Familial Mediterranean Fever Gene Research Articles

Autoinflammatory Diseases: A Review.

Autoinflammatory disease (AID) is a vast spectrum of disorders characterized by recurrent attacks of sterile inflammation. Since the first cloning of the familial Mediterranean fever gene in 1997, there has been a rapid rate of discovery of new AIDs. As of 2022, there have been 485 inborn errors of immunity documented by the International Union of Immunological Societies, for which many display aspects of autoinflammation. The pathophysiology of AIDs is complex. Although many are caused by rare mutations in genes that govern innate immunity, others are polygenic, where disease expression is thought to be triggered by environmental factors in genetically predisposed hosts. AIDs range in prevalence from common entities like gout to ultrarare monogenic diseases. Whereas AIDs were initially studied in pediatric populations, it is now apparent that they can present in adulthood and even in the elderly. AIDs can be clinically challenging given their rarity, as well as the heterogeneity in presentation and underlying etiology. Although the care of AIDs can span medical disciplines, the rheumatologist often plays a central role given the inflammatory nature of these illnesses. In this review, we explore the current understanding of the pathophysiology of these complex conditions and propose a classification system for AIDs. We place an emphasis on AIDs that present to the adult rheumatologist and discuss important AIDs that can mimic more classic rheumatic diseases such as systemic lupus erythematosus and inflammatory arthritis. Finally, we offer an approach to the clinical assessment, diagnosis, and management of AIDs.

Associations of MEFV gene variants, IL-33, and sST2 with the risk of Henoch-Schönlein purpura in children

ObjectiveHenoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children. HSP is a multifactorial inflammatory disease, but its pathogenesis is still unclear. The pathogenicity of familial Mediterranean fever gene (MEFV) variants in HSP remains controversial. The objective of this study was to evaluate relationships between MEFV variants and susceptibility to HSP and their associations with clinical outcomes. We also investigated levels of IL-33 and soluble suppression of tumorigenicity 2 (sST2) in children with HSP and their clinical significance. MethodsWe selected 100 children with HSP as the case group. The control group consisted of 50 children who visited the hospital for physical health examinations. All subjects were screened for MEFV gene exon mutations, and levels of IL-33 and sST2 were measured. ResultsThe frequency of MEFV variants was significantly greater in HSP patients than in healthy controls. The variant with the highest frequency was E148Q. The frequency of the C allele of the MEFV variant E148Q was 32 % in HSP patients and 18 % in controls (P-adjust = 0.04). Patients with the MEFV E148Q variant had more frequent joint involvement and recurrent purpura and higher levels of IL-33 and C-reactive protein (CRP). Levels of IL-33 and sST2 in children with HSP were significantly higher than those in the control group, and the sST2/IL-33 ratio in children with HSP was unbalanced (P-adjust <0.05). Logistic regression analysis revealed the presence of E148Q and an unbalanced sST2/IL-33 ratio to be independent risk factors for HSP. ConclusionThe results of this study suggest that the MEFV variant E148Q is associated with HSP susceptibility in Chinese children and that carriers of the variant may have more severe clinical manifestations and greater inflammatory responses. E148Q and the sST2/IL-33 ratio may play important roles in the pathogenesis of HSP.

Familial Mediterranean fever gene variations could trigger VPS16-associated early-onset dystonia and diabetes mellitus: clinical identification of a family with MEFV and VPS16 genetic variation association.

We describe the clinical pictures of an index case with dystonia and his family resulting from VPS16 and MEFV genetic variations based on previously published data and discuss the mechanisms that may have brought out the clinical findings. A 17-year-old male had generalized dystonia that started at age 6 years, non-febrile abdominal pain attacks and was diagnosed with type 1 diabetes at age 14 years. Meanwhile, his 13-year-old sister had the same clinical presentation. His father was diabetic and his mother was asymptomatic. There was no consanguinity between the parents. Genetic variations were detected with whole exome sequencing. VPS16 c.1513C>T/p.Arg505* (likely pathogenic), MEFV c.2080A>G p.Met694val (pathogenic) and MEFV c.1772T>C p.Ile591Thr (unknown significance) heterozygous variants were detected in his siblings. The father had VPS16 c.1513C>T/p.Arg505* and MEFV c.2080A>G p Met694val variations and the mother had MEFV c.1772T>C p.Ile591Thr variations. The occurrence of these diseases in siblings but their absence in the parents suggests the idea that the coexistence of two separate variations in the VPS16 and MEFV genes determines the phenotype. In addition, the increase in MEFV variation load in this family and the fact that DM occurs at an earlier age suggest that inflammation may cause an early diabetic clinical presentation.

Familial Mediterranean fever as a predictor of preeclampsia in pregnancy: Case report

Familial Mediterranean Fever (FMF) is an autosomal recessive auto inflammatory disorder characterized by recurrent fever and inflammation affecting the serosal membranes. Clinically, patients may experience attacks of recurrent fever and serositis, which can manifest with single or multiple simultaneous symptoms. While most patients are clinically diagnosed above the age of 2, cases diagnosed before 2 years of age, with an isolated fever clinical course, are believed to have a more severe course and an increased risk of developing amyloidosis. Preeclampsia, a serious complication of pregnancy, is characterized by hypertension and organ damage, most commonly affecting the kidneys and liver. In this article, we present a case of a pregnant woman who was admitted during the 27rd week of pregnancy with rapidly developing preeclampsia and HELLP syndrome, despite having no previous history of complications. During the follow-up, we discovered the presence of FMF and certain thrombophilia gene mutations. This case underscores the importance of considering specific diseases or syndromes under any presentation of preeclampsia. Timely identification of underlying conditions, such as FMF and thrombophilia, can aid in early intervention and appropriate management, potentially improving maternal and fetal outcomes

The Effect of Anti-Inflammatory Drugs on MEFV, PSTPIP1, Siva, and ASC Gene Expression Levels

Aim: Familial Mediterranean Fever (FMF) is the one of the most common autoinflammatory diseases. FMF is characterized by fever attacks and inflammation and colchicine treatment reduces the frequency and severity of FMF attacks. The FMF gene, MEditerranean FeVer (MEFV), encodes a protein called Pyrin, which regulates inflammation through its interactions with several proteins. These proteins are; Apoptosis-associated speck like protein with a CARD (ASC), Proline serine threonine phosphatase interacting protein 1 (PSTPIP1), 14.3.3 proteins and Siva proteins. In this study, we aimed to study the effect of anti-inflammatory drugs with different mechanisms of action on MEFV, PSTPIP1, Siva, and ASC gene expression levels. &#x0D; Material and Methods: We used differentiated monocytic cell line called THP-1 cells. Cells treated with colchicine, naproxen, prednol-L, acetylsalicylic acid, or azathioprine w and w/o lipopolysaccharide (LPS). After incubation, quantitative RT-PCR (qRT-PCR) was performed to measure MEFV, PSTPIP1, Siva, and ASC gene expression levels. &#x0D; Results: MEFV gene expression level was down regulated in colchicine, naproxen, and azathioprine treated cells whereas PSTPIP1 gene expression level was down regulated in naproxen and azathioprine treated cells with LPS. Siva gene expression level was up regulated in all treatments although ASC gene expression level was up regulated in only prednol-L treated cells with LPS.&#x0D; Conclusion: These anti-inflammatory drugs are known to have different mechanisms of action however they are all used to treat pain or inflammation. Since Pyrin, PSTPIP1, Siva, and ASC have pro and anti-inflammatory roles, the results showing an alteration in gene expression levels with specific drugs may indicate the possible mechanisms of therapeutic action.

How to Build a Fire: The Genetics of Autoinflammatory Diseases.

Systemic autoinflammatory diseases (SAIDs) are a heterogeneous group of disorders caused by excess activation of the innate immune system in an antigen-independent manner. Starting with the discovery of the causal gene for familial Mediterranean fever, more than 50monogenic SAIDs have been described. These discoveries, paired with advances in immunology and genomics, have allowed our understanding of these diseases to improve drastically in the last decade. The genetic causes of SAIDs are complex and include both germline and somatic pathogenic variants that affect various inflammatory signaling pathways. We provide an overview of the acquired SAIDs from a genetic perspective and summarize the clinical phenotypes and mechanism(s) of inflammation, aiming to provide a comprehensive understanding of the pathogenesis of autoinflammatory diseases.

Frequency of Familial Mediterranean Fever Gene Mutation in Patients Presenting With Joint Pain and Diagnosed With Acute Rheumatic Fever.

Introduction Acute rheumatic fever (ARF) is a non-suppurative systemic inflammatory disease that manifests 1-5 weeks following a Group A beta-hemolytic streptococcal infection. On the other hand, familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized as an autosomal recessive disease, with affected individuals having pathogenic mutations in the Mediterranean fever gene(MEFV)gene located on the short arm of chromosome 16. FMF and ARF have overlapping symptoms and signs, and both disorders are common in Turkey. In ARF, the target organ is the heart, while in FMF, the target organ is the kidney; both organs can benefit from prophylactic measures. Our study aims to determine the frequency of the FMF gene mutation in patients with ARF in Turkey and detect any overlapping conditions. Method Patients who were diagnosed with a first-attack ARF between May 2015 and May 2018 were retrospectively screened. Patients who underwent MEFV gene analysis considering FMF in the differential diagnosis were included in the study. Results In this study, no statistical difference was found between the presence of MEFV gene mutations, carditis, high anti-streptolysin-O antibody (ASO) levels, and the groups with monoarthritis, polyarthritis, and polyarthralgia (p >0.05). Conclusions In conclusion, patients with ARF should be evaluated for FMF to avoid irreversible complications.

POST COVID RECURRENT FEVER IN A CHILD WITH GENETIC SUSCEPTIBILITY TO FAMILIAL MEDITERRANEAN FEVER

<h3>Introduction</h3> Children and adults with post-acute sequelae of COVID (PASC) sometimes report recurrent fevers. We present the case of 13-year-old male with PASC recurrent fever who was found to have a heterozygous mutation in the gene associated with Familial Mediterranean fever (FMF). <h3>Case Description</h3> Our patient presented with recurrent fever 6 months after acute SARs-CoV-2 infection in January 2022. He endorsed prior episodes of unexplained fever and flushing prior but his recurrent fevers (39 C) post COVID had become more frequent occurring every few days. Laboratory analysis when he was afebrile demonstrated normal serum ESR, CRP, and CMP and normal cytokine levels. Genetic (In-Vitae) panel testing for autoinflammatory syndromes revealed a pathogenic heterozygous missense mutation in MEFV (p.A744S), the gene that controls pyrin production. A trial of colchicine was recommended, and he was referred to pediatric rheumatology. <h3>Discussion</h3> FMF is a genetic disorder that causes recurrent episodes of fever and almost always presents before age 20. Clinically significant FMF gene mutations lead to poorly functional pyrin; a protein that controls inflammation. Most children look and feel well between episodes but some children have such frequent episodes that they do not fully recover. In such cases, daily use of Colchicine should be considered as a safe and effective medication to control fever episodes. This report highlights the utility of genetic testing to identify potential causes of recurrent fever after COVID. Children with PASC related recurrent fevers should have genetic testing for susceptibility to FEF as this is a potentially treatable condition.

The frequency of fibromyalgia in familial Mediterranean fever and its impact on the quality of life.

Concomitant fibromyalgia syndrome (FMS) has been known to be more frequent in patients with several rheumatic diseases. In this study, our aim was to investigate the prevalence of FMS in patients with familial Mediterranean fever (FMF), to analyze the possible factors related to this frequency, and to evaluate the impact of FMS on the functionality and quality of life (QoL) of the patients with FMF. One hundred cases with FMF and 100 controls were included to this case-control study. FMS coincidence was investigated in all participants according to revised 2016 classification criteria. Demographic features, FMF disease duration, FMF gene mutations, drugs used, attack frequency per year, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum fibrinogen levels were recorded. FMF disease severity was assessed by International Severity Scoring System for Familial Mediterranean Fever (ISSF). For the assessments of QoL and functioning, FMF-QoL, Short form 36 (SF-36), and Health Assessment Questionnaire-Disability Index (HAQ-DI) were used, and for the assessment of FMS impact, the fibromyalgia impact questionnaire (FIQ) were used. We found an FMS frequency of 33% in patients with FMF in our study using the current FMS classification criteria. This result was significantly higher than in age- and gender-similar controls (6% FMS frequency; P < 0.05). The number of woman patients and FMF disease duration were significantly higher in patients with FMF + FMS than in patients with only FMF (P < 0.001). There was no significant difference in ISSF scores, ESR, CRP, and fibrinogen levels, management regimens, and FMF gene mutation distributions between FMF + FMS and FMF groups. FMF attack frequency was reported as significantly higher in FMF + FMS patients than in others (P < 0.000). In spite of similar FMF-QoL scores, there were significant differences in HAQ-DI and SF-36 scores between groups (P < 0.05). Higher impact of FMS presented negative correlation with functioning and general health, and positive correlation with QoL in FMF + FMS (P < 0.05). Concomitant FMS was a common clinical problem in patients with FMF regardless of the severity and characteristics of FMF. The FMS impact may affect function and QoL in patients of FMF. Considerations of the FMS component in the management of FMF may contribute to the holistic approach to FMF.

Genotyping of familial Mediterranean fever gene (MEFV)-Single nucleotide polymorphism-Comparison of Nanopore with conventional Sanger sequencing.

Through continuous innovation and improvement, Nanopore sequencing has become a powerful technology. Because of its fast processing time, low cost, and ability to generate long reads, this sequencing technique would be particularly suitable for clinical diagnostics. However, its raw data accuracy is inferior in contrast to other sequencing technologies. This constraint still results in limited use of Nanopore sequencing in the field of clinical diagnostics and requires further validation and IVD certification. We evaluated the performance of latest Nanopore sequencing in combination with a dedicated data-analysis pipeline for single nucleotide polymorphism (SNP) genotyping of the familial Mediterranean fever gene (MEFV) by amplicon sequencing of 47 clinical samples. Mutations in MEFV are associated with Mediterranean fever, a hereditary periodic fever syndrome. Conventional Sanger sequencing, which is commonly applied in clinical genetic diagnostics, was used as a reference method. Nanopore sequencing enabled the sequencing of 10 target regions within MEFV with high read depth (median read depth 7565x) in all samples and identified a total of 435 SNPs in the whole sample collective, of which 29 were unique. Comparison of both sequencing workflows showed a near perfect agreement with no false negative calls. Precision, Recall, and F1-Score of the Nanopore sequencing workflow were > 0.99, respectively. These results demonstrated the great potential of current Nanopore sequencing for application in clinical diagnostics, at least for SNP genotyping by amplicon sequencing. Other more complex applications, especially structural variant identification, require further in-depth clinical validation.

A recurrent side-changing febrile pleural effusion revealing familial mediterranean fever: a case report

Familial Mediterranean Fever (FMF), characterized by recurrent polyserositis, is an autosomal recessive disease involving essentially Mediterranean populations. We report the case of a 30-year-old Tunisian military patient complaining of fever and chest pain recurring on board a Navy military vessel, due to side-changing pleural effusion. On landing, a marked improvement of symptoms was noticed. Gene testing was performed when the diagnostic survey ruled out common etiologies, revealing a homozygous mutation of the FMF gene type M680l/M680l. The prescription of colchicine and the exemption from boarding led to the resolution of the symptoms with no recurrence of pleural effusion. Therefore, the diagnosis of FMF should be considered in a context of a recurrent pleural effusion in the youth, with a negative etiological assessment, notably in an ethnic group at risk. Thus, early diagnosis and adequate treatment may prevent the development of secondary amyloidosis, a serious complication of FMF.

Ultrasound Measurement of Femoral Cartilage Thickness in Patients with Familial Mediterranean Fever and its Relation to Amyloidosis and Other Disease Characteristics.

This study aimed to determine femoral cartilage thickness (FCT) in patients with familial Mediterranean fever (FMF) and healthy individuals and to assess the relationship of FCT with the development of amyloidosis and clinical features. Patients diagnosed with FMF according to the Tel-Hashomer criteria and healthy controls were included in the study. FCT of both knees was measured with a 7-12 MHz linear probe in maximum knee flexion. Three midpoint measurements were obtained from each knee: Lateral femoral condyle (LFC), intercondylar area (ICA), and medial femoral condyle (MFC). The patients' clinic characteristics include disease duration, medications, comorbid conditions, amyloidosis, chronic renal failure (CRF), FMF gene mutation, arthritis, sacroiliitis, PRAS score, and Physical Activity Questionnaire Short Form score were recorded. A total of 46 patients with FMF (36 women) and 20 age-sex-body mass index-matched controls (14 women) were enrolled in this study. The patients and controls' mean age were 37±12.9 and 37.5±8.6 years, respectively. Amyloidosis occurred in 7 patients (15.2%), CRF in 3 (6.5%), and knee arthritis in 8 (17%). Disease activity was mild in 55.8%, moderate in 20.9%, and severe in 23.23% of the patients. The mean FCT in millimeter values in the FMF and control groups was as follows: On the right side, LFC 1.9±0.5 and 2±0.52, ICA 2.2±0.77 and 2.25±0.97, and MFC 2±0.47 and 2.25±0.72; on the left side, LFC 1.9±0.4 and 2.05±0.55, ICA 2.25±0.87 and 2.25±0.87, and MFC 1.85±0.5 and 2.25±0.6. Patients with FMF had decreased cartilage thickness at the lateral condyle of both knees (p<0.05) and medial condyle of the left knee (p<0.05) compared with controls. FCT measurements were similar in patients with or without arthritis, amyloidosis, and CRF (p>0.05). FCT scores were not different among the disease activity groups (p>0.05). These findings suggest that patients with FMF have decreased FCT compared with controls, and there is no significant relationship between the FCT and amyloidosis and disease activity.

Frequencies of the MEFV Gene Mutations in Azerbaijan.

The MEFV (familial Mediterranean fever gene) researches were performed in the population of the Republic of Azerbaijan in 2016–2021. Seven mutations of the MEFV gene were identified in heterozygous, homozygous and compound homozygous conditions: R761H, M694I, M694V, V726A, R202Q, M680I and E148Q. The E148Q and R202Q mutations were discovered in exon 2 and R761H M694I, M694V, V726A, M680I were found in exon 10 in the population of the Republic of Azerbaijan. The highest gene frequency of the MEFV gene examined in 42 patients was 42.85% in the M694V mutations. The second highest frequency was the R761H and the third most frequent mutation was V726A. According to world literature, five mutations, M694V, V726A, M694I, R202Q, M680I and E148Q, constitute 75.0% of all mutations found today. In our studies, these five mutations belong to the same group, and makes up 57.6% of the total mutations found. In order to prevent hereditary disease such as the familial Mediterranean fever (FMF) in the population of the Republic of Azerbaijan, it is planned to carry out prenatal diagnosis (PND) of the at-risk families.

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&gt;G) and E148Q (c.442G&gt;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&gt;G) followed by E148Q (c.442G&gt;C) allele.

POS1359 REGIONAL DIFFERENCES IN DISEASE CHARACTERISTICS OF FAMILIAL MEDITERRANEAN FEVER IN TURKEY: PRELIMINARY REPORT

Background:Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease accompanied by recurrent attacks of fever and serositis. It is prevalent among Mediterranean populations, mainly Turks, Armenians; Jews and Arabs. As genetic factors are variable in the population, environmental factors can also affect phenotypic characteristics.Objectives:This study aimed to determine the geographic differences in disease characteristics and burden in patients with FMF in Turkey.Methods:Patients diagnosed with FMF according to the Tel-Hashomer criteria were included in this multi-center study. Patients were included from the different regions of Turkey. Demographic features and clinic characteristics of the patients including disease duration, medications, comorbid conditions, attack characteristics, amyloidosis, acute phase reactants, FMF gene mutations, arthritis, sacroiliitis, and febrile myalgia were recorded. PRASS disease activity score, FMF-QoL, HAD, and HAQ were assessed. Patients from different parts of Turkey were divided into 3 groups the Central Anatolia, Western, and Eastern. Disease activity, characteristics and burden were also investigated among 3 distinct geographic regions.Results:A total of 281 patients with FMF (195 women, 86 men) were enrolled in this study. The mean age of the patients was 34.9 (SD:12.3) years. While the patients in the eastern areas of Turkey were diagnosed earlier age (p&lt;0.001), the patients in the western area had a longer diagnostic delay time (p&lt;0.001). Patients enrolled from western regions tended to have higher ESR and PRASS scores than those from eastern and central Anatolian regions, but attack numbers per 6 months were similar among the regions. The highest proportion of patients who were M694V/M694V homozygous patients were in western, and then eastern and central Anatolia (19.5%, 18%, and 5.4%). While fever and arthritis were more common in the eastern, pleuritis and sacroiliitis were more common in the central anatolia. Peritonitis and erysipelas like erythema rates were similar among the regions. The majority of patients were receiving colchicine treatment in all three regions. FMF-QoL scores were highest in the eastern and lowest in the western (p=0.006). Patients enrolled in the central Anatolia region experienced more functional disability than those from the western and eastern regions (p=0.009). Anxiety and depression scores were similar between groups (p=0.385 vs p=0.549).Conclusion:These findings suggest that patients with FMF have diversity concerning the age at diagnosis, diagnostic delay time, disease activity, quality of life, and functional disability among the 3 regions. In the genotypic analysis, the M694V mutation is the most common pathogenic mutation in all regions. Regional genetic and environmental varieties may explain the areal differences. These relationships can occur more clearly in larger patient populations.

R761H M694I, M694V, V726A, R202Q, M680I AND E148Q MEFV GENE (FAMILIAL MEDITERRANEAN FEVER GENE) MUTATIONS IN THE AZERBAIJANİAN PATİENTS

MEFV gene (Familial Mediterranean Fever Gene) is located on chromosome 16 - 16.13.3., and it is composed of 3,242,028-3,256,776 nucleotides. It is specified as having an autosome-recessive hereditary type. Autosome-dominant hereditary species were also recorded(2,4). The MEFV RoRet genes family contains exon 10, consisting of 10,000 nucleotide sequences(5). The length of the transcript consists of 3.7 thousand nucleotide sequences consisting of 761 synthesized pyridine protein amino acid bases(1,3) MEFV gene researches were performed in the population of the Republic of Azerbaijan. Over 80 mutations have been identified so far. Four missense mutations (M680I, M694V, M694I, and V726A) in exon 10, together with E148Q in exon 2, account for the majority of FMF mutations in populations originating from areas around the eastern Mediterranean region. The various combinations of MEFV mutations are largely associated with the phenotypic variability of the disease. The most serious complication of FMF is the development of renal amyloidosis, which may be the only manifestation of the disease. The molecular-genetic study of the MEFV gene isolated from the genome DNA of 18 patients suspected of Family Disease Fever has identified 7 mutations: R761H M694I, M694V, V726A, R202Q, M680I and E148Q. All patients were of Azerbaijan origin, from the Mediterranean region of Azerbaijan. They were evaluated for clinical findings and family history of FMF. Seven mutations of MEFV gene were identified in heterozygous, homozygous and compound conditions: R761H M694I, M694V, V726A, R202Q, M680I and E148Q. The mutations E148Q and R202Q were discovered in exon 2 and R761H M694I, M694V, V726A, M680I were found in exon10 in the population of the Republic of Azerbaijan.

Endoplasmic Reticulum Aminopeptidase-1 (ERAP-1) Mutations in People with Familial Mediterranean Fever (FMF) Gene Mutations Without Disease

Endoplasmic Reticulum Aminopeptidase-1 (ERAP-1) Mutations in People with Familial Mediterranean Fever (FMF) Gene Mutations Without Disease

Evaluation of Dry Eye Syndrome in Patients With Familial Mediterranean Fever: A Cross-sectional Study

Objective. It has been reported that some autoimmune diseases are associated with dry eye syndrome. There are limited studies that relates dry eye syndrome in patients with Familial Mediterranean fever (FMF). The aim of this study is to evaluate the relationship between dry eye syndrome in patients with FMF comparing with healthy controls. Methods. Prospective cross-sectional study was carried out in departments of physical medicine and rehabilitation and ophthalmology clinics in a tertiary public institution with a sample of 46 participants including 23 FMF patients and 23 healthy controls. Detailed eye examination was performed in all cases and indicators of xerophthalmia were assessed by Schirmer-I test, tear break-up time (TBUT) and ocular surface disease index (OSDI). In patient group; results of FMF gene analysis, acute phase reactants, concomitant diseases and number of FMF attacks were noted. Results. The average Schirmer-I test results for right-eye were recorded as 14.74±8.38 for the FMF group and 13.09±10.54 for the healthy group; the TBUT scores were 14.69±5.32 in FMF group and 15±6.45 in the healthy group; and OSDI scores were 9.04±2.75 and 10.86±1.77 in the FMF group and the healthy control, respectively. There were no statistically significant differences between FMF and control groups in terms of Schirmer-I, TBUT, and OSDI scores (all p＞0.05). No correlation was identified between acute phase reactants and the OSDI, TBUT and Schirmer-I tests for right-eye (all p＞0.05). Conclusion. This study identified no correlation between dry eye and FMF. Ocular pathology is rare and infrequently reported in FMF. (J Rheum Dis 2020;27:270-276)

Comment on: The conundrum of juvenile spondyloarthritis classification: Many names for a single disease? Lesson learned from an instructive clinical case

Dear Editor, We read with great interest the paper titled “The conundrum of juvenile spondyloarthritis classification: Many names for a single disease? Lesson learned from an instructive clinical case” by Maniscalco et al1 which emphasizes the complexity of the clinical phenotypes of juvenile spondyloarthropathies (JSpA). All pediatric rheumatologists face these evolving phenotypes of these groups of diseases in their daily practice. To handle these classificational dilemmas, several classification criteria have been proposed for JSpA.2-4 The most recent one, International League of Associations for Rheumatology (ILAR) classification criteria for juvenile idiopathic arthritis (JIA), does not mentioned JSpA as a discrete subgroup and classifies these groups of diseases under three main groups: enthesitis-related arthritis, psoriatic arthritis and undifferentiated arthritis.2 The main concerns about these criteria are: the certain phenotypes of JSpA like inflammatory bowel disease-related arthritis, reactive arthritis were not included in these criteria, and some of the patients are classified as undifferentiated arthritis because of patients fulfilling two subtypes of JIA. It is obvious that these classification criteria are insufficient to reflect all phenotypes of JSpA and there is apparently a need for new sets of criteria.5 The nomenclature for juvenile spondyloarthropathies is not well-defined and still remains enigmatic. This term mainly encompasses enthesitis-related arthritis, psoriatic arthritis, juvenile ankylosing spondylitis, inflammatory bowel disease-related arthritis and reactive arthritis.6, 7 Contrary to adult SpA, JSpA rarely involves the axial skeleton in the early stages of the disease and it usually presents with asymmetric oligoarthritis of lower extremity joints and enthesitis. Therefore, enthesitis-related arthritis can be seen as an early presentation of JSpA. In addition to mentioned diseases, it is also shown that clinical features of JSpA can be seen in the course of familial Mediterranean fever (FMF) and Mediterranean fever gene mutation may be a susceptibility factor for enthesitis-related arthritis especially in regions endemic for FMF.8 In our cohort of patients with FMF, 10.2% of children also fulfilled classification criteria for JSpA.8 Moreover, chronic recurrent multifocal osteomyelitis (CRMO) was suggested to be an unusual form of SpA by several authors and Vittecoq et al9 showed that some of the patients with CRMO developed SpA. The insightful report by Maniscalco et al1 also supports this perspective. In adult patients, rheumatoid arthritis which is the most common cause of adult chronic arthritis and ankylosing spondylitis are well-defined as two distinct phenotypes and both of them have highly accepted classification criteria. In contrast, JSpA is considered under the JIA umbrella in ILAR classification criteria. Yet, this classification criteria obviously are not sufficient to cover this broad spectrum of JSpA (the reasons mentioned above). It is difficult to distinguish between oligoarticular JIA and JSpA especially in the early stages of disease and pediatric rheumatology societies should focus on establishing clearer definitions for JIA and JSpA and developing the new classification criteria which cover all frameworks of JSpA as a distinct disease. We think this approach will not only provide expanded covering but also, better understanding between pediatric and adult rheumatologists. No author of this paper has a conflict of interest, including specific financial interests, relationships and/or affiliations relevant to the subject matter or materials included.

The Frequency of Familial Mediterranean Fever Gene Mutations and the Correlations between Phenotype and Genotype in Turkish Children

Aim: Familial Mediterranian Fever is an autosomal recessive disease characterized by recurrent inflammatory attacks of serosal membranes. The aim of the current study was to determine the frequency of the Mediterranean fever (MEFV) gene pathogenic variants in 158 children (78 male, 80 female) diagnosed with Familial Mediterranean Fever (FMF) and to compare the phenotype-genotype correlation.&#x0D; Methods: In our retrospective case-control study, 158 FMF patients (78 males, 80 females) who were diagnosed with MEFV gene mutation in Bursa Yuksek Ihtisas Training and Research Hospital, Department of Pediatrics between January 2018 and June 2019 were included in the study. Mutation screening of the MEFV gene was performed for 12 mutations and the 8 most common mutations were taken into the study.&#x0D; Results: Abdominal pain (77.8%), fever (74%) and arthralgia (46.2%) were the most prevalent clinical features in our patients. The most frequent mutations were M694V, E148Q, V726A, M680I and P369S. In cases with M694 mutation, it was noted that the incidence of arthritis was 2.5 times, appendectomy frequency 3.1 times higher, and early diagnosis probability 3.2 times higher. The frequency of chest pain was 2.9 times higher in the M680I mutation, and the frequency of arthralgia was 2.2 times higher in the P369S mutation.&#x0D; Conclusion: Patient’s mutations in FMF patients are important for clinical expectations, and some mutations such as P369S are not as innocent as expected. However, reevaluation of phenotypes of mutations that are rare with more patients will be significant.