title: The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up.
abstract: OBJECTIVE
  To analyze the clinical manifestations and response to treatment in a cohort of adult patients presenting with recurrent inflammatory attacks and carrying low-penetrance TNFRSF1A variants, as well as to provide data on their long-term follow-up.
  
  
  METHODS
  We performed a retrospective chart review of 36 patients carrying low-penetrance TNFRSF1A variants. Moreover, 60 genetically negative patients treated for recurrent inflammatory attacks and 13 patients with structural TNFRSF1A mutations were also analyzed. Detailed demographic and clinical data were collected at the time of molecular screening and at each follow-up visit. Treatments and markers of inflammation were also assessed.
  
  
  RESULTS
  Individuals with low-penetrance TNFRSF1A variants have a lower family history for inflammatory attacks and present with a later disease onset compared with patients with structural mutations, but do not differ, in this respect, with genetically negative individuals. Moreover, low-penetrance variants are less frequently associated with a chronic disease course, with clinical manifestations such as abdominal pain and myalgia, and with amyloidosis. A distinctive clinical feature is a higher rate of pericarditis. Interestingly, mutation-negative patients were found to present with a significant history of recurrent pharyngitis during childhood. Patients with low-penetrance variants are mostly managed with short courses of steroids or non-steroidal anti-inflammatory drugs on attacks. Although the need for a biological treatment is significantly lower compared with patients with structural mutations, still approximately 20% of individuals with recurrent inflammatory attacks carrying low-penetrance variants ultimately require these therapies.
  
  
  CONCLUSIONS
  Our study confirms that low-penetrance TNFRSF1A variants can be associated with an autoinflammatory phenotype. Although a chronic disease course is rarely observed, some patients ultimately benefit from a biological treatment.
authors.affiliation: Interdepartmental Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, Policlinico Le Scotte, University of Siena, Viale Bracci 1, Siena 53100, Italy. Electronic address: cantariniluca@hotmail.com.
authors.forename: Luca
authors.initials: L
authors.lastname: Cantarini
authors.affiliation: Institute of Pediatrics, Università Cattolica Sacro Cuore, Rome, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Rigante
authors.affiliation: Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.affiliation: Interdepartmental Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, Policlinico Le Scotte, University of Siena, Viale Bracci 1, Siena 53100, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vitale
authors.affiliation: Rheumatology Unit, Department of Medicine, University of Padua, Padua, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Caso
authors.affiliation: Interdepartmental Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, Policlinico Le Scotte, University of Siena, Viale Bracci 1, Siena 53100, Italy.
authors.forename: Orso Maria
authors.initials: OM
authors.lastname: Lucherini
authors.affiliation: Rheumatology Unit, Department of Medicine, University of Padua, Padua, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Sfriso
authors.affiliation: Interdepartmental Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, Policlinico Le Scotte, University of Siena, Viale Bracci 1, Siena 53100, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Frediani
authors.affiliation: Rheumatology Unit, Department of Medicine, University of Padua, Padua, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Punzi
authors.affiliation: Interdepartmental Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, Policlinico Le Scotte, University of Siena, Viale Bracci 1, Siena 53100, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Galeazzi
authors.affiliation: Rheumatology Unit, Department of Pediatrics, Anna Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Rolando
authors.initials: R
authors.lastname: Cimaz
authors.affiliation: Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Obici
mesh_terms: D015746:Abdominal Pain / Q000209:etiology / Q000503:physiopathology; D000293:Adolescent; D000328:Adult; D000686:Amyloidosis / Q000209:etiology / Q000503:physiopathology; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D056660:Hereditary Autoinflammatory Diseases / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D063806:Myalgia / Q000209:etiology / Q000503:physiopathology; D019683:Penetrance; D010493:Pericarditis / Q000209:etiology / Q000503:physiopathology; D010641:Phenotype; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D012008:Recurrence; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human
keywords: Autoinflammatory disorders; Differential diagnosis; Recurrent fever; TNFRSF1A gene; Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)