Familial Mediterranean Fever

Abstract

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by MEditerranean FeVer gene (MEFV) mutations. In Japan, patients with FMF have been previously reported, including a mild or incomplete form. Several factors are presumed to contribute to the variable penetrance and to the phenotypic variability of FMF. We conducted the current study to investigate the correlation of variable clinical presentations and MEFV genotypic distributions in Japanese FMF patients.We analyzed demographic, clinical, and genetic data for 311 FMF patients enrolled in the study. Clinically, we classified FMF into 2 phenotypes: 1) the “typical” form of FMF, and 2) the “atypical” form of FMF according to the Tel Hashomer criteria. Patients with the typical FMF phenotype had a higher frequency of febrile episodes, a shorter duration of febrile attacks, more frequent thoracic pain, abdominal pain, a family history of FMF, and MEFV exon 10 mutations. Conversely, patients with the atypical FMF phenotype had a lower frequency of fever episodes and more frequent arthritis in atypical distribution, myalgia, and MEFV exon 3 mutations. Multivariate analysis showed that the variable associated with typical FMF presentation was the presence of MEFV exon 10 mutations. Typical FMF phenotype frequencies were decreased in patients carrying 2 or a single low-penetrance mutations compared with those carrying 2 or a single high-penetrance mutations (M694I), with an opposite trend for the atypical FMF phenotype. In addition, patients having more than 2 MEFV mutations had a younger disease onset and a higher prevalence of thoracic pain than those carrying a single or no mutations. Thus, MEFV exon 10 mutations are associated with the more typical FMF phenotype. In contrast, more than half of the Japanese FMF patients without MEFV exon 10 mutations presented with an atypical FMF phenotype, indicating that Japanese FMF patients tend to be divided into 2 phenotypes by a variation of MEFV mutations.

Atypical type of familial Mediterranean fever: An underdiagnosed cause of chronic aseptic meningitis

“…Some of the FMF patients without exon 10 and with especially exon 3 mutations presented with an atypical FMF symptoms 3. Our patient, however, had heterozygous mutations on exon2 and 5 (E148Q/S503C) of the MEFV gene.…”

“…Atypical FMF, unlike typical FMF, has the following features: clinical course of less than 12 h or more than 3 days, over 14 days in some cases, localized abdominal signs, or atypical distribution of arthritis 1. Colchicine is also effective 3. The present case developed fever, lower abdominal and back pain because of serositis, and headache because of chronic meningitis.…”

“…A study reported that 43% cases of Japanese FMF were of the atypical type 3. Atypical FMF, unlike typical FMF, has the following features: clinical course of less than 12 h or more than 3 days, over 14 days in some cases, localized abdominal signs, or atypical distribution of arthritis 1.…”

“…The MEFV exon 10 mutations, the low frequency of high‐penetrance in the FMF population, are a cornerstone for dividing into 2 phenotypes 1, 3. Some of the FMF patients without exon 10 and with especially exon 3 mutations presented with an atypical FMF symptoms 3.…”

“…Familial Mediterranean fever can be categorized as being “typical” and “atypical” 3. The clinical features of typical FMF are self‐limited bouts of fever lasting 12 h to 3 days, with symptoms of serositis, pleuritis, arthritis,1 and recurrent aseptic meningitis 4.…”