An unusual presentation of familial Mediterranean fever with co-existing polyarteritis nodosa and acute post-streptococcal glomerulonephritis

The homozygous M694V mutation in the MEFV gene may cause an augmented response to the streptococcal infection that plays a role in the development of APSGN and PAN. Both clinical manifestations may occur simultaneously after streptococcal infection in a child who is previously healthy but carries a MEFV mutation.

Evaluation of the Clinical Effects and Frequency of MEFV Gene Mutation in Patients with Inflammatory Bowel Disease

Background. The clinical and pathological features of inflammatory bowel disease (IBD) and Familial Mediterranean Fever (FMF) are similar. Objective. Here, the frequency of Mediterranean Fever (MEFV) gene mutation and its effect on the outcome of IBD were evaluated. Methods. DNA sequence analysis detected the variants on the MEFV gene in patients with IBD. The relationship between mutations and the need for steroids, immunomodulators, biologics, and surgery was assessed. Results. We evaluated 100 patients with IBD (55 with ulcerative colitis (UC) and 45 with Crohn’s disease (CD)) and 60 healthy individuals as controls. The frequency of MEFV gene mutation was 26.7% ( n = 12 ) and 14.5% ( n = 8 ) for UC and CD, respectively. No relationship was found between MEFV gene mutation and the need for steroids, immunomodulators, and biologics ( p = 0.446 ; p = 0.708 ; p > 0.999 , resp.); however, in UC, the need for surgery in those with mutation ( p = 0.018 ) and E148Q mutation alone was significant ( p = 0.037 ). Conclusion. The rate of MEFV gene mutations was high in patients with UC who required surgery. These patients have frequent and severe attacks, indicating that the mutations are related to disease severity. MEFV mutation as a modifier factor of IBD should be considered.

Increased Frequency of Mutations in the Gene Responsible for Familial Mediterranean Fever (MEFV) in a Cohort of Patients with Chronic Idiopathic Neutropenia

Introduction-Aim: Chronic idiopathic neutropenia (CIN) is a neutrophil disorder characterized by the prolonged and unexplained reduction in the number of peripheral blood (PB) absolute neutrophil counts (ANC). The underlying pathogenesis in CIN implicates the production of proinflammatory cytokines by activated lymphocytes and monocytes that induce excessive apoptotic death of the bone marrow (BM) granulocytic progenitor cells. Clonal hematopoiesis identified by next generation sequencing (NGS) of myeloid genes is found in 11% of CIN patients conferring an increased risk for MDS/AML transformation whereas the non-clonal patients display usually a benign course. The basis for the immune cell activation and proinflammatory cytokine production in CIN remains obscure. Based on previously reported data showing increased frequency of mutations of the MEFV gene encoding pyrin in patients with idiopathic inflammatory conditions other than typical Familial Mediterranean Fever (FMF), we sought to investigate the common MEFV mutations in a cohort of well characterized CIN patients. Patients-Methods: We have studied 50 patients fulfilling the previously reported diagnostic criteria of CIN (median ANC 1.5x10 9/L, range 0.2-1.7 x10 9/L), 44 females and 6 males with a median age of 56 years (range 25-87 years) and a long-follow-up (median 132 months, range 8-336 months) in the Department of Hematology of the University Hospital of Heraklion, Crete, Greece. Nonisotopic RNase cleavage assay (NIRCA) analysis was used as first screening method to detect MEFV exons 10 and 2 mutations in DNA extracted from PB or BM samples from CIN patients, confirmed by direct NGS analysis. These sequences contain the main disease-related mutations and polymorphisms. Results: Genetics alterations of MEFV were detected in 22 out of 50 CIN patients (44%). Pathogenic mutations (variants associated with typical or "atypical" FMF phenotype in Greek population) were identified in 10/50 CIN patients (20%). The 20% frequency of MEFV mutations in exon 10 and/or exon 2 in CIN patients is significantly higher compared to the carrier rate of common MEFV mutations in the healthy Greek population (0.7%) according to our previously reported data (P<0.0001, Fisher's exact test). NGS analysis confirmed the mutational pattern of NIRCA and specifically showed: (a) one patient with heterozygous I720M (ATC>ATG; Ile>Met), two patients with heterozygous A744S (GCC>TCC; Ala>Ser) and one with homozygosity, one patient with heterozygous M694V (ATG>GTG; Met>Val), one with heterozygous K695R (AAG>AGG; Lys>Arg) and one with heterozygous M680I (ATG>ATC; Met>Ile), all in exon 10, and (b) four patients with homozygous R202Q mutation in exon 2 (one patient with homozygous A744S co-mutation in exon 10) and two patients with R202Q heterozygosity combined with heterozygosity of I720M and A744S of exons 10, respectively. None of the patients displayed any symptoms/signs of FMF or other systemic inflammatory disease. No statistically significant differences were identified between MEFV mutated and non-mutated CIN patients in the severity of neutropenia or in lymphocyte, monocyte, hemoglobin and platelet counts. A significant difference was identified between the two patient groups in serum IgG (1440±264 vs 1133±245 mg/dl; P = 0.0023, Mann-Whitney test) but not IgA or IgM levels. Discussion: This study reports for the first time that 20% of unselected, consecutive patients with CIN carry mutations of the MEFV gene without clinical manifestations of FMF. Whether these patients represent atypical cases of FMF or the identified MEFV genetic alterations have a pathogenetic/modifying effect in the inflammatory responses associated with CIN is an open/novel field of research. As a first step we are currently investigating the neutrophil autophagic status, IL-1β production and the neutrophil extracellular trap (NET) formation in CIN patients with mutations in MEFV to clarify their potential effect in the immune deregulation known to characterize CIN. Disclosures No relevant conflicts of interest to declare.

P050 Consensus based practice guidelines for the management and treatment of Juvenile familial Mediterranean fever: the Egyptian College of Paediatric Rheumatology initiative

Background Familial Mediterranean fever (FMF) is the most common monogenic auto-inflammatory disease, with the highest prevalence amongst Mediterranean countries including Egypt (where there is high carrier rate of MEFV gene), characterized by recurrent attacks of fever and polyserositis. Mutations in the MEFV gene encoding pyrin has been associated with the disease, which causes exaggeration of the inflammatory response through uncontrolled interleukin production. Issuing updated treatment recommendations are vital for the treating healthcare professionals to get well acquainted with its diagnosis & treatment. To produce consensus-based recommendations to guide the early diagnosis, management and follow-up of patients with FMF. Methods The Patient/Population, Intervention, Comparison, and Outcomes (PICO) questions were developed and refined by the core team. A qualitative synthesis of scientific evidence based on systematic review and clinical experience was conducted to compile evidence for the diagnosis and management of FMF. A consensus process was conducted among the expert panel to generate the final recommendations and grade their strength. 3 rounds of Delphi process were carried out. Results Following 3 Delphi rounds, recommendations were developed for: early diagnosis, who to treat, treatment targets, genetic testing and its interpretation in association with clinical presentation, treatment of FMF and dealing with acute attacks, monitoring of management, identify treatment response, systemic affection, persistent attacks or inflammation, resistant cases, protracted symptoms, as well as remission status. Algorithm for patients’ diagnosis and management is provided. The final document comprises 12 recommendations, each presented with its degree of agreement (0–10), Level of agreement, grade of recommendation and rationale. The degree of agreement was >7/10 in all instances. Conclusion This guideline provides comprehensive approach to the accurate diagnosis and effective management/monitoring of FMF. It also represents a model for the incorporation of medical genetics practice into the more traditional domains of general medicine.

Spectrum of Mutations of Familial Mediterranean Fever Gene by Whole Sequencing Method in Iranian Patients

Background: Familial Mediterranean fever (FMF) is the most common type of periodic fever syndrome. The disease is most prevalent in the western Mediterranean population, but today it is widespread in the world due to the large ethnic migrations of Turks, Jews, Arabs and Armenians. The MEFV gene is the only gene known to be associated with the disease. Objectives: The aim of this study was to characterize pathogenic mutations in patients with typical FMF symptoms by sequencing the entire MEFV gene. Methods: This is a descriptive-analytical study that was performed during ten years from 2009 to 2019. On 252 patients after clinical diagnosis based on existing criteria to determine mutations referred to Tehran Medical Genetics Laboratory and the whole sequencing method for MEFV gene was used to determine mutations. Results: Out of 252 patients, 143 (56.7%) had pathogenic variants, and 109 (43.3%) had no variants reported as pathogenic mutations. Variants were identified as fallow: (1) 8.7% as homozygous; (2) 22.2% as compound heterozygous; (3) 25.7% as heterozygous. The most common variants were M694V (c.2080A > G) and E148Q (c.442G > C). Conclusions: This study showed that the age of onset of the disease was in the first and second decades of life amongst our patients and the most common complaints of patients were periodic fever and abdominal pain. The most frequent allele was M694V (c.2080A > G) followed by E148Q (c.442G > C) allele.

The Assessment of Selected miRNA Profile in Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is the most prevalent autoinflammatory disease. Typical findings are recurrent fever attacks with serositis, skin rash, and synovitis. FMF is caused by mutations in the MEFV gene, encoding pyrin protein. Pyrin functions in innate immunity and triggers inflammation via inflammatory mediators’ production and acts as the primary regulatory component of the inflammasome. On the other hand, various miRNAs play crucial roles in the pathogenesis of different types of cancers and immune-related and neurodegenerative diseases. However, their association with FMF is still unclear. Therefore, in this study, we assessed the roles of selected thirteen miRNAs associated with immune functions. We recruited genetically diagnosed 28 FMF patients and 28 healthy individuals. The expression profiling of the miRNAs was determined by qRT-PCR and normalized to SNORD61. Our analysis revealed that miR-34a-5p, miR-142-3p, miR-216a-5p, miR-340-5p, miR-429, and miR-582-5p were upregulated, whereas miR-107, miR-569, and miR-1304-5p were downregulated in the FMF patients. Among them, miR-107 was found to be the most remarkable in M694V homozygous mutants compared to other homozygous mutants. During clinical follow-up of the patients with M694V mutation, which is closely related to amyloidosis, evaluation of mir-107 expression might be crucial and suggestive. Our results showed that miRNAs might serve a function in the pathogenesis of FMF. Further studies may provide novel and effective diagnostic and therapeutic agents that target examined miRNAs. Targeting miRNAs in FMF seems to be promising and may yield a new generation of rational therapeutics and diagnostic or monitoring tools enabling FMF treatment.