A Case of Familial Mediterranean Fever with Extensive Lymphadenopathy and Complex Heterozygous Genotype Presenting in the Fourth Decade

Familial Mediterranean fever (FMF) is an inherited disease caused by loss of function mutations in the MEFV gene encoding pyrin, a negative regulator of interleukin-1. The disease is characterized by recurrent fever and self-limited attacks of joint, chest, and abdominal pain but lymphadenopathy is an infrequent manifestation. While mesenteric lymphadenopathy has been described in several cases in the literature; hilar, paratracheal, axillary, pelvic, and retroperitoneal lymphadenopathy are extremely rare and have been reported separately in very few individuals. In this report, we present a patient with late-onset FMF with extensive lymphadenopathy in all of the aforementioned anatomic regions. Genetic analysis identified three heterozygous pyrin mutations in a patient with no affected family members. Genetic investigation of the patient’s mother identified a novel carrier haplotype E148Q/P369S. The proband also inherited the previously described and rare A744S mutation previously not thought to be a disease-defining lesion. This unique compound heterozygous genotype resulted in a novel genotype-phenotype association producing an atypical clinical presentation of FMF that fits within the pattern of several case reports of late-onset disease with respect to clinical course and therapeutic response.

Download Full-text

A new MEFV gene mutation in an Iranian patient with familial Mediterranean fever

Reumatismo ◽

10.4081/reumatismo.2019.1141 ◽

2019 ◽

Vol 71 (2) ◽

pp. 85-87

Author(s):

S. Farjadian ◽

F. Bonatti ◽

A. Soriano ◽

M. Reina ◽

A. Adorni ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Mutational Analysis ◽

Novel Mutation ◽

Present Report ◽

Case Reports ◽

Mefv Gene ◽

Recurrent Fever ◽

Iranian Patient ◽

Mediterranean Fever ◽

Exon 10

Familial mediterranean fever (FMF) is an inherited autoinflammatory disorder characterized by recurrent episodes of fever and painful inflammation involving the intra-abdominal organs, the lungs and the joints, which is highly prevalent in specific ethnic groups including the Iranians. We report a 12-year-old boy from Iran, with a clinical history of recurrent fever. Based on the suggestive clinical data, mutational analysis revealed the presence of the novel c.1945C>T heterozygous variant in exon 10, which leads to a leucine to phenylalanine change at position 649 of the protein. The mutation was inherited from the mother. This novel mutation lies in exon 10 of the MEFV gene, which encodes for a domain called B30.2-SPRY, located in the C-terminal region of the pyrin protein and contains the most frequent mutations associated with FMF. The present report expands the spectrum of MEFV gene mutations associated with FMF. The uniqueness of this study, compared with other published case reports, consists in the new mutation found in the MEFV gene. In fact, new mutations in this gene are of high interest, in order to better understand the role of this gene in autoinflammation.

Download Full-text

Il-1antagonist Treatment in Recurrent Aseptic Meningitis Related to Familial Mediterranean Fever

10.21203/rs.3.rs-71444/v1 ◽

2020 ◽

Author(s):

Ruth Livny ◽

Yuval Bitterman ◽

Riva Brik ◽

Yonatan Butbul Aviel

Keyword(s):

Nervous System ◽

Familial Mediterranean Fever ◽

Aseptic Meningitis ◽

Inflammatory Diseases ◽

Case Reports ◽

Interleukin 1 ◽

Colchicine Treatment ◽

Cns Involvement ◽

Mediterranean Fever ◽

Recurrent Aseptic Meningitis

Abstract Background Familial Mediterranean fever (FMF) is an autosomal recessive, auto-inflammatory disease, presenting with recurrent bouts of fever and polyserositis. FMF has been associated with central nervous system (CNS) manifestations such as Headache and Myalgia. The occurrence of other forms of nervous system involvement is rare, including seizures, sinus vein thrombosis, pseudotumor cerebri and more. There are only few case reports of aseptic meningitis due to FMF. Case presentation We present the case of a 14 year-old girl diagnosed with FMF, who experienced recurrent episodes of severe headache and aseptic meningitis while on maximal dose of colchicine therapy. She had a dramatic response to anakinra with symptoms resolving completely within a few days without recurrence. Subsequently, we identified seven cases in the literature describing recurrent aseptic meningitis in patients with underlying FMF; all showed response to colchicine treatment, without treatment failure. Conclusion Our case suggests a role for Interleukin 1 (IL-1) antagonists for cases of CNS involvement secondary to FMF in patients who fail to respond to colchicine, and might imply that anakinra could be effective in other auto-inflammatory diseases with CNS involvement.

Download Full-text

Increased Procoagulant Response of Monocytes from Patients with Familial Mediterranean Fever

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661642 ◽

1986 ◽

Vol 56 (02) ◽

pp. 211-213 ◽

Cited By ~ 13

Author(s):

Anne Courillon-Mallet ◽

Michael Bevilacqua ◽

Jean-Luc Wautier ◽

Michel Dervichian ◽

Daniel Cattan ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Clinical Manifestation ◽

Interleukin 1 ◽

Coagulation Factor ◽

Unknown Etiology ◽

Mononuclear Leukocytes ◽

Inherited Disease ◽

Mediterranean Fever ◽

The Difference ◽

Cellular Dysfunction

SummaryFamilial Mediterranean Fever (FMF) is an inherited disease of unknown etiology characterized by recurrent inflammatory episodes. Circulating fibrin was found in patients with FMF in absence of clinical manifestation of thrombosis and was statistically less frequently observed in patients treated with colchicine. These results suggest a cellular dysfunction. Therefore, we examined the procoagulant activity (PCA) of isolated mononuclear leukocytes and purified monocytes from FMF patients (n = 20). No PCA was detectable on freshly-isolated monocytes. After several hours of culture, FMF monocytes contained more PCA than control cells and the difference was more marked after endotoxin stimulation. Data obtained with coagulation factor-deficient plasma and anti-human apoprotein III antiserum indicated that the enhanced PCA in FMF monocytes is thromboplastin-like. Lysozyme and interleukin 1 production by monocytes were similar in patients and controls. The increased monocyte PCA appears to be due to an intrinsic and selective higher responsiveness of monocytes.

Download Full-text

POS1368 ANTI-IL-1 THERAPIES IN COLCHICINE-RESISTANT OR İNTOLERANT PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER: SINGLE CENTER EXPERIENCE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3257 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 966.1-966

Author(s):

M. E. Derin ◽

B. Karakaş ◽

B. Karataş ◽

N. Çabuk Çelik ◽

İ. Yalçin ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Interleukin 1 ◽

Mefv Gene ◽

Gene Mutations ◽

Recurrent Fever ◽

Long Term Effects ◽

Single Center Experience ◽

Eular Recommendations ◽

Mediterranean Fever

Background:Familial Mediterranean Fever (FMF) is a hereditary auto-inflammatory disease characterized by recurrent fever and serosal inflammation (1). The goal of FMF treatment is to prevent the attacks and to minimize subclinical inflammation between attacks The main treatment of FMF is colchicine however anti-interleukin-1 treatments are recommended in colchicine resistant and/or intolerant FMF patients (2).Objectives:The aim of this study is to evaluate the efficacy of anti-interleukin-1 (anti-IL-1) agents in 81 FMF patients with resistant/intolareted to colchicine or complicated with amyloidosis.Methods:Between January 2014 and December 2020, eighty-one patients who were diagnosed as FMF according to the criteria of Tel-Hashomer that following-up at Cumhuriyet University Medical Faculty Rheumatology-Internal Medicine Department were included in to the study.Results:45 (55.6%) male and 36 (44.4%) female were included in the study. The median age of the patients was 25 years (min:17-max: 60) and the median age at diagnosis was 15 years (min 3-max 46). 44 patients (54.3%) used Anakinra (100 mg/day), and 27 (45.7%) canakinumab (150mg/8month) were used. 49 cases were resistant to colchicine,16 were intolerant to colchicine, 16 (20%) cases were comlicated with amyloidosis. 10 patients had renal transplantation. MEFV gene mutations are shown in Table 1. Median duration of anti-IL-1 agent use was 24 month (min:4-max 52). 9 patients were resistant to anakinra, 18 patients had side effects which anakinra related. After a median follow up 12 months overall clinical response was %95 (frequency of attacks <1/6months). median proteinuria decreased from 3500 mg /day to median 1500 mg /day (p: 0.04) (Table 2). IL-6 treatment was started in 4 patients because of ineffective canakinumab. Five pregnant patients were followed up with anakinra during pregnancy and there were no problems.Conclusion:Anti-interleukin-1 agents are effectively and safely in the treatment of FMF patients. There are still unanswered questions in FMF treatment such as other factors affecting the frequency of attacks, colchicine resistance is not defined precisely and the importance of some mutations. The effect of anti IL-1 agents on FMF patients with amyloidosis is not clearly. According to our experience, these treatments are effective in patients with glomerular filtration rate> 60 ml/min. For answers to these and similar questions, Large and long follow-up studies are needed for long-term effects.References:[1]Özen S, Batu ED, Demir S., Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management. Front Immunol. 2017 Mar 23;8:253. doi: 10.3389/fimmu.2017.00253. eCollection 2017.[2]Seza Özen ve ark. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016 Apr;75(4):644-51.Disclosure of Interests:None declared

Download Full-text

AB0730 ASSOCIATION OF SPONDYLOARTHRITIS AND FAMILIAL MEDITERRANEAN FEVER AND IMPACT ON DISEASE PHENOTYPE: A SYSTEMATIC REVIEW OF THE LITERATURE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6009 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1659.3-1659

Author(s):

N. Ziade ◽

A. Nassar

Keyword(s):

Disease Management ◽

Familial Mediterranean Fever ◽

Literature Search ◽

Association Studies ◽

Case Reports ◽

Genome Wide Association Studies ◽

Systematic Literature Search ◽

Disease Phenotype ◽

Mefv Mutation ◽

Mediterranean Fever

Background:Spondyloarthritis (SpA) and Familial Meditaerranean fever (FMF) may co-exist in certain populations, and have some overlapping manifestations (oligo-arthritis, hip involvement). Their association may impact disease phenotype and may affect disease management.Objectives:To evaluate the association of SpA and FMF and its impact on disease phenotype and management.Methods:A systematic literature search was conducted with the keywords spondyloarthritis and familial mediterranean fever from Janurary 1990 to January 2020 in PubMed and using manual cross-reference methods.Results:The search retrieved 74 articles, out of which 37 articles were relevant to the study question; most of the articles were case reports, with some large cohort studies of FMF and SpA (Flowchart in Figure 1).In large FMF cohorts, the prevalence of SpA was higher compared to the general population (7.5-13%, OR around 10). M694V was a risk factor for SpA. These FMF-SpA patients were older at diagnosis, had lower fever attacks, and higher disease duration, inflammatory back pain, chronic arthritis, enthesopathy, persistent inflammation and higher resistance to Colchicine. In case series, they were responsive to anti-TNF therapy.In large SpA cohorts, MEFV mutation, particularly M694V, was found in 15-35% (even without associated FMF). In most cohorts, MEFV mutation carriers didn’t have any distinct disease phenotype, except for some reports of higher ESR, more hip involvement, higher BASFI and higher BASDAI. Genome-wide association studies and case reports suggest an implication for IL-1 and thus a role for Anakinra therapy in these patients.Conclusion:In FMF or SpA patients with resistance to conventional therapy, the evaluation of disease association should be performed as it may have significant impact on disease management.References:[1]Li et al, Plos Genetics 2019. Watad et al, Frontiers Immunol 2019. Atas et al, Rheumatol Int 2019. Cherqaoui et al, JBS 2017. Zhong et al. Plos One 2017. Ornek et al, Arch Rheumatol 2016. Cinar et al, Rheumatol Int 2008. Durmur et al, JBS 2007.Figure 1.Flowchart of the systematic literature search (Spondyloarthritis, Familial Mediterranean Fever; January 1990-2020).Disclosure of Interests:Nelly Ziade Speakers bureau: Abbvie, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Aref Nassar: None declared

Download Full-text

Neonatal-Onset Familial Mediterranean Fever in an Infant with Human Parainfluenza Virus-4 Infection

Neonatology ◽

10.1159/000514694 ◽

2021 ◽

pp. 1-5

Author(s):

Alexandre Michev ◽

Alessandro Borghesi ◽

Caterina Tretti ◽

Maddalena Martella ◽

Amelia Di Comite ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Parainfluenza Virus ◽

Compound Heterozygous ◽

Inborn Errors ◽

Immunological Responses ◽

Inflammatory Conditions ◽

Neonatal Onset ◽

Mediterranean Fever ◽

Compound Heterozygous Variants ◽

Human Parainfluenza Virus

Unusual, severe infections or inflammatory episodes in newborns and infants are largely unexplained and often attributed to immature immune responses. Inborn errors of immunity (IEI) are increasingly recognized as the etiology of life-threatening inflammatory and infectious diseases in infancy. We describe a patient with a unique neonatal-onset Familial Mediterranean Fever (FMF) due to compound heterozygous variants in <i>MEFV</i>, presenting as pleuritis following human parainfluenza virus-4 infection. Diagnostic challenges of FMF in infancy include the interpretation of the attacks as infectious episodes. Newborns and infants with acute, recurrent, or chronic, unusually severe infectious or inflammatory conditions should be screened for IEI, including both disorders with defective immunological responses and autoinflammatory disorders.

Download Full-text

Late-onset familial Mediterranean fever in Japan

Modern Rheumatology ◽

10.1080/14397595.2019.1621440 ◽

2019 ◽

Vol 30 (3) ◽

pp. 564-567 ◽

Cited By ~ 1

Author(s):

Dai Kishida ◽

Masahide Yazaki ◽

Akinori Nakamura ◽

Ayako Tsuchiya-Suzuki ◽

Yasuhiro Shimojima ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Late Onset ◽

Mediterranean Fever

Download Full-text

Interleukin-1 Targeting Drugs in Familial Mediterranean Fever: A Case Series and a Review of the Literature

Seminars in Arthritis and Rheumatism ◽

10.1016/j.semarthrit.2010.11.003 ◽

2011 ◽

Vol 41 (2) ◽

pp. 265-271 ◽

Cited By ~ 131

Author(s):

Ulrich Meinzer ◽

Pierre Quartier ◽

Jean-François Alexandra ◽

Véronique Hentgen ◽

Frédérique Retornaz ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Interleukin 1 ◽

Case Series ◽

Review Of The Literature ◽

Mediterranean Fever

Download Full-text

Abdominal syndrome in monogenic autoinflammatory disease – is it just a familial Mediterranean fever?

Modern Rheumatology Journal ◽

10.14412/1996-7012-2020-4-144-149 ◽

2020 ◽

Vol 14 (4) ◽

pp. 144-149

Author(s):

S. O. Salugina ◽

E. S. Fedorov ◽

N. G. Volf

Keyword(s):

Familial Mediterranean Fever ◽

Autoinflammatory Disease ◽

Bowel Perforation ◽

Interleukin 1 ◽

Diagnostic Features ◽

Peritoneal Adhesions ◽

Strict Adherence ◽

Surgical Interventions ◽

Abdominal Symptoms ◽

Mediterranean Fever

Gastrointestinal (GI) manifestations, such as abdominal pain, nausea, vomiting, and diarrhea, are common autoinflammatory disease (AID) symptoms. The abdominal symptomatology reflecting serositis is one of the most important classification and diagnostic criteria for the classic monogenic AID (MAID) – familial Mediterranean fever (FMF). Failure to timely diagnose FMF frequently leads to unjustified surgical interventions. Other periodic fevers may also present as abdominal symptoms; however, the latter are outside their diagnostic features. These diseases include, first of all, tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Interleukin 1 (IL1) inhibitors serve as the major targeted drugs for the treatment of TRAPS. Russia has registered the IL1 inhibitor canakinumab that prevents the development of organ damages, including those in the GI tract. The paper describes a clinical case of the classic manifestations of TRAPS (fever, rash, periorbital edema, arthritis, and elevated levels of acutephase inflammatory markers) concurrent with severe abdominalgia during attacks and with the development of severe peritoneal adhesions, which led to bowel perforation and emergency surgical intervention. The prolonged persistence of inflammatory attacks before the initiation of therapy, as well as violation of the IL1 inhibitor administration regimen facilitated the development of an urgent exacerbation. Thus, TRAPS should be included in the differential diagnostic circle for patients with severe gastrointestinal manifestations characterized by an attack-like course. These patients need timely prescription of targeted therapy, strict adherence to the dosing and intervals between drug administrations, and careful monitoring to prevent serious complications with the visceral organs, including the gastrointestinal tract, and their immediate correction.

Download Full-text

A delayed diagnosis: recurrent fever and beta thalassaemia

BMJ Case Reports ◽

10.1136/bcr-2018-225802 ◽

2018 ◽

pp. bcr-2018-225802

Author(s):

Michael Samarkos ◽

Marina Mantzourani ◽

Christina Nika ◽

Vasiliki Kalotychou

Keyword(s):

Familial Mediterranean Fever ◽

Cognitive Biases ◽

Genetic Disorders ◽

Delayed Diagnosis ◽

The Other ◽

Recurrent Fever ◽

Autoinflammatory Disorder ◽

Beta Thalassaemia ◽

Mediterranean Fever ◽

Thalassaemia Intermedia

Familial Mediterranean fever and beta-thalassaemia are two genetic disorders, with a largely common geographical distribution. However, they have not much else in common, as the first is an autoinflammatory disorder, while the other is a haemoglobinopathy. We describe a patient with known beta-thalassaemia intermedia who presented with recurrent fevers and he was diagnosed with familial Mediterranean fever 2 years later. We discuss whether there is an association between the two disorders and the cognitive biases that lead to the delay in the diagnosis of familial Mediterranean fever.

Download Full-text