Mediterranean Fever Gene Research Articles

Amyloid goiter secondary to familial Mediterranean fever with E148Q mutation: A unique case.

Amyloid goiter secondary to familial Mediterranean fever with E148Q mutation: A unique case.

Juvenile-onset systemic lupus erythematosus and MEFV polymorphism: A case–control association study among Iranian children

Introduction and objectivesThis study is designed to evaluate the potential influences of Mediterranean fever gene (MEFV) gene polymorphism on systemic lupus erythematosus (SLE) in a cohort of juvenile patients. A case–control study was performed on Iranian patients with a mixed ethnicity population. Patients and methodsGenotypes of 50 juvenile cases, and 85 healthy controls were investigated for identifying M694V and R202Q polymorphism. Genotyping was done utilizing amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to detect M694V and R202Q mutations, respectively. Main findingsOur study indicates significant differences in the alleles and genotypes frequencies of MEFV polymorphism between SLE patients and healthy controls (P<0.05). Also, an association was found between renal involvement (50% vs. 8.3%, P=0.000, OR=0.91, 95% CI=0.30–0.278) in juvenile SLE patients and M694V polymorphism incident; But there was no association with other clinical manifestations. Principal conclusionWe found a significant association between R202Q and M694V polymorphism of the MEFV gene and susceptibility to SLE in the studied population; However, further studies on detailed characterization of these polymorphisms’ impacts on the key elements responsible for SLE pathogenesis is of great importance.

Possible Association of Mutations in the MEFV Gene with the Intestinal Phenotype of Behçet's Disease and Refractoriness to Treatment.

Mediterranean fever (MEFV) gene mutations are responsible for familial Mediterranean fever (FMF) and associated with other inflammatory diseases. However, the effects of MEFV gene mutations on intestinal Behçet's disease (BD) are unknown. In this study, we investigated these mutations and clinical features in patients with intestinal BD. MEFV gene analysis was performed in 16 patients with intestinal BD, 10 with BD without intestinal lesions, and 50 healthy controls. Clinical features of patients with intestinal BD were retrospectively assessed. The rates of MEFV gene mutations in patients with intestinal BD, BD without intestinal lesions, and healthy controls were 75%, 50%, and 38%, respectively. Only 2 of 12 patients with intestinal BD harboring MEFV gene mutations (17%) were controlled without immunosuppressive treatment, while 8 patients (67%) required therapy with tumor necrosis factor (TNF) inhibitors. Among patients with intestinal BD without MEFV gene mutations (four patients), three (75%) were controlled by the administration of 5-aminosalicylic acid with or without colchicine, and one (25%) required TNF inhibitors. All patients who underwent intestinal resection had MEFV gene mutations. Immunohistochemical analysis and in situ hybridization with interleukin-1β (IL-1β) showed a high expression of IL-1β only in injured areas, suggesting that IL-1β may be involved in the formation of ulcers in patients with intestinal BD carrying MEFV gene mutations. Mutations in the MEFV gene may be associated with intestinal lesions of BD and refractoriness to treatment.

Periodic Fever in Children: A Report of Three Unusual Cases

Introduction: Periodic fever syndrome (PFS) is a rare monogenic autoinflammatory disease group. The innate immune system abnormalities have a characteristic onset and spontaneous inflammation without any infectious or autoimmune trigger. It differs from autoimmune disorders (e.g., systemic lupus erythematosus (SLE)) occurring due to a defect in the adaptive immune system with auto-antibodies. Case Presentation: The clinical features of three patients presented with a periodic pattern of fever and a different constellation of symptoms were investigated. The final diagnosis of Periodic fever syndrome was reached based on standard diagnostic criteria and genetic testing. All three cases were observed to present with recurrent fever episodes at an interval of 6 - 12 weeks, 3 - 4 weeks, and one month, respectively. The first patient, presenting with a diffuse erythematous plaque-like lesion along the calf with severe calf pain and tenderness with signs of meningeal irritation, was diagnosed with a tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) like phenotype. The genetic panel was negative in this case. The second patient presenting with recurrent pharyngitis, cervical adenitis, and tonsillitis unresponsive to antibiotics was diagnosed with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. The last patient presenting with recurrent monoarthritis, hepatosplenomegaly, and a positive Mediterranean fever (MEFV) gene mutation was diagnosed with familial Mediterranean fever (FMF). All three patients had normal growth and development. Conclusions: Although periodic fever syndrome was an uncommon entity, it was recommended that this syndrome should be considered when a patient presented with recurring fever episodes with a characteristic constellation of symptoms.

The Clinical Journey of a Patient with Familial Mediterranean Fever: One Gene, Three Diseases.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease characterized by recurrent self-limiting attacks of fever and serositis (Ben-Chetrit E and Levy M, Lancet 1998; 351: 659–664). The gain-of-function mutations in the responsible gene encoding pyrin, known as the MEditerranean FeVer (MEFV) gene, cause a reduction in the activation threshold of pyrin inflammasome triggering recurrent clinical attacks, subclinical inflammation, and a tendency for other inflammatory diseases (Jamilloux Y et al., Rheumatology (Oxford) 2018; 57: 100–111). Familial Mediterranean fever is more prevalently seen in the Middle Eastern communities. A relatively severe disease phenotype together with several diseases associated with FMF was frequently reported around this part of the world (Ben-Chetrit E and Yazici H, Clinical and Experimental Rheumatology 2019; 37 (Suppl 121): 18–22).

Evaluation of the frequency of MEFV gene variants in patients with a pre-diagnosis of Familial Mediterranean Fever (FMF) in southeast Turkey.

Purpose: Familial Mediterranean Fever (FMF) is a hereditary auto inflammatory disease (MIM#249100). The most common symptoms are high fever, abdominal pain and arthralgia. FMF is the result of variations in the MEditerraneanFeVer (MEFV) gene, which is located on chromosome 16p13.3, consists of 10 exons and encodes the pyrin (marenostrin) protein. The frequency of MEFV gene variants that cause FMF varies according to ethnic groups, countries and even different regions in the same country. In this study, we aimed to determine the frequency and distribution of MEFV gene alterations that cause Familial Mediterranean fever in southeastern Turkey.&#x0D; Materials and Methods: A total of 6,660 patients with a prediagnosis of FMF, including 3,495 women and 3,165 men, were included in the study. Fragment analysis was performed to investigate the MEFV gene variations of the patients and the 19 most common variants in the Turkish population were examined.&#x0D; Results: We found at least one variation in 50.17% (3,341) of our 6,660 patients. In our patients, 108 different genotypes; in Exon 2, 3, 5 and 10 and we identified 16 different variations. We found 2,120 (63.21%) patients heterozygous, 693 (20.74%) compound heterozygotes, 275 (8.23%) homozygous and 261 (7.81%) complex genotypes. The 5 variants with the highest allele frequency are respectively; R202Q (27.84%), M694V (22.83%), E148Q (21.98%), V726A (7.42%), and M680I(G&gt;C) (6.39%).&#x0D; Conclusion: We identified the most common prevalence of MEFV gene alteration in a large patient group in our region. High R202Q mutation rates were among the remarkable results of this study.

Patients Without a Rheumatic Disease Diagnosis in a Pediatric Rheumatology Unit: Retrospective Analysis and Comparison Between Pre-pandemic and Pandemic Periods.

Children with suspicious complaints of rheumatic diseases are generally referred to a pediatric rheumatologist. We aimed to evaluate the profile of patients referred to the pediatric rheumatology unit and were not diagnosed with a rheumatic disease and to assess the impact of the coronavirus disease-2019 pandemic on referral complaints. All new outpatients who applied to the pediatric rheumatology department between March 2019 and February 2021 and were not diagnosed with rheumatic disease were included. We also compared the frequency of admission symptoms during the pre-pandemic (March 2019-February 2020) and pandemic periods (March 2020-February 2021). A total of 1089 patients without a rheumatic disease diagnosis (568 female, 52.2%; median age 10.0 years) were included in this study. The most common complaint for referral was prolonged or recurrent fevers (13.4%) followed by anti-nuclear antibody positivity (13.1%), arthralgia (13.0%), skin findings (7.5%), and the presence of heterozygous mutations in the Mediterranean fever gene (6.9%). During the pandemic year, the number of patients referred for back pain increased significantly (P = .028). A total of 682 of 1089 patients were consulted from other departments in our center (62.6%). Of these, the most frequent consultation request was from general pediatrics (43.6%). The rheumatic disease was excluded in 11.3% of the patients. Prolonged or recurrent fever and anti-nuclear antibody positivity were the most frequent complaints of referrals to a pediatric rheumatology unit in patients who did not have a rheumatic disease. The rate of back pain was more common in children during the pandemic period.

Immunogenic Potential of the Mediterranean Fever Gene in Patients with Coronavirus Disease: A Cross-Sectional Study.

In December 2019, an outbreak of pneumonia caused by the novel coronavirus disease 2019 (COVID-19) became a pandemic and caused a global health crisis. This study evaluates the immunogenic potential of the Mediterranean fever (MEFV) gene in patients with COVID-19. A cross-sectional study was conducted from March to April 2020 in various COVID-19 referral centers in Ardabil, Iran. Blood samples of 50 hospitalized patients with confirmed COVID-19 were evaluated for MEFV gene mutation using the amplification refractory mutation system polymerase chain reaction (ARMS-PCR) and Sanger sequencing. Statistical analysis was performed using SPSS software, version 22.0. Mutations of the MEFV gene were found in 6 (12%) of the patients. All mutations were heterozygous, and no homozygous or compound heterozygous forms were detected. The total mutant allele frequency was 6% and the carrier rate was 12%. The most common allele of the MEFV variant was E148Q, detected in 3 (6%) patients. No mutant variant of the MEFV gene was detected in deceased patients. None of the mutation carriers had familial Mediterranean fever (FMF) symptoms or a family history of FMF. MEFV gene mutations may have immunogenic potential in patients with COVID-19. A preprint version of this article has already been published at https://www.researchsquare.com/article/rs-69373/latest.pdf.

Identification and Validation of Key Gene Modules and Pathways in Coronary Artery Disease Development and Progression.

The development and progression of atherosclerosis represent a chronic process involving complex molecular interactions. Therefore, identifying the potential hub genes and pathways contributing to coronary artery disease (CAD) development is essential for understanding its underlying molecular mechanisms. To this end, we performed transcriptome analysis of peripheral venous blood collected from 100 patients who were divided into four groups according to disease severity, including 27 patients in the atherosclerosis group, 22 patients in the stable angina group, 35 patients in the acute myocardial infarction group, and 16 controls. Weighted gene co-expression network analysis was performed using R programming. Significant module-trait correlations were identified according to module membership and genetic significance. Metascape was used for the functional enrichment of differentially expressed genes between groups, and the hub genes were identified via protein-protein interaction network analysis. The hub genes were further validated by analyzing Gene Expression Omnibus (GSE48060 and GSE141512) datasets. A total of 9,633 messenger ribonucleic acids were detected in three modules, among which the blue module was highly correlated with the Gensini score. The hub genes were significantly enriched in the myeloid leukocyte activation pathway, suggesting its important role in the progression of atherosclerosis. Among these genes, the Mediterranean fever gene (MEFV) may play a key role in the progression of atherosclerosis and CAD severity.

Frequency of rheumatic diseases in patients with familial Mediterranean fever

Purpose: Mutations in the Mediterranean FeVer (MEFV) gene, which causes familial Mediterranean fever (FMF), may also cause the emergence of other specific rheumatic diseases. This study aims to determine the frequency of other rheumatologic diseases in paediatric FMF patients, evaluate whether there are clinical and genetic differences between those with and without concomitant rheumatologic diseases, and compare the data with previous studies.&#x0D; Materials and methods: The files of FMF patients who were followed up at the paediatric rheumatology department were reviewed retrospectively. Demographic data, MEFV mutations, treatment, disease severity scores, and concomitant rheumatic diseases were recorded from the files.&#x0D; Results: There were 303 FMF patients (154 female/149 male). The mean age at diagnosis was 7.04±3.9 years. The mean disease duration was 5.33±3.13 years. In the cohort, 41 FMF patients (13.5%) were diagnosed with another rheumatic disease. There were 22 cases of juvenile idiopathic arthritis (53.6%), seven cases of vasculitis (17%), six cases of periodic fever aphthous stomatitis and adenitis syndrome (14.6%), three cases of Behçet disease (7.3%), two cases of acute rheumatic fever (4.8%), and one case of systemic lupus erythematosus (2.4%). 32 of these 41 FMF patients (78%) had the M694V mutation (homozygous in 11, heterozygous in 21). Disease activity scores PRAS and ISSF scores were higher in FMF with rheumatic diseases (p=0.002 and p

The Mediterranean Fever Gene Mutations and Its Association with HRQoL, Depression and Fatigue in Patients with Familial Mediterranean Fever Associated Spondyloarthropathies

The Mediterranean Fever Gene Mutations and Its Association with HRQoL, Depression and Fatigue in Patients with Familial Mediterranean Fever Associated Spondyloarthropathies

Does having MEFV gene sequence variants affect the clinical course and colchicine response in children with PFAPA syndrome?

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. • 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. •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.

Investigation of Neutrophil Extracellular Trap (NET) Induction in Patients with Chronic Idiopathic Neutropenia Bearing Mutations in the Mediterranean Fever (MEFV) Gene

Introduction: Chronic idiopathic neutropenia (CIN) is a disorder characterized by the prolonged and unexplained reduction in the number of circulating neutrophils. The pathophysiology of CIN has been associated with an inflammatory bone marrow microenvironment consisting of activated T-cells with an oligoclonal/monoclonal profile and intermediate CD14bright/CD16+ monocytes that induce the apoptotic death of the granulocytic progenitor cells. To probe further the basis of immune cell activation in CIN we have recently investigated by next generation sequencing (NGS) the frequency of mutations in the MEFV gene encoding pyrin, in a cohort of 50 CIN patients without any signs/symptoms of Familial Mediterranean Fever (FMF). We have found that 9/50 patients displayed variants associated with typical or atypical FMF phenotype in the Greek population implicating exon 10 and/or exon 2 (Skendros P et al. Blood, 138, Sup.1, p3124;2021). Aim:MEFV mutations have been associated with increased neutrophil activation in FMF and other inflammatory diseases, neutrophil entry in autophagy and extrusion of Neutrophil Extracellular Traps (NETs) decorated with the pro-inflammatory cytokine IL-1β. The aim of the current study is to investigate the association between MEFV mutations and NET formation in neutrophils of CIN patients. Patients-Methods: We studied 20 CIN patients (17 females and 3 males) aged 27 to 78 years. Six CIN patients harbored at least one MEFV mutation with potential clinical significance (A744S homo/R202Q homo, I720M hetero, R202Q homo, K965R hetero, A744S hetero, M694V hetero) and 14 were negative for MEFV pathogenic mutations. The MEFV R202Q mutation is located in exon 2 whereas all the rest mutations are located in exon 10. We isolated neutrophils from healthy subjects (n=5), age- and sex- matched with the patients, and co-cultured them with serum from CIN patients. We used the supernatants of the cultures to quantify NETs with Sytox green staining for extracellular DNA and/or ELISA for dsDNA/MPO complexes. We also used the serum-treated neutrophils for the evaluation of NETosis by immunostaining using confocal microscopy. In addition, neutrophils isolated from CIN patients were used to detect their direct response to spontaneous NETosis induction. Statistical analysis was performed with one-way ANOVA adjusting for multiple comparisons. Results: By co-culturing patients' sera with healthy neutrophils obtained from five different healthy donors, we did not identify statistically significant differences in NETosis evaluation between the three study groups i.e. CIN patients with MEFV mutations, CIN patients negative for pathogenic MEFV mutations, and healthy individuals. On an individual basis, the patient harboring the double homozygous MEFV mutations (A744S/R202Q) displayed increased NETosis in immunostaining, Sytox and ELISA evaluation, as compared to MEFV unmutated CIN patients and healthy individuals. In addition, ex vivo culture of patients' neutrophils and microscopic observation gave us the indication that CIN patients, regardless of their MEFV gene variants, present increased NETosis compared to healthy individuals, suggesting an overactivation status of neutrophils in CIN. Conclusions: The neutrophils of CIN patients display increased NETosis irrespectively of the MEFV mutation status and may thus contribute to the inflammatory processes associated with the disease, a field that has not been investigated so far. Although in our study MEFV mutations did not appear to contribute significantly to inflammatory processes through the NETosis mechanism in CIN patients, their involvement in other aspects of immune deregulation such as through the mTOR/autophagy pathway remains to be further explored.

Investigation of the effect of vascular endothelial growth factor gene 936 C/T polymorphism in familial Mediterranean fever patients

Objectives: This study aims to investigate the effect of vascular endothelial growth factor (VEGF) gene 936C/T polymorphism (rs3025039) on the appearance of phenotypic characteristics of familial Mediterranean fever (FMF) patients that differ with respect to MEditerranean FeVer (MEFV) gene mutations. Here, we investigated a single functional polymorphism in the VEGF gene. Methods: The study group consisted of 223 FMF patients with definite diagnosis according to Tel-Hashomer criteria who carried MEFV gene mutations, while 208 FMF patients with definite diagnosis of FMF but without any mutations, making up the control group, were included in the study. The VEGF gene 936C/T polymorphism was genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Results: Genotype and allele frequencies of the VEGF rs3025039 polymorphism between the two groups were significantly different (p = 0.03 and p = 0.011, respectively). The TT genotype was found to be more frequent in the study group than in controls (4.9% vs. 3.3%, respectively). Conclusions: Our results seem to indicate that the VEGF 936C/T polymorphism affects the appearance of the phenotypic characteristics of FMF. It is possible that other variants of this gene may also have similar effects.

Screening for Fabry’s disease in a high-risk subpopulation of FMF

BackgroundFamilial Mediterranean fever (FMF) is an autosomal recessive disease associated with mutations in the Mediterranean fever gene (MEFV) that manifests with recurrent episodes of febrile serositis. Fabry’s disease (FD) is an X-linked lysosomal storage disease caused by mutations in the alpha-galactosidase A gene and presents with a wide range of gastrointestinal, skin, vascular, renal and neurological manifestations. FMF and FD share similar manifestations, which may lead to misdiagnosis of one as the other; mostly FD is misdiagnosed as FMF. Moreover, various overlapping manifestations may stem from comorbidities, commonly coupled to FMF (such as Behcet's disease, inflammatory bowel disease, glomerulonephritis, fibromyalgia, and multiple sclerosis), as well as from colchicine adverse effects, which may add to the diagnostic confusion. Thus, we postulated that screening FMF for FD will lead to the identification of patients falsely diagnosed with FMF or who, in addition to FMF, suffer from FD that was previously missed.MethodsTo identify missed FD among the FMF population, we performed chemical and genetic analyses for FD in blood samples obtained from a cohort of FMF patients followed in the specialized FMF center of our institution. To increase the likelihood of detecting patients with FD, we enriched the surveyed FMF population with patients exhibiting manifestations shared by patients with FD or who deviate from the typical FMF presentation.Results and conclusionsOf 172 surveyed FMF patients in a cohort derived from a clinic dedicated to FMF, none had FD. Thus, the postulation of increased odds for detecting FD in patients with FMF was not confirmed. Further exploration for FD in FMF population, is nevertheless recommended.

Can RDW be used as a screening test for subclinical inflammation in children with FMF? Is RDW related to MEFV gene mutations?

Subclinical inflammation, an insidious feature of familial Mediterranean fever (FMF), can lead to life-threatening amyloidosis. We aimed to investigate acute phase reactants and complete blood count parameters to identify a useful marker for subclinical inflammation in children with FMF. A secondary aim was to identify an association between subclinical inflammation and specific Mediterranean fever (MEFV) gene mutations. This study included 420 pediatric patients with FMF. Laboratory parameters of patients during the attack-free period and MEFV gene mutation analyses were recorded. Of the 420 patients, 88 (21%) had subclinical inflammation. Of those with subclinical inflammation, 48 (55%) had mutations in exon 10, 36 (41%) had M694V mutation, and 10 (11%) had M694V homozygous mutation. Red cell distribution width (RDW) value was higher in exon 10, M694V, and M694V homozygous mutations compared to other mutations. RDW was positively correlated with serum amyloid A (SAA) (r = 0.390, p = 0.0001). Analysis of a receiver-operating characteristic curve of RDW revealed that its optimal cut-off value for subclinical inflammation was 12.69%, its sensitivity was 64.10%, and its specificity was 50.90%. The area under the curve was 0.616 (p = 0.004, 95% confidence interval = 0.538-0.695). We suggest that RDW can be used as a screening test as a marker of subclinical inflammation. A high RDW value should alert the clinician about subclinical inflammation in FMF children's patients with M694V (heterozygous, homozygous, compound heterozygous) mutation. Key Points • Subclinical inflammation in FMF patients can lead to amyloidosis. • RDW can be a predictor of subclinical inflammation. • RDW can be used as a screening test for subclinical inflammation in FMF patients with M694V mutation.

Acute Recurrent Pericarditis as the Inaugural Manifestation of Familial Mediterranean Fever.

Familial Mediterranean fever (FMF) is an inherited autosomal recessive disorder commonly found among individuals of Mediterranean or Middle Eastern descent and caused by Mediterranean Fever gene (MEFV) mutations on chromosome 16. It is the most frequent periodic febrile syndrome among the autoinflammatory syndromes. Typical febrile attacks include serosal inflammation, but although FMF is characterized by recurrent polyserositis, there is a little documentation of pericardial disease among patients.We report the case of a patient who presented recurrent pericarditis. Each episode occurred with a high fever and elevation of the C-reactive protein level. Treatment with colchicine was effective. The patient was found to be heterozygous for the V726A mutation.LEARNING POINTSThe aetiology of recurrent pericarditis is still largely unknown.The occurrence of pericarditis as a manifestation of familial Mediterranean fever is controversial.

Determining the origin of different variants associated with familial mediterranean fever by machine-learning

A growing number of familial Mediterranean fever (FMF) patients in Israel do not have a single country of origin for all four grandparents. We aimed to predict the Mediterranean fever gene (MEFV) variant most likely to be found for an individual FMF patient, by a machine learning approach. This study was conducted at the Sheba Medical Center, a referral center for FMF in Israel. All Jewish referrals included in this study carried an FMF associated variant in MEFV as shown by genetic testing performed between 2001 and 2017. We introduced the term ‘origin score’ to capture the dose and different combinations of the grandparents’ origin. A machine learning approach was used to analyze the data. In a total of 1781 referrals included in this study, the p.Met694Val variant was the most common, and the variants p.Glu148Gln and p.Val726Ala second and third most common, respectively. Of 26 countries of origin analyzed, those that increased the likelihood of a referral to carry specific variants were identified in North Africa for p.Met694Val, Europe for p.Val726Ala, and west Asia for p.Glu148Gln. Fourteen of the studied countries did not show a highly probable variant. Based on our results, it is possible to describe an association between modern day origins of the three most common MEFV variant types and a geographical region. A strong geographic association could arise from positive selection of a specific MEFV variant conferring resistance to endemic infectious agents.

A patient with familial Mediterranean fever mimicking diarrhea-dominant irritable bowel syndrome who successfully responded to treatment with colchicine: a case report

BackgroundIrritable bowel syndrome is a functional gastrointestinal disease. Visceral hypersensitivity is the most important pathophysiology in irritable bowel syndrome. Currently, diagnosis of irritable bowel syndrome is based on symptoms and exclusion of other organic diseases. Although the diagnosis of irritable bowel syndrome can be made based on the Rome IV criteria, one may speculate that complete exclusion of other organic diseases is not so easy, especially in cases uncontrolled with standard therapies.Case presentationWe present herein a case of familial Mediterranean fever in a young Japanese patient who had been suffering from an irritable bowel syndrome-like clinical course. A 25-year-old Japanese male had been diagnosed as having diarrhea-predominant irritable bowel syndrome 5 years earlier. Unfortunately, standard therapies failed to improve irritable bowel syndrome symptoms. After careful medical history-taking, we understood that he had also experienced periodic fever since 10 years ago. Although no mutation was identified in the Mediterranean fever gene, not only periodic fever but abdominal symptoms improved completely after colchicine administration. He was therefore diagnosed as having familial Mediterranean fever and that the abdominal symptoms may be related to the disease.ConclusionsFamilial Mediterranean fever should be considered as a cause of irritable bowel syndrome-like symptoms.

Autoinflammatory syndromes with coexisting variants in Mediterranean FeVer and other genes: Utility of multiple gene screening and the possible impact of gene dosage

ObjectiveTo assess the possible impact conferred by co-existing variants in MEditerranean FeVer (MEFV) and other genes on systemic autoinflammatory disease (SAID) phenotype. MethodsConsecutive patients (n = 42) who underwent screening for SAIDs by next generation sequencing (NGS) targeting 26 genes, and carried at least one MEFV gene variant, were retrospectively studied. A total of 63 MEFV gene variants mainly located in exon 10 (n = 29) and exon 2 (n = 19) were identified in 21 patients with juvenile- and 21 with adult-onset disease. ResultsThe candidate clinical diagnosis was Familial Mediterranean Fever (FMF) in 11, polygenic SAIDs (PFAPA, Still's disease, atypical SAPHO and inflammatory bowel disease) in 9, whereas the disease could not be clinically defined in 22 patients. Notably, 33 out of the 42 patients (79%) had at least one co-existing variants in 19 genes other than MEFV. NGS confirmed all clinical diagnoses and helped defining diagnosis in 59% of the remaining cases. Patients with undefined SAIDs (n = 9) or atypical FMF phenotype (n = 12) carried significantly more disease-causing variants in genes other than MEFV compared to patients with typical FMF (n = 9). More than one variants in these genes were significantly associated with adult-onset disease, while disease–causing variants in the same genes were also associated with an overall more severe SAID phenotype. ConclusionCo-existing variants in SAID-related genes may explain the phenotypic variability of these diseases. Further studies should validate combined molecular and clinical data in order to better understand the cumulative gene dosage effect and improve the classification of these patients.