Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry.
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.
['Levy|R|R|', 'Gérard|L|L|', 'Kuemmerle-Deschner|J|J|', 'Lachmann|H J|HJ|', 'Koné-Paut|I|I|', 'Cantarini|L|L|', 'Woo|P|P|', 'Naselli|A|A|', 'Bader-Meunier|B|B|', 'Insalaco|A|A|', 'Al-Mayouf|S M|SM|', 'Ozen|S|S|', 'Hofer|M|M|', 'Frenkel|J|J|', 'Modesto|C|C|', 'Nikishina|I|I|', 'Schwarz|T|T|', 'Martino|S|S|', 'Meini|A|A|', 'Quartier|P|P|', 'Martini|A|A|', 'Ruperto|N|N|', 'Neven|B|B|', 'Gattorno|M|M|', '|||']
D000293:Adolescent D000328:Adult D000483:Alleles D018771:Arthralgia D001168:Arthritis D002352:Carrier Proteins D002648:Child D002675:Child, Preschool D015331:Cohort Studies D003231:Conjunctivitis D056587:Cryopyrin-Associated Periodic Syndromes D005060:Europe D005076:Exanthema D005260:Female D005838:Genotype D018095:Germ-Line Mutation D006261:Headache D006319:Hearing Loss, Sensorineural D006579:Heterozygote D006801:Humans D007223:Infant D008297:Male D008581:Meningitis D009154:Mutation D063806:Myalgia D000071199:NLR Family, Pyrin Domain-Containing 3 Protein D010211:Papilledema D010641:Phenotype D012042:Registries D012189:Retrospective Studies D012720:Severity of Illness Index D014605:Uveitis D055815:Young Adult
Familial Mediterranean Fever Fever Syndromes Inflammation