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Zeitschrift für Rheumatologie

, Volume 76, Issue 4, pp 313–321 | Cite as

Zur Genetik der Cryopyrin-assoziierten periodischen Syndrome

  • J. B. Kümmerle-Deschner
  • P. Lohse
Leitthema
  • 357 Downloads

Zusammenfassung

Die Syndrome FCAS („familial cold autoinflammatory disease“), MWS („Muckle-Wells syndrome“) und CINCA/NOMID („chronic infantile neurologic, cutaneous, and articular syndrome“/„neonatal-onset multisystem inflammatory disease“) wurden ursprünglich als 3 unterschiedliche Erkrankungen beschrieben. Nach der Identifikation ihrer gemeinsamen genetischen Ursache 2001 und 2002 werden sie als Kontinuum einer Entität verstanden und mit CAPS („cryopyrin-associated periodic syndromes“) bezeichnet. Mutationen im NLRP3-Gen auf dem Chromosom 1q44 lassen sich bei vielen betroffenen Patienten nachweisen. Diese führen zur Synthese des veränderten Genprodukts Cryopyrin. Als Bestandteil des NLRP3-Inflammasoms aktiviert es Caspase 1 und verursacht dadurch eine Überproduktion von IL-1β. IL-1β ist der Motor der überschießenden Inflammation, die bei CAPS beobachtet wird. Bei klinisch erkrankten Patienten, bei denen mit herkömmlicher Genanalyse kein Nachweis einer Mutation möglich ist (bis zu 40 % im Falle des CINCA/NOMID-Phänotyps) kann mithilfe moderner NGS („next generation sequencing“)-Technologien in etlichen Fällen eine somatische Mutation gefunden werden. NLRP3-Varianten mit niedriger Penetranz werden dagegen auch bei nicht erkrankten Familienmitgliedern identifiziert und kommen in niedriger Häufigkeit in der Normalbevölkerung vor. Ein Teil der Betroffenen stellt sich jedoch mit den typischen Zeichen der Autoinflammation vor. Der Phänotyp unterscheidet sich allerdings vom klassischen CAPS. Die Patienten zeigen vermehrt unspezifische systemische Zeichen und in geringerem Umfang eine Organbeteiligung. Während der Nachweis einer Mutation im NLRP3-Gen den Verdacht bestätigen kann, basiert die Diagnose des CAPS nach wie vor auf dem klinischen Befund. Vor Kurzem publizierte Diagnosekriterien verzichten daher auf die Forderung nach einem Mutationsnachweis.

Schlüsselwörter

NLRP3-Gen Autoinflammation Penetranz Mutation Diagnose 

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.

Keywords

NLRP3 gene Autoinflammation Penetrance Mutation Diagnosis 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

J.B. Kümmerle-Deschner und P. Lohse geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Klinik für Kinder- und Jugendmedizin, autoinflammation reference center TübingenUniversitätsklinikum TübingenTübingenDeutschland
  2. 2.TengenDeutschland

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