Menoufia Medical Journal

: 2014  |  Volume : 27  |  Issue : 4  |  Page : 722--726

Update in familial Mediterranean fever

Ali M El Shafie1, Rizk A Baz2, Fatma N Hamed Farag1,  
1 Department of Pediatric, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Biochemistry and Genetics Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Correspondence Address:
Fatma N Hamed Farag
Ellozy Algadida, Shebin, Dakahlia


Objective This study aimed to enhance the diagnostic and therapeutic options for familial Mediterranean fever (FMF) in children. Data summary Data sources : medical textbooks, medical journals, and medical websites with updated information. Study selection: systematic reviews that discussed the various aspects of FMF epidemiology, etiology, and management. Data extraction: web search was performed on the PubMed medical databases and the full text of the relevant paper was critically analyzed and interpreted. Data synthesis: the results of the included studies were summarized and incorporated into the review article«SQ»s main text, with a focus on the various conclusions studied and comparison with similar studies. Conclusion FMF is not an uncommon disease. The disease has many presentations and fever is not an essential component in the diagnosis. Amyloidosis is the most devastating complication of FMF. Colchicine treatment can reduce the frequency and severity of attacks and prevent complications including amyloidosis.

How to cite this article:
El Shafie AM, Baz RA, Hamed Farag FN. Update in familial Mediterranean fever.Menoufia Med J 2014;27:722-726

How to cite this URL:
El Shafie AM, Baz RA, Hamed Farag FN. Update in familial Mediterranean fever. Menoufia Med J [serial online] 2014 [cited 2020 Apr 4 ];27:722-726
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Full Text


Familial Mediterranean fever (FMF) is an autoinflammatory disease and belongs to the heterogeneous group of hereditary recurrent fever syndromes. It is caused by Mediterranean fever gene (MEFV) mutations on chromosome 16 [1].

It is more prevalent among non-Ashkenazi Jewish, Turkish, Armenian, and Arab populations. Turkey appears to have the highest concentration of FMF patients worldwide, with a reported prevalence of FMF ranging from 1 : 400 to 1 : 1000 [2].

Besides the genetic etiology, there are many factors that are incorporated into the pathogenesis of FMF including hyperaldosteronemia and increased interlekin-6 levels [3].

A recent study found that the most common triggering factors for FMF attacks with serositis were cold exposure, emotional stress, and tiredness, whereas standing for long duration, long duration of travel, and tiredness were the triggering factors for the attacks with musculoskeletal symptoms [4].

Clinically, FMF can be distinguished into three phenotypes: type 1, which is commonly associated with recurrent short episodes of inflammation and serositis, type 2, characterized by the evidence of reactive amyloid-associated (AA) amyloidosis; and type 3, which is the 'silent' homozygous or compound heterozygote state, in which two MEFV mutations are detected without signs or symptoms of FMF, nor of AA amyloidosis. In recent years, it has been observed that heterozygous mutation carriers can also have a mild or an incomplete form of FMF, named 'FMF-like' disease [5].

Moreover, a recent study reported cochlear involvement in children with FMF, who showed increased hearing thresholds at higher frequencies [6].

Recent trends in diagnosis have shown that the detection of inflammatory changes using MRI may aid in early diagnosis, thus contributing toward early and adequate treatment [7]. Also, it has been shown that the mean platelet volume is decreased in patients with FMF [8].

Colchicine is the standard therapy and it has been found to be a safe drug in the treatment of children with FMF, even in infancy. The significant adverse effect of colchicine is diarrhea, which can be controlled by a decrease in the dose of colchicine and transitory elevation of transaminases [9].

Infliximab (a monoclonal antibody against tumor necrosis factor a) was found to be very effective in controlling gastrointestinal system findings and protracted arthritis, and it also had a favorable impact on the clinical findings of nephrotic syndrome in FMF patients [10] [Table 1] and [Figure 1].{Figure 1}{Table 1}


FMF is an autosomal recessive systemic autoinflammatory disorder characterized by recurrent episodes of fever accompanied by peritonitis, pleuritis, pericarditis, and/or arthritis, sometimes accompanied by an erysipelas-like skin rash [11].

FMF has been established as a common condition among individuals of Mediterranean descent, with carrier rates as high as 1 : 7 in particular populations. In Arab countries, because of the high prevalence, it is considered a public health concern and has a significant effect on the health and welfare of children and adults. However, no studies have been carried out to determine the prevalence of FMF in children [11].

Attacks can be triggered by different types of factors, many of which are still unknown. Triggers known at present are physical and emotional stress, exposure to cold, fat-rich meals, banal infections, drugs as cisplatin [12], and menstrual cycle [13]. In another study, it was found that the most common triggering factors for the attacks with serositis were exposure to cold (59.3%), emotional stress (49.8%), tiredness (40.0%), and menstruation (33.7% in females). Standing for longer duration (78.8%), long duration of travel (64.1%), and tiredness (47.8%) were the triggering factors for the attacks with musculoskeletal symptoms [4].

FMF classically presents with unprovoked, recurrent attacks of fever and painful polyserositis mainly affecting the peritoneum (most common), synovium, and pleura that usually (but not always) begin in childhood [11].

The majority of affected individuals (80%) present before 10 years of age and 90% before the age of 20 years [14]. Acute episodes may last from 24 to 72 h and have variable frequency, often without a recognized triggering event. Some commonly reported precipitating causes include viral illness, emotional stress, excessive/intense physical activity, high-fat diet, extremes of temperature, and menstruation in women. The frequency of attacks may vary from once per week to once every 5-10 years, with the median frequency being approximately once a month [11].

FMF has many atypical presentations. Recurrent monoarthritis can be the sole manifestation of FMF; in such cases, the actual diagnosis may not be established for some time and only after extensive investigations [15]. Pleuritis can rarely present as the sole manifestation of FMF [16]. Recurrent pericarditis, although rare, can present as the sole manifestation of FMF [17]. Recurrent urticaria has been reported as a rare manifestation of FMF [18].

Meningitis can occur rarely in FMF. In each of the cases reported, the patients' attacks of recurrent aseptic meningitis resolved after treatment with colchicine [19]. An increased frequency of MEFV mutations has been found in individuals with Behcet's disease [20].

Using tissue Doppler imaging, Ozdemir et al. [21] have reported that although left ventricular functions were comparable in the patients and healthy children, right ventricular diastolic function indices were impaired in patients with FMF during childhood. Impaired right ventricular diastolic function may be an early manifestation of cardiac involvement in children with FMF.

Clinically, FMF can be distinguished into three phenotypes: type 1, which is commonly associated with recurrent short episodes of inflammation and serositis, including fever, peritonitis, synovitis, pleuritis, but also pericarditis, orchitis, or meningitis episodes; type 2, characterized by the evidence of amyloidosis as the first clinical manifestation of the disease in an otherwise asymptomatic individual; and type 3, referred to the 'silent' homozygous or compound heterozygote state, in which two MEFV mutations are detected without signs or symptoms of FMF, nor of AA amyloidosis [22].

Environmental and genetic factors, including MEFV mutations and background modifiers genes, contribute toward affecting the FMF phenotype. In the past few years, many population studies have been carried out to investigate the genotype-phenotype correlations, particularly the role of genetic factors in the phenotype and the development of amyloidosis. Several studies have suggested that patients with some of the MEFV mutations, mainly the M694V mutation, had more severe symptoms and findings and/or were at a higher risk of developing amyloidosis [23].

However, different mutations are not always correlated with phenotypic variations: marked diversity of clinical characteristics has been observed among patients carrying the same mutations, even among members of the same family [24].

Also, the role of E148Q sequence variation remains controversial: initially, it was described as a disease-causing mutation with low penetrance and mild symptoms. Other studies, because of a similar frequency of E148Q among FMF patients and healthy controls, considered it a benign polymorphism [25], although there are evidences that when E148Q appears on the same allele with the V726A mutation and constitutes the E148Q-V726A complex allele, patients who are homozygous or compound heterozygotes for the complex allele had more severe disease compared with patients homozygous for V726A [26].

The MEFV gene is composed of 10 exons and most patients have mutations in exon 10, the longest exon in this gene. Through the network 'Infevers', a website dedicated to mutations responsible for hereditary autoinflammatory diseases, it is possible to check the number of variants of MEFV identified. To date, 218 MEFV mutations have been detected as responsible for the phenotypic variance observed in the disease [27].

M694V, V726A, M680I, M694I (conservative mutations clustered in exon 10), and E148Q (clustered in exon 2) are considered to be common mutations related to FMF, and they are detected with a frequency that alters according to ethnicity. M694V is more commonly found among Sephardic Jews, Turks, and Armenians; E148Q among European and Turks patients; M694I is more frequent among Arabs; and M680I is detected particularly among Armenians [28].

Generally, M694V homozygosis is associated with a severe form of the disease, whereas mutations E148Q and V726A have been correlated with reduced penetrance and a milder form of the disease. However, it has been observed that homozygotes for the complex V726A-E148Q allele are also as severely affected as M694V homozygotes, indicating the wide allelic variability in disease expression [26].

Colchicine is the principal therapy in FMF. On the basis of numerous case series, letters, and controlled trials, it appears that colchicine reduces attack frequency, decreases severity, and shortens the duration of the acute attacks in most FMF patients. Furthermore, colchicine can prevent, arrest, or even reverse renal amyloidosis in patients who have already developed this complication [29].

In a recent Egyptian study on pediatric patients, it was found that the dose of colchicine required to control the attacks was significantly lower and patients' response to colchicine therapy was significantly better in the heterozygous group than in the homozygous group [30].

Colchicine should be introduced in children with FMF as soon as the diagnosis has been established and should be continued for life.

Suggested dosages according to the ages of the children are as follows: the oral starting doses should be 0.5 mg/day or less (for children<5 years of age) and 1.0 mg/day (for children 5-10 years of age), and patients older than 10 years of age can take more than 1.0 mg colchicines daily. The dosage of colchicine should be increased in a stepwise manner (e.g. 0.25 mg/step) up to a maximum of 2.0 mg/day to control the disease in patients who do not clinically respond to the standard dosage.

In high-risk patients (e.g. after kidney transplantation, patients with amyloidosis), higher colchicine doses (≤2 mg/day) should be administered independent of the dose needed for controlling the clinical symptoms. However, creatinine should be normal; otherwise, the dose should be reduced and adjusted.

Monitoring should be performed in the presence of impaired renal or liver function. For patients with severe renal failure (GFR<10 ml/min), the dosage should be reduced by 50% (e.g. ≤1 mg/day).

The most common side effects of colchicines are gastrointestinal. Therapeutic oral doses of colchicine may cause cramping, abdominal pain, hyperperistalsis, diarrhea, and vomiting. Rarer side effects of colchicine include bone marrow suppression and neuromyopathy, which is most commonly observed in elderly patients with renal insufficiency. Colchicine overdose may lead to a cholera-like syndrome associated with dehydration, shock, and acute renal failure, alopecia, bone marrow failure, hepatocellular failure, disseminated intravascular coagulation, epileptic seizures, coma, and death [31].

In a recent study carried out to identify any adverse effects of colchicine in pediatric patients with FMF, clinical presentation, Mediterranean fever gene genotype, disease duration, colchicine dose, laboratory tests, and reported adverse effects in children with FMF were analyzed. Of the 153 patients with FMF, 22 (14.4%) developed diarrhea during a follow-up of 4 years; the dose of colchicine was reduced to control this symptom in only four patients. In 18 (11.8%) patients, a mild transitory increase in transaminases (45-158 IU/l) was found during a follow-up of 1 year. Blood cell counts and kidney function tests were normal in all patients. No correlation was found between the adverse effects and the patient's age, disease onset, treatment duration, or any of the clinical characteristics of the disease. The authors concluded that colchicine is a safe drug for the treatment of children with FMF, even in infancy. The significant adverse effect of colchicine is diarrhea (in a small number of patients), which can be controlled by a decrease in the dose of colchicine and transitory elevation of transaminases [9].


FMF is not an uncommon disease. The disease has many presentations and fever is not an essential component in the diagnosis. Amyloidosis is the most devastating complication of FMF. Colchicine treatment can reduce the frequency and severity of attacks and prevent complications including amyloidosis.


A national study should be carried out to determine the prevalence of FMF in Egypt.

Pediatricians should be aware of the various clinical presentations of the disease, particularly in infants and young children with recurrent abdominal pain.

Early treatment can prevent complications.

Screening of gene mutations of FMF should be performed in patients with recurrent abdominal pain.


Conflicts of interest

There are no conflicts of interest.


1Lainka E, Bielak M, Lohse P, Timmann C, Stojanov S, von Kries R, et al. Familial Mediterranean fever in Germany: epidemiological, clinical, and genetic characteristics of a pediatric population. Eur J Pediatr 2012; 171 :1775-1785.
2 Akar S, Yuksel F, Tunca M, Soysal O, Solmaz D, Gerdan V, et al. Familial Mediterranean fever: risk factors, causes of death, and prognosis in the colchicine era. Medicine (Baltimore) 2012; 91 :131-136.
3 Dzhndoian ZT, Martirosian NG. The role of aldosterone and IL-6 in the pathogenesis of inflammation in familial Mediterranean fever. Georgian Med News 2012; 206 :44-48.
4 Karadag O, Tufan A, Yazisiz V, Ureten K, Yilmaz S, Cinar M, et al. The factors considered as trigger for the attacks in patients with familial Mediterranean fever. Rheumatol Int 2013; 33 :893-897.
5 Soriano A, Manna R. Familial Mediterranean fever: new phenotypes. Autoimmun Rev 2012; 12 :31-37.
6 Koybasi S, Atasoy HÝ, Bicer YO, Tug E. Cochlear involvement in familial Mediterranean fever: a new feature of an old disease. Int J Pediatr Otorhinolaryngol 2012; 76 :244-247.
7 Ishiguro T, Takayanagi N, Kobayashi K, Migita K, Yanagisawa T, Hoshi T, Sugita Y. Magnetic resonance imaging can detect thoracic inflammation due to familial Mediterranean fever. Mod Rheumatol 2013; 23 :604-607.
8 Sahin S, Senel S, Ataseven H, Yalcin I, Sahin S, Senel S, et al. Does mean platelet volume influence the attack or attack-free period in the patients with Familial Mediterranean fever?. Platelets 2013; 24 :320-323.
9 Padeh S, Gerstein M, Berkun Y. Colchicine is a safe drug in children with familial Mediterranean fever. J Pediatr 2012; 161 :1142-1146.
10Ozçakar L, Onat AM, Kaymak SU, Ureten K, Akinci A. Selective serotonin reuptake inhibitors in familial Mediterranean fever: are we treating depression or inflammation? Rheumatol Int 2005; 25 :319-320.
11El-Shanti H, Majeed HA, El-Khateeb M. Familial mediterranean fever in Arabs. Lancet 2006; 367 :1016-1024.
12Toubi E, Gershoni-Baruch R, Kuten A. Cisplatin treatment triggers familial Mediterranean fever attacks. Tumori 2003; 89 :80-81.
13Ben-Chetrit E, Ben-Chetrit A. Familial Mediterranean fever and menstruation. BJOG 2001; 108 :403-407.
14Telatar M, Grody WW. Molecular genetic testing for familial Mediterranean fever. Mol Genet Metab 2000; 71 :256-260.
15Lidar M, Kedem R, Mor A, Levartovsky D, Langevitz P, Livneh A. Arthritis as the sole episodic manifestation of familial Mediterranean fever. J Rheumatol 2005; 32 :859-862.
16Ten Oever J, de Munck DRRecurrent pleurisy as sole manifestation of familial Mediterranean fever. Ned Tijdschr Geneeskd 2008; 152 : 887-890.
17Tutar HE, Imamoglu A, Kendirli T, Akar E, Atalay S, Akar N. Isolated recurrent pericarditis in a patient with familial Mediterranean fever. Eur J Pediatr 2001; 160 :264-265.
18Alonso R, Cisteró-Bahima A, Enrique E, San Miguel-Moncín MM. Recurrent urticaria as a rare manifestation of familial Mediterranean fever. J Investig Allergol Clin Immunol 2002; 12 :60-61.
19Karachaliou I, Karachalios G, Charalabopoulos A, Charalabopoulos K. Meningitis associated with familial Mediterranean fever. Int J Clin Pract Suppl 2005; 147 :60-61.
20Ayesh S, Abu-Rmaileh H, Nassar S, Al-Shareef W, Abu-Libdeh B, Muhanna A, Al-Kafri F Molecular analysis of MEFV gene mutations among Palestinian patients with Behcet′s disease. Scand J Rheumatol 2008; 37 :370-374.
21Ozdemir BH, Ozdemir FN, Sezer S, Sar A, Haberal M. Does colchicine have an antifibrotic effect on development of interstitial fibrosis in renal allografts of recipients with familial Mediterranean fever?. Transplant Proc 2006; 38 :473-476.
22Camus D, Shinar Y, Aamar S, Langevitz P, Ben-Zvi I, Livneh A, et al. ′Silent′ carriage of two familial Mediterranean fever gene mutations in large families with only a single identified patient. Clin Genet 2012; 82 :288-291.
23Shinar Y, Livneh A, Langevitz P, Zaks N, Aksentijevich I, Koziol DE, et al. Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol 2000; 27 :1703-1707.
24Kutlay S, Sengul S, Keven K, Erturk S, Erbay B. Two sisters with familial Mediterranean fever: lack of correlation between genotype and phenotype?. J Nephrol 2006; 19 :104-107.
25Tchernitchko D, Legendre M, Cazeneuve C, Delahaye A, Neil F, Amselem S. The E148Q MEFV allele is not implicated in the development of familial Mediterranean fever. Hum Mutat 2003; 22 :339-340.
26Gershoni-Baruch R, Brik R, Shinawi M, Livneh A. The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever. Eur J Hum Genet 2002; 10 :145-149.
27Milhavet F, Cuisset L, Hoffman HM, Slim R, El-Shanti H, Aksentijevich I, et al. The infevers autoinflammatory mutation online registry: update with new genes and functions. Hum Mutat 2008; 29 :803-808.
28Majeed HA, El-Shanti H, Al-Khateeb MS, Rabaiha ZA. Genotype/phenotype correlations in Arab patients with familial Mediterranean fever. Semin Arthritis Rheum 2002; 31 :371-376.
29ªimºek B, Islek I, ªimºek T, Küçüködük S, Cengiz K. Regression of nephrotic syndrome due to amyloidosis secondary to familial Mediterranean fever following colchicines treatment. Nephrol Dial Transplant 2000; 15 :281-282.
30Talaat HS, Mohamed MF, El Rifai NM, Gomaa MA. The expanded clinical profile and the efficacy of colchicine therapy in Egyptian children suffering from familial Mediterranean fever: a descriptive study. Ital J Pediatr 2012; 38 :66.
31Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet 1998; 35:659-664.