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Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry
  1. R Levy1,
  2. L Gérard2,
  3. J Kuemmerle-Deschner3,
  4. H J Lachmann4,
  5. I Koné-Paut5,
  6. L Cantarini6,
  7. P Woo7,
  8. A Naselli8,
  9. B Bader-Meunier1,
  10. A Insalaco9,
  11. S M Al-Mayouf10,
  12. S Ozen11,
  13. M Hofer12,
  14. J Frenkel13,
  15. C Modesto14,
  16. I Nikishina15,
  17. T Schwarz16,
  18. S Martino17,
  19. A Meini18,
  20. P Quartier1,
  21. A Martini8,19,
  22. N Ruperto8,
  23. B Neven1,
  24. M Gattorno8,
  25. for PRINTO and Eurofever
  1. 1Paediatric Rheumatology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
  2. 2Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France
  3. 3Division of Pediatric Rheumatology, University Hospital Tübingen, Tuebingen, Germany
  4. 4National Amyloidosis Centre, University College London Medical School, Royal Free Campus, London, UK
  5. 5Paediatric Rheumatology, CEREMAI, CHU de Bicêtre, Assistance Publique-Hôpitaux de Paris, Paris, France
  6. 6Rheumatology Unit, Policlinico le Scotte, University of Siena, Siena, Italy
  7. 7Centre of Paediatric and Adolescent Rheumatology—UCL, London, UK
  8. 8Pediatria II, Reumatologia, Istituto Giannina Gaslini, Genoa, Italy
  9. 9Division of Rheumatology, Department of Pediatric Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
  10. 10Department of Pediatric, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  11. 11Department of Paediatric Nephrology and Rheumatology, Hacettepe University, Ankara, Turkey
  12. 12Paediatric Rheumatology Unit of Western Switzerland, CHUV, University Hospital of Lausanne, Lausanne, Switzerland
  13. 13Department of Paediatrics, University Medical Center Utrecht, Utrecht, Netherlands
  14. 14Reumatologia, Hospital Valle de Hebron, Barcelona, Spain
  15. 15Children's Department, Institute of Rheumatology RAMS, Moscow, Russian Federation
  16. 16Section of Paediatric Rheumatology and Osteology, University School of Medicine Children's Hospital, Würzburg, Germany
  17. di Scienze Pediatriche e dell'Adolescenza, Clinica Pediatrica Universita’ di Torino, Turin, Italy
  18. 18Pediatric Immunology and Rheumatology Unit, Pediatric Clinic, Spedali Civili and University of Brescia, Brescia, Italy
  19. 19Department of Paediatrics, University of Genoa, Italy
  1. Correspondence to Dr Bénédicte Neven, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, F-75015 Paris, France; benedicte.neven{at}


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.

  • Fever Syndromes
  • Inflammation
  • Familial Mediterranean Fever

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