title: Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry.
abstract: OBJECTIVE
  To evaluate genetic, demographic and clinical features in patients with cryopyrin-associated periodic syndrome (CAPS) from the Eurofever Registry, with a focus on genotype-phenotype correlations and predictive disease severity markers.
  
  
  METHODS
  A web-based registry retrospectively collected data on patients with CAPS. Experts in the disease independently validated all cases. Patients carrying NLRP3 variants and germline-mutation-negative patients were included.
  
  
  RESULTS
  136 patients were analysed. The median age at disease onset was 9 months, and the median duration of follow-up was 15 years. Skin rash, musculoskeletal involvement and fever were the most prevalent features. Neurological involvement (including severe complications) was noted in 40% and 12% of the patients, respectively, with ophthalmological involvement in 71%, and neurosensory hearing loss in 42%. 133 patients carried a heterozygous, germline mutation, and 3 patients were mutation-negative (despite complete NLRP3 gene screening). Thirty-one different NLRP3 mutations were recorded; 7 accounted for 78% of the patients, whereas 24 rare variants were found in 27 cases. The latter were significantly associated with early disease onset, neurological complications (including severe complications) and severe musculoskeletal involvement. The T348M variant was associated with early disease onset, chronic course and hearing loss. Neurological involvement was less strongly associated with V198M, E311 K and A439 V alleles. Early onset was predictive of severe neurological complications and hearing loss.
  
  
  CONCLUSIONS
  Patients carrying rare NLRP3 variants are at risk of severe CAPS; onset before the age of 6 months is associated with more severe neurological involvement and hearing loss. These findings may have an impact on treatment decisions.
authors.affiliation: Paediatric Rheumatology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Levy
authors.affiliation: Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Gérard
authors.affiliation: Division of Pediatric Rheumatology, University Hospital Tübingen, Tuebingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Kuemmerle-Deschner
authors.affiliation: National Amyloidosis Centre, University College London Medical School, Royal Free Campus, London, UK.
authors.forename: H J
authors.initials: HJ
authors.lastname: Lachmann
authors.affiliation: Paediatric Rheumatology, CEREMAI, CHU de Bicêtre, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Koné-Paut
authors.affiliation: Rheumatology Unit, Policlinico le Scotte, University of Siena, Siena, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Cantarini
authors.affiliation: Centre of Paediatric and Adolescent Rheumatology-UCL, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Woo
authors.affiliation: Pediatria II, Reumatologia, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Naselli
authors.affiliation: Paediatric Rheumatology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Bader-Meunier
authors.affiliation: Division of Rheumatology, Department of Pediatric Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Insalaco
authors.affiliation: Department of Pediatric, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: S M
authors.initials: SM
authors.lastname: Al-Mayouf
authors.affiliation: Department of Paediatric Nephrology and Rheumatology, Hacettepe University, Ankara, Turkey.
authors.forename: S
authors.initials: S
authors.lastname: Ozen
authors.affiliation: Paediatric Rheumatology Unit of Western Switzerland, CHUV, University Hospital of Lausanne, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Hofer
authors.affiliation: Department of Paediatrics, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Frenkel
authors.affiliation: Reumatologia, Hospital Valle de Hebron, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Modesto
authors.affiliation: Children's Department, Institute of Rheumatology RAMS, Moscow, Russian Federation.
authors.forename: I
authors.initials: I
authors.lastname: Nikishina
authors.affiliation: Section of Paediatric Rheumatology and Osteology, University School of Medicine Children's Hospital, Würzburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Schwarz
authors.affiliation: Dip.to di Scienze Pediatriche e dell'Adolescenza, Clinica Pediatrica Universita' di Torino, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Martino
authors.affiliation: Pediatric Immunology and Rheumatology Unit, Pediatric Clinic, Spedali Civili and University of Brescia, Brescia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Meini
authors.affiliation: Paediatric Rheumatology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Quartier
authors.affiliation: Pediatria II, Reumatologia, Istituto Giannina Gaslini, Genoa, Italy Department of Paediatrics, University of Genoa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Martini
authors.affiliation: Pediatria II, Reumatologia, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Ruperto
authors.affiliation: Paediatric Rheumatology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Neven
authors.affiliation: Pediatria II, Reumatologia, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Gattorno
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D018771:Arthralgia / Q000209:etiology / Q000235:genetics; D001168:Arthritis / Q000209:etiology / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003231:Conjunctivitis / Q000209:etiology / Q000235:genetics; D056587:Cryopyrin-Associated Periodic Syndromes / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D005060:Europe; D005076:Exanthema / Q000209:etiology / Q000235:genetics; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D006261:Headache / Q000209:etiology / Q000235:genetics; D006319:Hearing Loss, Sensorineural / Q000209:etiology / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008581:Meningitis / Q000209:etiology / Q000235:genetics; D009154:Mutation; D063806:Myalgia / Q000209:etiology / Q000235:genetics; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010211:Papilledema / Q000209:etiology / Q000235:genetics; D010641:Phenotype; D012042:Registries; D012189:Retrospective Studies; D012720:Severity of Illness Index; D014605:Uveitis / Q000209:etiology / Q000235:genetics; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human
keywords: Familial Mediterranean Fever; Fever Syndromes; Inflammation