A Unique Complex Variation Profile in a Patient with Familial Mediterranean Fever (FMF): Triple Homozygous E148Q-P369S-R408Q – “Case Report”

Tocilizumab is effective in a familial Mediterranean fever patient complicated with histologically proven recurrent fasciitis and myositis.

Renal amyloidosis in familial Mediterranean fever

Prevalence of the MEFV Gene Mutations in Childhood Polyarteritis Nodosa

Familial Mediterranean Fever (FMF, MIM 249100) is an autosomal recessive disease mainly affecting patients of the Mediterranean basin. It is an autoinflammatory periodic disorder characterised by recurrent episodes of fever and abdominal pain, synovitis and pleuritis. FMF is caused by mutations in the Mediterranean Fever (MEFV) gene located on chromosome 16p13.3. Several mutations in the MEFV gene have been characterised in different populations. However, very little is known about mutations in the MEFV gene in patients with Moroccan origin. The aim of this study is to determine the clinical components of FMF and characterise mutations in the MEFV gene in Moroccan patients. The study was carried out on 120 unrelated Moroccan patients referred to the department of medical genetics in Rabat for suspicious FMF over a period of 10 years. Patients were screened for the most common MEFV mutations by direct sequencing of exons 2 and 10. Of the 120 unrelated patients investigated, 56 patients (47%) were carriers of one or two MEFV mutations, and 64 patients (53%) had no detected mutations. Of those with mutations, 24 were homozygous (44%), 13 were compound heterozygotes (24%), and 19 patients had only 1 identifiable mutation (32%). The most frequent mutation in Moroccan patients is M694V (47%), followed by M694I (32%), A744S (6.5%), M680L (4%), M694del (2%) and E148Q (6.5%). The R761H, K695R and I692del mutations were rarely encountered (less than 1%). The V726A mutation was not found in our study. Our data represent the first report of MEFV gene mutations causing FMF in Moroccans patients. The M694V and M694I mutations are the most common mutations found in MEFV gene in Moroccan population; while the most common mutation in Arabs from the Middle-East region, the V726A, was not found in our population.

Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease characterized by recurrent bouts of fever and serositis. Mediterranean Fever (MEFV) gene mutations may cause not just FMF but various serositis including arthritis, enterocolitis, aseptic meningitis, pulmonary disease, and pericarditis. In this report, we present a 44-year-old female carrying MEFV gene variant. She was admitted to our hospital with a high fever, right back pain during inspiration, and lower-left abdominal pain. Laboratory findings showed high inflammatory response. Computed tomography (CT) indicated pleurisy of the right lobe and inflammation of the left uterine appendage. Transvaginal sonography and magnetic resonance imaging (MRI) indicated hydrosalpinx of the left oviduct. The symptoms of recurrent fever and transient serositis suggested FMF, and abdominal pain was resolved after taking colchicine. Later, it turned out that she had MEFV gene mutation (exon2 G304R heterozygous). Although she did not meet the criteria of FMF, this is the first reported MEFV variant carrier with transient hydrosalpinx. Attacks in female patients with FMF are triggered by menstruation. Moreover, FMF and associated amyloidosis may cause both male and female infertility. Although male patients with FMF may present with acute scrotum, diagnostic criteria of FMF do not include inflammation of uterine appendages. Internal medicine physicians need to cooperate with gynecologists to diagnose female patients carrying MEFV gene variants.

Familial Mediterranean fever (FMF) is the most common autoinflammatory disease characterized by recurrent serositis attacks and fever. The discovery of the Mediterranean fever (MEFV) gene has been a milestone in FMF etiopathogenesis. Our knowledge about the relationship between the MEFV gene and FMF phenotype increases each day. This study aims to investigate the relationship between MEFV gene mutations and the FMF clinical findings of a single-center FMF cohort. Gender, age, age at symptom onset, age at diagnosis, clinical characteristics, and MEFV gene analysis of the patients were recorded. A total of 837 FMF patients were included in this study. There were 515 females and 322 males. The age at symptom onset was 18.3±10.9 years, while the age at diagnosis was 24.4±10.9 years. The most common symptom that accompanied fever was peritonitis (91.1%), while the other common clinical findings were pleuritis (45%), myalgia (44%), and arthritis (36%). A total of 47 patients developed amyloidosis. A total of 553 (66%) FMF patients had M694V mutation, 221 (26%) of which were homozygous, while 332 (40%) were heterozygous. Exon 10 mutation frequency was 759 (91%), while the non-exon 10 mutation frequency was 78 (9%). There was no wild type among the patients. In conclusion, the fact that a vast majority of the disease burden was constituted by the exon 10, especially M694V mutations and that none of the 837 patients from our cohort had a wild-type FMF proved the significance of MEFV gene mutation analysis. Therefore, we speculate that it is necessary to examine the MEFV gene mutations in each FMF suspected case. It seems plausible to re-evaluate the FMF diagnosis for cases in which a wild type MEFV gene mutation occurs.

Introduction: Familial Mediterranean fever (FMF) is an autoinflammatory fever syndrome distinguished by recurrent attacks of spontaneous peritonitis, pleuritis, fever, and arthritis. It is specifically seen in the ethnic groups of Mediterranean origin, but sporadic cases have been reported in Eastern Europe and America due to migrations. There is a number of cardiac manifestations associated with FMF. Methods: Using PubMed as the search engine, the literature search was done for articles published between 1958 and 2020. To summarize the body of available evidence, a scoping review was carried out to find relevant articles and case reports in patients of FMF with cardiovascular manifestations. Results: In the literature, there is a number of mechanisms explaining the cause of cardiac involvement in FMF, including the subclinical inflammation and secondary (AA) amyloid deposition in the vessels and the myocardium. There is a variable and often spurious course of these manifestations and it can be associated with a poor prognosis such as an acute myocardial infarction. In FMF patients, polyarteritis nodosa and Henoch-Schönlein purpura are seen more significantly as compared to the general population with increased frequency of mutations in Mediterranean fever (MEFV) gene. Through unclear mechanisms, Behçet’s disease is associated with MEFV gene mutations and shares vascular manifestations with FMF. There is an interplay of IL-1 and MEFV gene, which impart an important role in inflammatory attacks of FMF. There is an intima-media thickening of blood vessels AA to persistent inflammation which can lead to atherosclerotic plaque formation resulting in atherosclerotic cardiovascular disease. Conclusion: FMF and its associated cardiovascular diseases are interlinked to 2 main mechanisms: subclinical atherosclerosis and amyloid deposition, and colchicine is the primary treatment of patients with FMF which shows the regression of amyloid deposits and prevents cardiovascular sequelae.

The primary aim of this study was to document the treatment modalities used in periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome and look for the efficacy and safety of colchicine in the treatment of PFAPA patients. The secondary aim was to search for whether having MEFV (Mediterranean fever) gene sequence variants affect the clinical course and response to colchicine. The study was conducted in 2 pediatric rheumatology centers. The patients that have been diagnosed with PFAPA syndrome between December 2017 and December 2021 were evaluated retrospectively. The study included 157 patients with PFAPA syndrome (54.8% boys and 45.2% girls). The median follow-up duration was 18 (IQR: 12–30) months. One hundred and fifty-five patients (98.7%) had exudative pharyngitis, 120 patients (76.4%) had aphthous stomatitis, and 82 patients (52.2%) had cervical lymphadenitis during the attacks. Clinical features during attacks were not affected by the presence or absence of the MEFV gene sequence variants. Corticosteroid treatment during attacks was given to 152 patients (96.8%). The frequency of fever attacks did not change in 57 patients (37.5%), increased in 57 patients (37.5%), and decreased in 38 patients (25%) after corticosteroid use. Colchicine was given to 122 patients (77.7%) in the cohort. After colchicine treatment, complete/near-complete resolution of the attacks was observed in 57 patients (46.7%). Colchicine led to partial resolution of the attacks in 59 patients (48.4%). In only 6 patients (4.9%), no change was observed in the nature of the attacks with colchicine treatment. The median duration of the attacks was 4 (IQR: 4–5) days before colchicine treatment, and it was 2 (IQR: 1–2.5) days after colchicine treatment. Also, a significant decrease in the frequency of the attacks was observed before and after colchicine treatment [every 4 (IQR: 3–4) weeks versus every 10 (IQR: 8–24) weeks, respectively, (p < 0.001)]. The overall response to colchicine was not affected by MEFV sequence variants. It was seen that the frequency of fever attacks decreased dramatically in both groups, and children with MEFV variants had significantly less attacks than children without MEFV variants after colchicine treatment (every 11 weeks vs every 9.5 weeks, respectively, p: 0.02).Conclusion: Colchicine seems to be an effective and safe treatment modality in PFAPA treatment. It led to a change in the nature of the attacks either in the frequency, duration, or severity of the attacks in 95.1% of the patients. This study has shown that having MEFV gene sequence variants did not affect the clinical course or response to colchicine. We recommend that colchicine should be considered in all PFAPA patients to see the response of the patient, irrespective of the MEFV gene mutations.What is Known:• Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is the most common periodic fever syndrome in the world. Familial Mediterranean fever (FMF) is the most common cause of periodic fever syndrome in Turkey.• Colchicine has become a new treatment option in PFAPA.What is New:• Some PFAPA patients have Mediterranean fever (MEFV) gene variants, and it is speculated that PFAPA patients with MEFV gene mutations respond better to colchicine.• The aim of this study was to look for this hypothesis. We have seen that the clinical phenotype and colchicine response of PFAPA patients were not affected by MEFV gene sequence variants.

Familial Mediterranean fever (FMF), an autoinflammatory disease, is very common in populations of Mediterranean ancestry. It is an autosomal recessive genetic disorder caused by mutations in theMEFVgene. The gene encodes a protein called pyrin or marenostrin which is involved in inflammatory pathways. From more than 150 mutations discovered in theMEFVgene so far, five (M694V, V726A, M680I, M694I and E148Q) are the most common in classically affected populations (Armenians, Arabs, Jews and Turks). Specific mutations and genotypes were found to be associated with severe or mild clinical forms of FMF, while various genetic and environmental modifying factors alter the phenotype. Some evolutionary aspects of the disease are being intensively studied: the origin of principalMEFVmutations, modification of pyrin's structure and function during phylogenesis, possible selective advantage ofMEFVheterozygotes.Key conceptsFamilial Mediterranean fever (FMF,MIM 249100) is an autoinflammatory genetic disease with autosomal recessive mode of inheritance and is frequently encountered in populations of Mediterranean area.FMF is manifested by periodic attacks of fever and inflammation in the peritoneum, synovium or pleura. Renal amyloidosis is the most serious complication of the disease.The highest incidence of the disorder is registered in four ethnic groups (Armenians, Arabs, Jews and Turks) that are considered as ‘classically affected populations’.The illness is caused by mutations in theMEFV(MEditerraneanFeVer) gene, located on chromosome 16 (16p13.3) and is composed of 10 exons.MEFVencodes a protein named pyrin, or marenostrin, which is involved in innate immune response.More than 150MEFVmutations have been discovered so far; five mutations (M694V, V726A, M680I and M694I in exon 10 and E148Q in exon 2) are the most frequent in classically affected populations.Clinical course of FMF depends on theMEFVgenotype and is also under the influence of modifying factors of genetic and environmental nature.MainMEFVmutations were estimated to have a relatively ancient origin with subsequent spread during migrations and contacts between ancestral populations of the area.Unusually high incidence ofMEFVmutations in classically affected populations might be explained by the hypothesis of heterozygote advantage (i.e. overdominance), when heterozygote genotype has higher relative fitness than either the homozygote dominant or homozygote recessive genotype.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder with recurrent fever, abdominal pain, serositis, articular manifestations, erysipelas-like erythema, and renal complications as its main features. Caused by the mutations in the MEditerranean FeVer (MEFV) gene, it mainly affects people of Mediterranean descent with a higher incidence in the Turkish, Jewish, Arabic, and Armenian populations. As our understanding of FMF improves, it becomes clearer that we are facing with a more complex picture of FMF with respect to its pathogenesis, penetrance, variant type (gain-of-function vs. loss-of-function), and inheritance. In this study, MEFV gene analysis results and clinical findings of 27,504 patients from 35 universities and institutions in Turkey and Northern Cyprus are combined in an effort to provide a better insight into the genotype-phenotype correlation and how a specific variant contributes to certain clinical findings in FMF patients. Our results may help better understand this complex disease and how the genotype may sometimes contribute to phenotype. Unlike many studies in the literature, our study investigated a broader symptomatic spectrum and the relationship between the genotype and phenotype data. In this sense, we aimed to guide all clinicians and academicians who work in this field to better establish a comprehensive data set for the patients. One of the biggest messages of our study is that lack of uniformity in some clinical and demographic data of participants may become an obstacle in approaching FMF patients and understanding this complex disease.

Mutations of the Mediterranean fever (MEFV) gene, which encodes pyrin protein, leads to familial Mediterranean fever (FMF) and a connection between MEFV mutations and rheumatic diseases has been suggested. The aim of this study was to explore the frequency and clinical significance of MEFV mutations in children with juvenile idiopathic arthritis (JIA). In this study, children with JIA, who had no typical symptoms of FMF, were screened for the mutations in exons 2 and 10 of the MEFV gene by direct sequencing. A total of 96 children, 56 girls (58.3%), with a median age of 11 years (2-18 years) were included. Patients were classified according to JIA subgroups as oligoarthritis in 43 (44.8%), rheumatoid factor-negative polyarthritis in 22 (22.9%), rheumatoid factor-positive polyarthritis in 2 (2.1%), systemic arthritis in 12 (12.5%) patients, enthesitis-related arthritis in 16 (16.7%), and psoriatic arthritis 1 (1.04%). A total of 31 children (32.3%) had MEFV mutations: 25 heterozygous, 2 homozygous, and 4 compound heterozygous. There were 22 (11.4%) exon 10 mutations (M694V, R761H, K695R, V726A, R653H) and 15 (7.8%) exon 2 mutations (E148Q, G304R, E148V, T267I). The allele frequencies of MEFV mutations were found to be 19.27%, which is higher than the general population [p = 0.03, (odds ratio (OR):1.93, 95% confidence interval (CI): 1.09-3.41)]. MEFV mutation carrier rates were significantly higher in antinuclear antibody (ANA) negative than in ANA positive patients [p = 0.01, (OR: 0.25, 95% CI: 0.085-0.74)] and in males than in females [p = 0.001, (OR: 0.197, 95% CI: 0.078-0.495)]. Also, there was a statistically significant difference between the MEFV mutation carrier rates and the subgroups of JIA (p = 0.005). These findings suggest that mutations of the MEFV gene may be responsible for rheumatic diseases other than FMF, and patients with JIA especially males, ANA negatives, and ERA subgroups should be screened for MEFV gene mutations in countries where FMF is frequent.

Familial Mediterranean fever (FMF) is a disease characterized by recurrent fever, serositis, arthritis and unspecific myalgia. It is prevalent among Mediterranean people and has been shown to be associated with mutations in the Mediterranean fever (MEFV) gene which, encodes pyrin a regulatory protein of the inflammasome. As heterozygous mutations in MEFV can be associated with only mild inflammatory symptoms, such as arthralgia or chronic fibromyalgic pain, FMF may be underdiagnosed in the current diagnostic work-up of musculoskeletal diseases. The selection of patients was carried out according to the following criteria: myofacial pain syndrome, seronegative oligoarthralgia, a slight inflammatory constellation and ethnic origin from the Mediterranean area. When these criteria were fulfilled a molecular genetic investigation was carried out This article presents evidence that 9 out of 12 Mediterranean patients with recurrent myofascial pain syndrome and mild inflammation revealed heterozygote mutations in the MEFV gene and 7 of these patients benefitted from treatment with colchicine. As colchicine treatment not only improved the myofascial pain but also prevented FMF-associated amyloidosis and nephropathy, differential diagnosis of fibromyalgia in patients of Mediterranean origin should include FMF and a genetic screening of the MEFV locus.

Familial Mediterranean fever (FMF) is the most common hereditary inflammatory periodic disease, characterized by recurrent episodes of fever, abdominal pain, synovitis and pleurisy. The aim of this study was to determine the frequency and distribution of Mediterranean fever (MEFV) gene mutations and to investigate the clinical characteristics and genotype-phenotype correlation in patients with FMF in Aydin, a province in western Anatolia, Turkey. Therefore, we retrospectively analysed MEFV gene mutations in 383 patients with suspected FMF and the clinical features of 327 among them. The MEFV gene mutations were investigated using the reverse dot-blot hybridization technique. We detected 26 different genotypes and 11 different mutations. The most common mutations in our cohort were p.M694V (41.15%), p.E148Q (20.35%), p.M680I(G/C) (12.39%) and p.R761H (9.73%). Abdominal pain (86.2%), fever (80.7%), arthralgia (57.2%), vomiting (36.1%), arthritis (34.6%), fatigue (31.5%), anorexia (22.9%) and chest pain (19.0%) were the most prevalent clinical features in our patients. This is the first study from Aydin in which the distribution of MEFV gene mutations and clinical features were evaluated in patients with FMF. We found that the most common mutation was p.M694V in our region, while the frequency of the p.R761H mutation was higher compared to other regions of Turkey with respect to extracted data from previous similar studies. Presented results supported the clinical findings in the literature that the homozygous p.M694V and compound heterozygous genotype were associated with more severe courses in FMF patients.

Familial Mediterranean fever (FMF) is a systemic autoinflammatory disorder caused by inherited mutations in the MEFV (Mediterranean FeVer) gene, located on chromosome 16 (16p13.3) and encoding the pyrin protein. Despite the existing data on MEFV mutations, the exact mechanism of their effect on the development of the pathological processes leading to the spontaneous and recurrent autoinflammatory attacks observed in FMF, remains unclear. Induced pluripotent stem cells (iPSCs) are considered an important tool to study the molecular genetic mechanisms of various diseases due to their ability to differentiate into any cell type, including macrophages, which contribute to the development of FMF. In this study, we developed iPSCs from an Armenian patient with FMF carrying the M694V, p.(Met694Val) (c.2080A>G, rs61752717) pathogenic mutation in exon 10 of the MEFV gene. As a result of direct differentiation, macrophages expressing CD14 and CD45 surface markers were obtained. We found that the morphology of macrophages derived from iPSCs of a patient with the MEFV mutation significantly differed from that of macrophages derived from iPSCs of a healthy donor carrying the wild-type MEFV gene.

The spectrum of MEFV gene mutations and genotypes in Van province, the eastern region of Turkey, and report of a novel mutation (R361T)