title: [Genetics of cryopyrin-associated periodic syndrome].
abstract: Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological, cutaneous and articular syndrome/neonatal onset multisystem inflammatory disease (CINCA/NOMID) were originally described as three distinct diseases. After the identification of their common genetic origin in 2001 and 2002, they are now perceived as a continuum of one disease entity and labelled cryopyrin-associated periodic syndromes (CAPS). Mutations in the NLRP3 gene on chromosome 1q44 can be detected in many affected patients. These lead to the synthesis of an altered gene product named cryopyrin. This is part of the NLRP3 inflammasome and causes the activation of caspase 1 and an excess production of IL-1β, which is the driving force behind the inflammatory reactions observed in CAPS patients. In symptomatic patients, confirmation of a mutation using traditional methods of genetic analysis may not always be successful (up to 40% in the case of CINCA/NOMID phenotypes); however, in many cases somatic mutations can be found using modern methods, such as next generation sequencing (NGS) technologies. In contrast, low-penetrance NLRP3 variants may also be identified in healthy family members and are present in low frequencies in the general population. Some of the mutation carriers nevertheless present with typical signs of autoinflammation; however, their phenotype is different compared to the classical CAPS presentation. These patients display unspecific systemic inflammatory signs more frequently but show an organ involvement less often. While the detection of NLRP3 gene mutations may be viewed as confirmatory, CAPS is still predominantly a clinical diagnosis; therefore, recently published diagnostic criteria do not require the demonstration of a mutation.
authors.affiliation: Klinik für Kinder- und Jugendmedizin, autoinflammation reference center Tübingen, Universitätsklinikum Tübingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Deutschland. kuemmerle.deschner@uni-tuebingen.de.
authors.forename: J B
authors.initials: JB
authors.lastname: Kümmerle-Deschner
authors.affiliation: , Hohentwielstr. 32, 78250, Tengen, Deutschland.
authors.forename: P
authors.initials: P
authors.lastname: Lohse
mesh_terms: D056587:Cryopyrin-Associated Periodic Syndromes / Q000175:diagnosis* / Q000235:genetics*; D016207:Cytokines / Q000235:genetics*; D019317:Evidence-Based Medicine; D020022:Genetic Predisposition to Disease / Q000235:genetics; D056660:Hereditary Autoinflammatory Diseases / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D058847:Inflammasomes / Q000235:genetics; D009154:Mutation / Q000235:genetics; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics*
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human
keywords: Autoinflammation; Diagnosis; Mutation; NLRP3 gene; Penetrance