Familial Mediterranean fever is no longer a rare disease in Japan.

Kiyoshi Migita,Toshimasa Shimizu,Tadashi Nakamura,Keita Fujikawa,Katsumi Eguchi,Yoshifumi Ubara,Kazunaga Agematsu,Masataka Umeda,Koh-Ichiro Yoshiura,Tomohiro Koga,Fumiaki Nonaka,Yuka Jiuchi,Atsushi Kawakami,Satoshi Yamasaki,Yoshikazu Nakashima,Chieko Kawahara,Junya Masumoto,Akihiro Yachie,Michio Yasunami,Yuichi Izumi ,Naoki Iwanaga

doi:10.1186/s13075-016-1071-5

Abstract

BackgroundThe aim of this study was to evaluate the clinical manifestations and prevalence of familial Mediterranean fever (FMF) in Japanese patients with unexplained fever and rheumatic manifestations.MethodsWe enrolled 601 patients with unexplained fever or suspected FMF throughout Japan between 2009 and 2015. Patients were divided into three groups according to Tel Hashomer criteria: sure FMF, probable FMF, and non-FMF patients, including definitive rheumatic diseases. Mutation detection in exons 1, 2, 3, and 10 of the FMF gene MEFV was performed by direct sequencing.ResultsA total of 192 patients (31.9 %) were diagnosed with FMF according to FMF diagnostic criteria. These could be divided into sure FMF (56.3 %, n = 108) and probable FMF (43.7 %, n = 84) patients. Fever, abdominal symptoms, and thoracic symptoms were significantly more common in FMF than non-FMF patients. Among FMF patients, 26 (13.5 %) had concomitant rheumatic diseases. Most FMF patients (94.3 %, 181/192) carried at least one MEFV mutation. Allele frequencies of M694I (13.5 % vs 0 %) and E148Q (39.1 % vs 24.8 %) mutations were significantly higher in FMF compared with healthy subjects. Allele frequencies of common MEFV mutations in FMF patients were M694I (13.5 %), P369S (8.6 %), R408Q (8.1 %), G304R (2.9 %), R202Q (4.4 %), E148Q (39.1 %), L110P (11.7 %), and E84K (3.1 %). Patients with a sure FMF phenotype had a higher frequency of MEFV exon 10 mutation (M694I) and a lower frequency of MEFV exon 3 mutations (P369S, R408Q) compared with those with a probable FMF phenotype.ConclusionThe high prevalence of FMF in Japanese patients with unexplained fever was confirmed in the present study. FMF should be suspected in cases of unexplained fever or non-specific rheumatic manifestations, and mutational analysis of MEFV could be useful to predict the clinical phenotypes of FMF in Japan.

Highlights

The aim of this study was to evaluate the clinical manifestations and prevalence of familial Mediterranean fever (FMF) in Japanese patients with unexplained fever and rheumatic manifestations
On the basis of Tel Hashomer criteria [13], patients were divided into three groups: sure FMF—certain clinical diagnosis in the presence of two major criteria or one major and two minor criteria; probable FMF—clinical diagnosis considered probable in the presence of one major and one minor criterion or two minor criteria; and non-FMF—clinical diagnosis considered unlikely in the presence of only one minor and no major criteria
The clinical diagnosis of FMF is not easy [3]. It has mainly been based on clinical signs, MEditerranean FeVer gene (MEFV) genetic analysis is useful in Japan [14]

Summary

Introduction

The aim of this study was to evaluate the clinical manifestations and prevalence of familial Mediterranean fever (FMF) in Japanese patients with unexplained fever and rheumatic manifestations. Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by short, recurrent bouts of fever [1]. FMF diagnosis is difficult because of the lack of specific clinical signs. It is prevalent in Mediterranean and Middle Eastern populations [3], where clinical diagnosis has been prompt, but non-Mediterranean FMF patients have been reported [4]. A crucial issue for genetic counseling is that some patients presenting with manifestations of sure FMF are heterozygotes of MEFV variants [7].

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