Analysis of Cryopyrin-Associated Periodic Syndromes (CAPS) in German Children: Epidemiological, Clinical and Genetic Characteristics

Abstract

Background: Cryopyrin-associated periodic syndromes (CAPS) are rare disorders belonging to the group of hereditary periodic fever (HPF) syndromes. These auto-inflammatory diseases (AID) are characterized by recurrent episodes of inflammation with attacks of fever variably associated with serosal, synovial and/or cutaneous inflammation, usually in a self-limiting manner, and with a mostly monogenic origin. The aims were to determine the incidence of CAPS and the spectrum of mutations in the NLRP3 (formerly=CIAS1) gene and to describe the clinical manifestations.

Patients and methods: A prospective surveillance of children with CAPS was conducted in Germany during a time period of 3 years (2003–2006). Monthly inquiries were sent to 370 children's hospitals by the German Paediatric Surveillance Unit (Clinic-ESPED, n1) and to 2 laboratories (Laboratory-ESPED, n2). Inclusion criteria were children ≤16 years of age, disease-associated NLRP3 mutation, more than 3 self-limiting episodes of fever > 38.5 °C, and increased inflammation markers. Clinical, epidemiological and genetic data were evaluated via questionnaires.

Findings: 6 out of 14 patients were identified in Clinic-ESPED (n1) and 13/14 in Laboratory-ESPED (n2). Clinical and laboratory surveys overlapped in 5 of 14 cases. The incidence of CAPS in German children was estimated to be 3.43 per 10⁷ person-years. The patients carried 11 different NLRP3 mutations and were classified as MWS (n=6), CINCA (n=4), FCAS (n=1) and undefined CAPS (n=3).

Interpretation: The incidence of CAPS in Germany is very low and corresponds to 2–7 newly diagnosed patients ≤16 years per year.

Zusammenfassung

Hintergrund: Die Cryopyrin-assoziierten periodischen Syndrome (CAPS) sind seltene Erkrankungen, die zu der Gruppe der hereditären periodischen Fiebersyndrome (HPF) gehören. Diese auto-inflammatorischen Erkrankungen (AID) sind charakterisiert durch rekurrierende Entzündungsepisoden mit Fieberschüben, welche variabel mit Serositis, Synovitis und/oder Hautbeteiligung einhergehen, gewöhnlich selbstlimitierend verlaufen und meist monogenen Ursprungs sind.

Ziele: Inzidenzermittlung der CAPS sowie Beschreibung des Spektrums der Mutationen im NLRP3-Gen und der klinischen Manifestationen in dem untersuchten Kollektiv.

Patienten und Methoden: Eine prospektive bundesweite ESPED-Umfrage zur Inzidenzbestimmung wurde bei Kindern mit CAPS über insgesamt 3 Jahre durchgeführt (2003–2006). Monatlich wurden Meldekarten an 370 Kinderkliniken über ESPED (Klinik-ESPED, n1) und Fragebögen direkt an 2 Laboratorien (Labor-ESPED, n2) verschickt. Einschlusskriterien: Kinder ≤16 Jahre, krankheitsassoziierte NLRP3-Mutation, mehr als 3 selbstlimitierende Fieberepisoden > 38,5°C und erhöhte Entzündungsmarker. Klinische, epidemiologische und genetische Daten wurden durch Fragebögen ermittelt.

Ergebnisse: 6 von 14 Patienten wurden über die Klinik-ESPED (n1) und 13/14 über die Labor-ESPED (n2) identifiziert. 5/14 Kindern wurden überlappend in n1 und n2 dokumentiert. Die Inzidenz der CAPS wurde mit 3,43 pro 10⁷ Personenjahre berechnet. Die Patienten trugen 11 verschiedene NLRP3-Mutationen und wurden als MWS (n=6), CINCA Syndrom (n=4), FCAS (n=1) und unklar definierte CAPS (n=3) klassifiziert.

Schlussfolgerung: Die Inzidenz der CAPS ist sehr gering. Deutschlandweit werden pro Jahr ca. 2–7 neu diagnostizierte Fälle im Alter ≤16 Jahre erwartet.

Key words

CAPS - HPF - AID - ESPED - NLRP3 - CIAS1

Schlüsselwörter

CAPS - HPF - AID - ESPED - NLRP3 - CIAS1

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Correspondence