Genotype-Phenotype and Genotype-Origin Correlations in Children with Mediterranean Fever in Germany – an AID-Net Study

M. Jeske; P. Lohse; T. Kallinich; T. Berger; C. Rietschel; D. Holzinger; C. Kamlah; P. Lankisch; R. Berendes; G. Dueckers; G. Horneff; E. Lilienthal; J. P. Haas; A. Giese; F. Dressler; J. Berrang; L. Braunewell; U. Neudorf; T. Niehues; D. Föll; E. Lainka

doi:10.1055/s-0033-1355372

Klin Padiatr 2013; 225(06): 325-330
DOI: 10.1055/s-0033-1355372

Original Article

Genotype-Phenotype and Genotype-Origin Correlations in Children with Mediterranean Fever in Germany – an AID-Net Study

Genotyp-Phänotyp- sowie Genotyp-Herkunft-Korrelationen bei in Deutschland lebenden Kindern mit Familiärem Mittelmeerfieber (AID-NET)

M. Jeske

¹Pediatric Rheumatology, University Children′s Hospital, Essen, Germany

,

P. Lohse

²Human Genetics, Laboratory Medicine and Human Genetics, Singen, Germany

,

T. Kallinich

³Pediatric Pneumology and Immunology, Charité University Medicine Berlin, Germany

,

T. Berger

⁴Pediatric Rheumatology, Witten/Herdecke University Children’s Hospital, Datteln, Germany

,

C. Rietschel

⁵Pediatric Rheumatology, Clementine Children’s Hospital, Frankfurt/Main, Germany

,

D. Holzinger

⁶Pediatric Rheumatology and Immunology, University Children’s Hospital, Muenster, Germany

,

C. Kamlah

⁷Pediatric Rheumatology, University Children’s Hospital, Hamburg, Germany

,

P. Lankisch

⁸Department of Pediatric Oncology, Hematology and Clinical Immunology, Center of Child and Adolescent Health, Heinrich-Heine-University Duesseldorf, Germany

,

R. Berendes

⁹Pediatric Rheumatology, St. Marien’s Children’s Hospital, Landshut, Germany

,

G. Dueckers

¹⁰Pediatric Immunology and Rheumatology, HELIOS Klinikum’s Hospital, Krefeld, Germany

,

G. Horneff

¹¹Centre of Pediatric Rheumatology, Asklepios Clinic, St. Augustin, Germany

,

E. Lilienthal

¹²Pediatric Rheumatology, Ruhr-University Children’s Hospital, Bochum, Germany

,

J. P. Haas

¹³German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany

,

A. Giese

¹⁴Central Patient Admission/Emergency Department, Marienhospital, Herne, Germany

,

F. Dressler

¹⁵Pediatric Rheumatology Clinic, Hannover Medical School, Hannover, Germany

,

J. Berrang

¹⁶Pediatric Rheumatology, Westfaelisches Kinderzentrum, Dortmund, Germany

,

L. Braunewell

¹Pediatric Rheumatology, University Children′s Hospital, Essen, Germany

,

U. Neudorf

¹Pediatric Rheumatology, University Children′s Hospital, Essen, Germany

,

T. Niehues

¹⁰Pediatric Immunology and Rheumatology, HELIOS Klinikum’s Hospital, Krefeld, Germany

,

D. Föll

⁶Pediatric Rheumatology and Immunology, University Children’s Hospital, Muenster, Germany

,

E. Lainka

¹Pediatric Rheumatology, University Children′s Hospital, Essen, Germany

› Author Affiliations

Abstract

Introduction:

Familial Mediterranean fever (FMF) is the most inherited common autoinflammatory disease (AID) with mutations in the MEFV (MEditerraneanFeVer) gene.

Methods:

The Mor- and Pras-Score modified for children and C-reactive protein (CRP) were used to assess FMF disease severity in Germany. We evaluate the applicability of the 2 severity scores and the correlations between ethnic origin, phenotype, and genotype.

Results:

Among 242 children (median 5 age at diagnosis), we detected 431 pyrin mutations and 22 different sequence variants, including one new mutation (p.Gly488Asp). The 5 most frequent alterations were p.Met694Val (55.2%), p.Met680lle (11.8%), p.Val726Ala (10%), p.Glu148Gln (7.9%) and p.Met694IIe (2.3%). The prevailing ancestries of 223 cases were Turkish (82.5%) and Lebanese (8.1%). Homozygous p.Met694Val substitution (30.2%) was associated with a more severe disease activity by Mor-Score, as well as with a higher mean CRP (74 mg/l) compared to patients with other mutations. Indeed, Mor- and Pras-Score were inconsistent with each other. A typical distribution of mutations in different ethnic populations was obvious, but not statistically verifiable due to the low number of cases.

Conclusion:

The homozygous p.Met694Val substitution was associated with a more severe disease activity in our German cohort. The common severity scores were inconsistent in children.

Zusammenfasstung

Einleitung:

Das Familiäre Mittelmeerfieber (FMF) ist die häufigste vererbliche autoinflammatorische Erkrankung (AID) mit Mutationen im MEFV(MediterraneanFeVer)-Gen.

Methodik:

Zur Bestimmung des Erkrankungsschweregrades bei FMF-Patienten in Deutschland benutzten wir die für Kinder modifizierten Scores nach Mor et al. bzw. Pras et al. und das C-reaktive Protein (CRP). Wir untersuchten die Übereinstimmung der beiden Scores für die Erkrankungsaktivität und korrelierten zu Herkunft, Phenotyp und Genotyp.

Ergebnisse:

Bei 242 Patienten (Alter im Median: 5 Jahre zum Diagnosezeitpunkt) erfassten wir insgesamt 431 Pyrinmutationen mit 22 verschiedenen Sequenzvariationen, einschließlich einer neuen Mutation (p.Gly488Asp). Die 5 häufigsten Mutationen waren p.Met694Val (55,2%), p.Met680lle (11,8%), p.Val726Ala (10%), p.Glu148Gln (7,9%) und p.Met694IIe (2.3%). Die vorwiegende ethnische Herkunft von 223 Fällen war türkisch (82,5%) oder libanesisch (8%). P.Met694Val homozygot (30,2%) trat signifikant häufiger in Verbindung mit einem schwereren Erkrankungsgrad (nach Mor) sowie einem höheren mittleren CRP-Wert (74 mg/l) im Vergleich zu Patienten mit anderen Mutationen auf. Allerdings waren Mor- und Pras-Score nicht konsistent miteinander. Obwohl eine typische Mutationsverteilung in den verschiedenen ethnischen Gruppen auffiel, konnte dies aufgrund der niedrigen Patientenanzahl nicht statistisch nachgewiesen werden.

Zusammenfassung:

Der Genotyp p.Met694Val homozygot war in unserer deutschen FMF-Kinderkohorte mit einer schwereren Erkrankungsaktivität assoziiert. Beide bekannten Scores für die Erkrankungsschweregrade waren für Kinder inkonsistent.

Key words

FMF - AID - MEFV gene - pyrin - phenotype - HRF

Schlüsselwörter

FMF - AID - MEFV-Gen - Pyrin - Phänotyp - HRF

Full Text

References

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Supplementary Material

Supplementary Material