title: Disease Phenotype and Outcome Depending on the Age at Disease Onset in Patients Carrying the R92Q Low-Penetrance Variant inTNFRSF1AGene.
abstract: BACKGROUND
  Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory disease caused by mutations in theTNFRSF1Agene. R92Q, a low-penetrance variant, is usually associated with a milder TRAPS phenotype than structural or pathogenic mutations. No studies differentiating R92Q-related disease in patients with pediatric and adult onset have been performed to date.
  
  
  OBJECTIVE
  To analyze clinical features and disease outcomes in patients diagnosed with TRAPS associated with R92Q variant and to investigate differences between patients with pediatric and adult disease onset.
  
  
  METHODS
  A retrospective review of patients with R92Q-related disease from four reference centers for autoinflammatory diseases was performed. Clinical and laboratory features, family history of autoinflammatory diseases, treatments received, and outcomes during follow-up were recorded and separately analyzed in pediatric and adult patients. Our results were included in the analysis with other reported pediatric and adult R92Q-related disease series.
  
  
  RESULTS
  Our series encompassed 18 patients (9 females and 9 males) with R92Q variant. In 61% of patients, disease onset occurred during infancy and in 39%, during adulthood, with a median diagnostic delay of 5 years and a follow-up of 5.4 years. A positive family history of autoinflammatory disease was detected in 28% of patients. All patients presented with febrile recurrent episodes. Other common symptoms included arthralgia/arthritis (61%), myalgia (39%), asthenia/fatigue (44%), abdominal pain (39%), headache (33%), odynophagia (33%), skin rash (28%), and chest pain (22%). During attacks, 80% of patients increased acute phase reactants levels. No patient had developed amyloidosis during the study period. At the end of follow-up, 28% of patients were asymptomatic and treatment free, 50% were receiving non-steroidal anti-inflammatory drugs or glucocorticoids on demand, and 22% were being treated with biologic agents. When differences between pediatric and adult patients were globally analyzed, adults tended to have longer attacks duration and presented more frequently with chest pain and headache, while abdominal pain, vomiting, cervical adenitis, and pharyngitis predominated in pediatric patients. No differences in outcomes and treatment requirements were observed in both age groups.
  
  
  CONCLUSIONS
  This study has contributed to characterize R92Q-related disease by identifying trends in disease phenotypes depending on the age at disease onset.
authors.affiliation: Department of Immunology-CDB, Hospital Clinic, IDIBAPS , Barcelona , Spain.
authors.forename: Estíbaliz
authors.initials: E
authors.lastname: Ruiz-Ortiz
authors.affiliation: Pediatric Rheumatology Unit, Department of Pediatrics, Hospital Sant Joan de Déu, University of Barcelona , Barcelona , Spain.
authors.forename: Estíbaliz
authors.initials: E
authors.lastname: Iglesias
authors.affiliation: Rheumatology Unit, Department of Internal Medicine, Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia, Rome, Italy; Campus Bio-Medico University, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soriano
authors.affiliation: Autoimmune and Systemic Diseases Unit, Department of Internal Medicine, Hospital Vall d'Hebron , Barcelona , Spain.
authors.forename: Segundo
authors.initials: S
authors.lastname: Buján-Rivas
authors.affiliation: Department of Immunology-CDB, Hospital Clinic, IDIBAPS , Barcelona , Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Español-Rego
authors.affiliation: Clinical Unit of Autoinflammatory Diseases and Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clinic, IDIBAPS, University of Barcelona , Barcelona , Spain.
authors.forename: Raul
authors.initials: R
authors.lastname: Castellanos-Moreira
authors.affiliation: Clinical Unit of Autoinflammatory Diseases and Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clinic, IDIBAPS, University of Barcelona , Barcelona , Spain.
authors.forename: Adrià
authors.initials: A
authors.lastname: Tomé
authors.affiliation: Department of Immunology-CDB, Hospital Clinic, IDIBAPS , Barcelona , Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Yagüe
authors.affiliation: Pediatric Rheumatology Unit, Department of Pediatrics, Hospital Sant Joan de Déu, University of Barcelona , Barcelona , Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Antón
authors.affiliation: Clinical Unit of Autoinflammatory Diseases and Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clinic, IDIBAPS, University of Barcelona , Barcelona , Spain.
authors.forename: José
authors.initials: J
authors.lastname: Hernández-Rodríguez
keywords: R92Q; adult onset; autoinflammatory diseases; low-penetrance variants; pediatric onset; tumor necrosis factor receptor-associated periodic syndrome