors: Obici
authors: Unit of Autoinflammatory Diseases, CHU Montpellier, UM1, INSERM U844, Montpellier, France.
authors: I
authors: I
authors: Touitou
authors: Rheumatology Unit, Policlinico le Scotte, University of Siena, Siena, Italy.
authors: L
authors: L
authors: Cantarini
authors: Department of Paediatrics, University Medical Center Utrecht, Utrecht, Netherlands.
authors: J
authors: J
authors: Frenkel
authors: Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues (Barcelona), Spain.
authors: J
authors: J
authors: Anton
authors: Centre de référence national des maladies auto-inflammatoires, CEREMAI, rhumatologie pediatrique, CHU Le Kremlin Bicetre (University of Paris SUD, APHP), Le kremlin Bicetre (Paris), France.
authors: I
authors: I
authors: Kone-Paut
authors: Dipartimento di Pediatria, Unità di Immunologia e Reumatologia Pediatrica, Clinica Pediatrica dell'Università di Brescia, Spedali Civili, Brescia, Italy.
authors: M
authors: M
authors: Cattalini
authors: Unité d'Immunologie, Hématologie et Rhumatologie Pediatrique, Université Paris-Descartes, Hôpital Necker-Enfants Malades, Centre de référence national pour les Arthrites Juveniles, APHP, IHU Imagine, Paris, France.
authors: B
authors: B
authors: Bader-Meunier
authors: Reumatologia, Ospedale Pediatrico Bambin Gesù, Roma, Italy.
authors: A
authors: A
authors: Insalaco
authors: Service de pediatrie generale, Hopital A Mignot, Centre de référence national des maladies auto-inflammatoires, Le Chesnay (Paris), France.
authors: V
authors: V
authors: Hentgen
authors: Unidad De Reumatologia Pediatrica, Hospital Universitario La Paz, Madrid, Spain.
authors: R
authors: R
authors: Merino
authors: Reumatologia, Hospital Valle de Hebron, Barcelona, Spain.
authors: C
authors: C
authors: Modesto
authors: Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia.
authors: N
authors: N
authors: Toplak
authors: Kinderkrankenhaus St. Marien, Landshut, Germany.
authors: R
authors: R
authors: Berendes
authors: Department of Pediatric Nephrology and Rheumatology, Hacettepe University, Ankara, Turkey.
authors: S
authors: S
authors: Ozen
authors: Dept di Pediatria, Ospedale A Meyer, Firenze, Italy.
authors: R
authors: R
authors: Cimaz
authors: Rheumatology & Immunology, Dr von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
authors: A
authors: A
authors: Jansson
authors: Center of Paediatric and Adolescent Rheumatology-UCL, Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
authors: P A
authors: PA
authors: Brogan
authors: National Amyloidosis Centre, Royal Free Campus, University College Medical School, London, UK.
authors: P N
authors: PN
authors: Hawkins
authors: Pediatria II, Istituto Giannina Gaslini, Genova, Italy.
authors: N
authors: N
authors: Ruperto
authors: Istituto Giannina Gaslini, Pediatria II and Università degli Studi di Genova, Genova, Italy.
authors: A
authors: A
authors: Martini
authors: Center of Paediatric and Adolescent Rheumatology-UCL, Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
authors: P
authors: P
authors: Woo
authors: Pediatria II, Istituto Giannina Gaslini, Genova, Italy.
authors: M
authors: M
authors: Gattorno
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018450:Disease Progression; D005076:Exanthema / Q000209:etiology; D005260:Female; D005334:Fever / Q000209:etiology; D005838:Genotype; D056660:Hereditary Autoinflammatory Diseases / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000209:etiology; D010641:Phenotype; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D012042:Registries; D012189:Retrospective Studies; D013997:Time Factors; D055815:Young Adult
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human
keywords: Amyloidosis; Fever Syndromes; Inflammation
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