Case Of Familial Mediterranean Fever Research Articles

Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases

The spectrum of periodic fever syndromes (PFS)/autoinflammation diseases is continuously expanding. This review provides an overview of the primary research and an update on the main clinical developments in these disorders published in the past 12-18 months. IL-1β is pivotal to the pathogenesis of most of the PFS. In familial Mediterranean fever (FMF) MEFV mutations lead to gain of pyrin function, resulting in inappropriate IL-1β release that is dependent on ASC but not the NLRP3 inflammasome. Anti-IL-1 therapy is effective in tumour necrosis factor receptor-associated periodic syndrome (TRAPS), whilst both spontaneous and pathogen-associated molecular patterns (PAMPs) induced IL-1β release have been demonstrated in NLRP12-associated periodic syndrome (NAPS12). Somatic NLRP3/CIAS1 mosaicism is a significant cause of cryopyrin-associated periodic syndromes (CAPS). Close connections have also been established between metabolic and inflammatory pathways. In TRAPS increased reactive oxygen species (ROS) of mitochondrial origin leads to production of pro-inflammatory cytokines, whilst NLRP3 inflammasome activation in type 2 diabetes (T2D) is induced by oligomers of islet amyloid polypeptides (IAPP). Caspase 1 activation and IL-1β release is central to the pathogenesis of many autoinflammatory syndromes. This is supported by the effectiveness of anti-IL-1 biologics in treatment of these disorders.

A case of Familial Mediterranean Fever at the Baltic Sea

A case of Familial Mediterranean Fever at the Baltic Sea

Enhanced exon 2 skipping caused by c.910G>A variant and alternative splicing of MEFV genes in two independent cases of familial Mediterranean fever

Most reported cases of familial Mediterranean fever (FMF) involve missense mutations of MEFV concentrated within exon 10. We experienced two independent pedigrees of a unique variant in the MEFV gene that might cause excessive exon 2 skipping due to enhanced alternative splicing. In this study, we tried to elucidate the molecular mechanism of the MEFV variant as a cause of the FMF phenotype. Peripheral blood was obtained from volunteers and two patients with homozygous c.910G>A variant of the MEFV gene. MEFV messenger RNA (mRNA) expression patterns in mononuclear cells and granulocytes were compared using forward and reverse primers from exons 1 and 3, respectively. Expression profiles of pyrin were examined by transfecting wild-type and variant MEFV genes into HEK293T cells. Expression of normal-sized mRNA was extremely reduced in these patients, whereas that of aberrant short mRNA, deleting exon 2 (Δex2), was significantly increased. Immunohistochemical and immunoblotting analyses revealed a truncated immunoreactive pyrin protein in cells transfected with Δex2 cDNA. The MEFV gene c.910G>A variant results in accelerated aberrant splicing with abnormal protein size, presumably leading to anomalous pyrin function. This is the first report to show that an MEFV variant other than missense mutation is responsible for the FMF phenotype.

A Japanese case of familial Mediterranean fever presenting diffuse bone marrow uptake of FDG-PET and high levels of neutrophil membrane CD64 expression

A Japanese case of familial Mediterranean fever presenting diffuse bone marrow uptake of FDG-PET and high levels of neutrophil membrane CD64 expression

Successful treatment of renal AA amyloidosis in familial Mediterranean fever with pegylated alpha-2a interferon

Renal AA amyloidosis is a severe consequence of chronic inflammatory diseases such as familial Mediterranean fever (FMF). FMF is caused by mutations in the MEFV gene, resulting in defective control of granulocyte-mediated inflammation. Interferon-alpha is known to induce MEFV expression in monocytes and granulocytes in vitro. We present the first case of colchicine-resistant FMF in which a durable disease remission and regression of renal amyloidosis was induced by chronic treatment with pegylated interferon-alpha.

A Case of Familial Mediterranean Fever Diagnosed in Adult.

A Case of Familial Mediterranean Fever Diagnosed in Adult.

Genotype–phenotype studies in a large cohort of Armenian patients with familial Mediterranean fever suggest clinical disease with heterozygous MEFV mutations

Familial Mediterranean fever (FMF) is an autoinflammatory disorder generally caused by recessively inherited mutations in the MEFV gene. FMF is quite prevalent in Armenian population in which majority of patients have two mutated alleles, yet in 18% of symptomatic patients just one mutation has been detected. To explain this finding, we analyzed the symptoms and genotypes of 1,299 patients, including 236 affected heterozygous patients with definite diagnosis of FMF. We selected a subset of 63 heterozygous, homozygous and asymptomatic normal individuals and completely sequenced their MEFV genes (exons) to discover any other mutations potentially missed by currently used screening method. Besides four synonymous polymorphisms in exon two and five, we found a T267I mutation in one heterozygous patient with a severe case of FMF who should have been designated as compound heterozygous, yet the other genotypes were all accurate. We used binomial probability distribution of symptoms in homozygous FMF patients to estimate the likelihood of their occurrences in heterozygous patients and demonstrated the assemblage of patients into groups with similar clinical criteria using statistical clustering. We found extremely high probabilities for the presence of FMF symptoms in heterozygous individuals and determined that symptoms were equally likely to occur in both analyzed genotypes. Therefore, our study supports the rising evidence that a single MEFV mutation could be associated with mild FMF symptoms. However, heterozygous patients presenting with severe phenotype should be further analyzed for less common second MEFV mutation using gene sequencing.

A case of familial Mediterranean fever associated with compound heterozygosity for the pyrin variant L110P-E148Q/M680I in Japan

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent and self-limited fever attacks and serositis/arthritis. The M694V, M694I, M680I, V726A, and E148Q mutations in MEFV, the gene responsible for FMF, account for most FMF cases in Mediterranean populations. In Japan, M694I and E148Q are most frequently detected; M694V, M680I, and V726A have not been identified so far. We report the first case of FMF associated with M680I in Japan.

Adulter Morbus Still, Schnitzler-Syndrom und autoinflammatorische Syndrome im Erwachsenenalter

Adult-onset Still's disease (AoSD), Schnitzler syndrome, and cases of adult-onset autoinflammatory syndromes [10-15% of cases of familial Mediterranean fever (FMF) and tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS)] are characterized by a genetic predisposition, with increased interleukin (IL)-1beta and IL-18 production and TNF-alpha signaling, respectively. As a result, periodic fever and inflammation at barrier tissues (synovial tissues, serous membranes, and the skin) are encountered in such patients. Pathophysiological insights into these diseases have renewed interest in research on IL-1beta in rheumatic diseases and have opened new therapeutic avenues. Recently published studies have shown that patients with Schnitzler syndrome, methotrexate-refractory AoSD, and colchicine-refractory FMF or contraindications to colchicines in FMF respond well to treatment with the soluble IL-1 receptor antagonist anakinra. For TRAPS patients, the p75 TNF-alpha receptor/Fc-IgG1 fusion protein etanercept is the treatment of first choice.

MEFV mutations in Egyptian patients suffering from familial Mediterranean fever: analysis of 12 gene mutations

The objective of the study is to screen 12 MEFV gene mutations in Egyptian patients with familial Mediterranean fever (FMF) and to study the initial hypothesis that the phenotypic expression of the disease may be attributable to the existence of a particular mutation. We enrolled 136 Egyptian patients (74 males, and 62 females) with a clinical diagnosis of FMF. DNA was amplified by PCR and subjected to reverse hybridization for the detection of 12 MEFV gene mutations. The phenotypic expression of the disease was compared in two subgroups according to the presence of homozygote E148Q and M694V gene mutations. The most frequent gene mutations in the studied group were V726A, M694V, M680I, E148Q and M694I in 41.2, 32.4, 29.4, 25 and 20.6%, respectively. At least one of these main five founder mutations was present in 132 patients (97.1%). Thirty-two patients (23.5%) were homozygote for one of the main five founder mutations. The most common homozygote gene mutations were E148Q and M694V, each in 12 patients (8.8%). Significant increase in abdominal pain and arthritis was found in patients with homozygote M694V mutation compared to those with E148Q mutation. All patients with amyloidosis had M694V gene mutation. The increased frequency of V726A gene mutation and the rarity of amyloidosis in this study suggest that Egyptian patients may have a milder form of FMF compared to other populations. The five main founder mutations account for the vast majority of cases of FMF. M694V gene mutation may be associated with increased frequency of abdominal pain, arthritis and the presence of amyloidosis.

Malignant Peritoneal Mesothelioma in a Hemodialysis Patient with Familial Mediterranean Fever: A Case Report and Literature Review

Malignant mesothelioma is a rare tumor. The most common localization of mesothelioma is pleura. It rarely arises from the peritoneum. It has been suggested that familial Mediterranean fever (FMF) may cause the development of peritoneal mesothelioma. We describe a case of malignant peritoneal mesothelioma in a hemodialysis patient with FMF. The patient was a 56 year old female. A history of FMF was present since her childhood. She did not use colchicine and suffered from recurrent ascites. To the best of our knowledge, this is the seventh case of FMF diagnosed as having malignant peritoneal mesothelioma in the medical literature.

Recurrent bullous lesions associated with familial Mediterranean fever: a case report

Familial Mediterranean fever (FMF) is an inherited, recurrent, inflammatory disease. Of its various cutaneous features, erysipelas-like erythema is the best known and most common skin lesion. We present a new case of FMF with recurrent bullous lesions. A 41-year-old woman was admitted to our clinic with tense bullae, 20 x 20 mm in diameter on the left shin. The patient had a history of fever, abdominal pain, peritonitis attacks and infertility. A lesional skin biopsy revealed subepidermal bullae and neutrophilic infiltration around dermal vessels. Direct immunofluorescence analysis was negative. Over the period of investigation, the lesion regressed spontaneously; 1 month later, a similar lesion appeared on the right wrist. Diagnosis of FMF was made according to the Tel-Hashomer criteria. Recognition of this peculiar skin lesion may lead to an earlier diagnosis of the disease.

Autoinflammatory Diseases: Mimics of Autoimmunity or Part of its Spectrum? Case Presentation

Autoinflammatory diseases are very rare diseases presenting within a wide clinical spectrum. Recognition of the main clinical features are challenging due to overlapping or mimicking with autoimmune diseases. A case series is reviewed to illustrate typical and atypical features and the difficulties of these diagnoses in the low prevalence areas--a typical unrecognized case of familial Mediterranean fever (FMF) in a youngster, an atypical adult case with overlapping of FMF with Behçet disease, and an early presentation of FMF in infant presenting with inflammatory colitis, as well as the overlapping features within the cryopirin diseases spectrum in an 8-year-old boy who presented with systemic onset arthritis. These cases may represent examples of a very puzzling relationship among disorders of innate and adaptive immune systems and inflammation.

Clinical Study of 7 Cases of Familial MediterraneanFever with MEFV Gene Mutation

Familial Mediterranean fever (FMF) had been considered a rare disease in Japan, but since the identification of the causative gene (MEFV) for pyrin/marenostrin in 1997, the occurrence of FMF has been successively reported. We reviewed the clinical features of 7 patients diagnosed with FMF by gene analysis. During April 2003 and March 2005, we investigated the clinical symptoms, treatment and MEFV types of 7 FMF patients who consulted the General Outpatient Clinic of Chiba University Hospital. Six patients were in their 20-30s, and one was 54 years of age. There were 4 males and 3 females including a mother and child, and an adult male and his female cousin. Three were solitary incidences. In addition to intermittent fever, 4 patients had chest pain, 1 had abdominal pain, and 1 had chest or abdominal pain. The frequency of attacks was once per 3 months to 1 year in the early stage of the disease, but it slowly increased with disease progression. Leukocytosis and C-reactive protein (CRP) elevation were noted during attacks in all patients. On investigation of MEFV, heterozygosity for the compound pyrin L110P-E148Q/M694I, E148Q/M694I, L110P/E148Q and heterozygosity for pyrin variant M694I alone were detected. Daily administration of colchicine at 0.5 mg prevented attacks in 6 patients, however 1 patient required 1.0 mg for adequate prevention. Although the incidence is rare, internists should be aware of the characteristic symptoms of FMF: periodic fever and serositis symptoms, and its presence in Japan despite the disease name.

A Japanese Case of Familial Mediterranean Fever with Onset in the Fifties

The patient was a 63-year-old woman with attacks of fever and abdominal pain, starting from the age of 53 years and recurring every month. Despite various examinations at another hospital, the etiology remained unclear. She was under symptomatic treatment, and was referred to our department for further evaluation. Although she had onset in middle age, the clinical symptoms and examination findings suggested familial Mediterranean fever, and administration of colchitine inhibited the attacks completely. Therefore, the patient was diagnosed as having the disease. We were not able to analyze the entire MEFV gene, but detected only a heterozygous M694I mutation. Amyloidosis did not develop as a complication. The disease is rare in Japan, and its onset in the fifties is extremely rare in the world.

An unusual complication of familial Mediterranean fever: protracted arthritis with bilateral coxarthrosis and intraosseous amyloidosis of femoral head

Protracted arthritis is uncommon in familial Mediterranean fever (FMF) and rarely may result in degenerative joint damage, a well-known complication of FMF, usually affecting kidneys. We present an unusual case of FMF involving severe bilateral coxarthrosis leading to residual incapacity that was treated by total hip arthroplasty, and an unusual presentation of amyloidosis - intraosseous amyloidosis of the femoral head.

Sacroiliitis in familial Mediterranean fever and seronegative spondyloarthropathy: importance of differential diagnosis

Familial Mediterranean fever (FMF) is a multisystemic autosomal recessive disease, occasionally accompanied by sacroiliitis. Transient and non-erosive arthritis of the large joints is the most frequent articular involvement. Amyloidosis is also the most significant complication of FMF, leading to end stage renal disease. Here we present three cases of FMF with sacroiliitis and review the literature for spinal arthritic involvement of FMF. All cases were referred to our clinic with a diagnosis of seronegative spondyloarthropathy and with low back pain sourced by sacroiliitis. They also had homozygous M694V gene mutations and negative HLA B27 antigens. Molecular analysis of the gene mutation is recommended during the evaluation of uncertain cases in order to clarify diagnostic discrimination. We suggest that FMF with sacroiliitis, which is rare in rheumatological practice, should be considered in the differential diagnosis of seronegative spondyloarthropathy or other rheumatologic diseases causing spinal involvement.

A Japanese Case of Familial Mediterranean Fever with Homozygosity for the Pyrin E148Q Mutation

A Japanese Case of Familial Mediterranean Fever with Homozygosity for the Pyrin E148Q Mutation

An unusual presentation of familial Mediterranean fever with prolonged hip pain and amyloidosis

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent self‐limiting attacks of joint, chest and abdominal associated with fever. We present an unusual case of FMF with prolonged arthritis and amyloidosis. Familial Mediterranean fever should be considered in the differential diagnosis of prolonged hip pain, even in the absence of symptoms or signs of FMF.

A case of familial Mediterranean fever and polyarteritis nodosa complicated by spontaneous perirenal and subcapsular hepatic hemorrhage requiring multiple arterial embolizations

The association of familial Mediterranean fever (FMF) and polyarteritis nodosa (PAN) has been well established. These patients have been reported to have an overall better prognosis than other PAN patients. Herein we report a patient with FMF and PAN who died of sepsis following a severe course of recurrent bleeding episodes which required multiple embolization attempts. The 39-year-old Turkish male presented with abdominal pain of 1-month duration. He had been diagnosed with FMF at the age of 24. On admission, he had pallor with general ill appearance. Rebound tenderness was obtained in the right upper abdominal quadrant. He had mild anemia, leukocytosis, thrombocytosis, and hypoalbuminemia. On the 2nd day of his admission, he developed hypotension with a rapid decline in hemoglobin level. Abdominal angiography showed multiple aneurysms in the branches of renal arteries, superior mesenteric artery, and hepatic arterial system including left renal infarct, suggesting PAN. He was put on high-dose steroids and oral cyclophosphamide. Despite medical treatment, he developed intense abdominal pain, hypotension, tachycardia, and a rapid fall in hemoglobin on four occasions. Active bleeding sites were embolized in two different angiography sessions. Although the patient experienced no more recurrent bleeding, he died of multiorgan dysfunction syndrome resulting from sepsis 6 weeks after admission. Polyarteritis nodosa associated with FMF may follow a grave course despite immunosuppressive therapy. Arterial embolization should be considered in the presence of bleeding aneurysms in addition to immunosuppressive therapy.