Version July 2025
INTRODUCTION —
Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disorder and is associated with mutations in the MEFV (Mediterranean Fever) gene. FMF is characterized by recurrent attacks of fever and symptoms consistent with serosal inflammation. This topic will review the epidemiology, genetics, and pathogenesis of FMF. The clinical manifestations, diagnosis, and management of FMF are discussed in detail separately. (See "Clinical manifestations and diagnosis of familial Mediterranean fever" and "Management of familial Mediterranean fever".)
EPIDEMIOLOGY —
It is hypothesized that familial Mediterranean fever (FMF) originated more than 3000 years ago in Mesopotamia [1]. From there, the disease spread to Armenia and Turkey in the Ancient World. In the modern world, globalization has led to further spread to countries far from the Mediterranean basin.
The evolving geographic reach of FMF is reflected in regional variations in prevalence:
●Regions with a higher prevalence – FMF is most prevalent in individuals of Turkish, Armenian, Middle Eastern, Non-Ashkenazi Jewish, and Arab descent living mainly around the Mediterranean basin. Studies about the current prevalence of the disease in these countries are scarce [2]. However, previous studies showed that the prevalence rate in Turkey ranged from 1 in 150 to 1 in 10,000, depending on regional differences [3-6]; the highest reported prevalence (1 in 395) came from the central Anatolia region, while the lowest (6 in 10,000) was in the northwestern region of Turkey [3,6]. Armenia is the second most affected country, with an estimated FMF prevalence of 1 case per 500 people and a carrier rate of 1 in 7 [7]. In Israel, FMF prevalence varies by ethnic group, ranging from 1 in 500 to 1 in 1000 among non-Ashkenazi Jews, and 1 in 73,000 among Ashkenazi Jews [1,8]. Additionally, the carrier rates for MEFV variants are 1 in 5 among Iraqi Jews, 1 in 3.5 among Moroccan Jews, and 1 in 4.3 among Muslim Arabs [8].
●Regions with a lower prevalence – FMF has also been reported at a lower prevalence in many other areas outside the Mediterranean basin and in people with various types of ancestries, including patients in Greece, Italy, Japan, and China [9-12]. In the Balkans, the number of FMF patients and the carriage rate of MEFV variants decrease with increasing distance from Turkey [13], which may reflect the expansion of the Ottoman Empire in this area. In Italy, the prevalence of FMF is highest in the southern part and decreases gradually toward the northern region, which similarly may be explained in part by the historical migration of various populations including the area's ancient colonization by Greek and Arab individuals, the migration of Jewish people, and the brief presence of the Ottoman Empire [14]. In some countries, most patients with FMF have ancestral ties to regions with a higher carrier rate for FMF. As examples, most FMF patients in Germany have Turkish ancestry [15], while most of those in France have North African ancestry, and those in the United States frequently have Ashkenazi Jewish, Middle Eastern, and Armenian ancestry. However, some patients with FMF do not have these types of ancestral ties, as has been described in Japanese patients living in Japan and Chinese patients living in China [10-12,16].
In addition to its impact on prevalence, geography can also influence the disease severity and type of clinical manifestations in FMF [17]. As an example, a study of 382 patients with FMF found that the type and severity of symptoms were impacted by both the patient's genotype and geographic location [18]. This variability is probably due to differences in additional genetic modifiers and associated environmental factors. However, this may not be true for all areas; in one study of 75 adults with Turkish ancestry who had FMF, the disease severity was similar for those living in Turkey compared with those living in Germany [15]. (See 'Genotype-phenotype correlation' below and "Clinical manifestations and diagnosis of familial Mediterranean fever".)
The relatively high carrier rate of MEFV pathogenic variants among populations around the Mediterranean basin may be the result of an evolutionary advantage against infections. Pyrin (the protein encoded by the MEFV gene) is a crucial sensor for infections caused by microbes that produce exotoxins, such as Clostridioides (see 'Normal function of pyrin' below). Pathogenic variants in MEFV cause increased activity of pyrin, suggesting a lower threshold for activating the inflammatory response to fight infection. Thus, the devastating plagues of Yersinia pestis that previously affected the Mediterranean region could have created a selective advantage for MEFV variant carriers [19].
GENETICS
MEFV gene and variants — Familial Mediterranean fever (FMF) is usually considered an autosomal recessive disease related to biallelic pathogenic variants in the MEFV gene, which encodes pyrin. The MEFV gene has 10 exons and is located on the short arm of chromosome 16 (16p 13.3) [20,21]. There are more than 370 recognized variants in MEFV, which are mostly located in exons 2 and 10 [22]. The number of variants is increasing with the use of whole exome and all genome sequencing.
The potential pathogenicity of different variants depends upon their location along the gene [23]. The significance of the different variants has been evaluated by a consensus of clinicians and geneticists and is freely accessible online. Pathogenic variants are defined as those strongly associated with FMF, while "likely pathogenic" variants are associated with disease in most (>90 percent) of their carriers. In other cases, variants may be of uncertain significance (VUS), likely benign, or benign [24]. Up to two-thirds of registered variants distributed over the entire MEFV gene are either not classified or classified as VUS due to their unknown exact clinical association with FMF [25].
Five pathogenic founder mutations (M694V, M694I, M680I, V726A, and E148Q) account for approximately 75 percent of FMF genotypes from typical cases of FMF in Armenian, Turkish and Jewish populations [26]. M694V is the most common pathogenic variant in all of these populations, with a rate ranging from 20 to 90 percent of the FMF patients depending on their ancestry [27-29]. In addition, there are some phenotypic variations between the different mutations. (See 'Genotype-phenotype correlation' below.)
Approximately 10 to 20 percent of individuals who meet diagnostic criteria for FMF have no known pathogenic variant in MEFV. Potential explanations for this scenario include a mistaken diagnosis of FMF [30] or true FMF either with a limited genetic investigation of known pathogenic variants or as-yet-unidentified genetic variations [31].
Inheritance and penetrance of FMF — Most patients with FMF have two pathogenic variants in MEFV, meaning that their disease is inherited in an autosomal recessive pattern. However, approximately 30 percent of FMF patients in endemic countries harbor a single pathogenic variant (monoallelic disease) [32,33]. This observation raises the question of whether the disease can also be transmitted as an autosomal dominant trait. Some reports describe a dominant trait among patients with specific pathogenic variants such as M694VDel, a deletion mutation, and H478Y, T577N, and P373L, which result from missense mutations [34-37]. The deletion mutation may cause a major change in the encoded pyrin protein, leading to full expression of FMF. However, there is no clear explanation for the expression of FMF in those individuals carrying the other single missense mutations. At a population level, heterozygosity for pathogenic variants in MEFV is a risk factor for developing FMF, with the risk six- to eightfold higher than noncarriers of pathogenic variants in MEFV [38].
The penetrance of FMF appears to be variable, since most but not all individuals with a single pathogenic variant in MEFV are asymptomatic, and, rarely, patients with two pathogenic variants may be asymptomatic. Therefore, additional genetic and environmental modifiers may influence the penetrance of the disease. (See 'Other factors' below.)
Genotype-phenotype correlation — Patients fall into various phenotypic categories based on the presence of pathogenic variants in the MEFV gene and associated symptoms:
●Asymptomatic carriers – Symptom-free individuals with one or more identifiable pathogenic or non-pathogenic MEFV variants in cis (monoallelic) are called "asymptomatic carriers." More than 95 percent of the carriers of a single MEFV variant (heterozygotes) are asymptomatic.
●Phenotype 1 FMF – Patients who have typical symptoms of FMF and who carry one or more MEFV variants have "phenotype 1 FMF." Individuals with biallelic pathogenic variants in MEFV tend to have more severe disease than those with one or no pathogenic variants [39].
●Phenotype 2 FMF – Patients with biallelic MEFV pathogenic variants who present with renal amyloidosis (proteinuria) and who lack a typical history of FMF attacks are designated as "phenotype 2 FMF."
●Phenotype 3 FMF – Symptom-free individuals harboring two or more biallelic MEFV variants are defined as "phenotype 3 FMF" [40].
Certain variants in MEFV are associated with different disease severity and clinical manifestations. As examples, the pathogenic variants M694V and M680I are associated with the most severe forms of FMF and are clustered in exon 10, which encodes a motif known as the B30.2/SPRY domain at the C terminus of the protein. More information on specific variants includes the following:
●M694V – M694V homozygotes have a severe phenotype and are more likely to have early disease onset, arthritis, erysipelas-like skin lesions, high fever, splenomegaly, and more frequent attacks than in individuals with other MEFV pathogenic variants [41]. In addition, patients with this pathogenic variant require higher doses of colchicine to prevent attacks as compared with patients with other genotypes.
The M694V pathogenic variant affects the majority of patients with FMF who are of North African Jewish ancestry; these patients are known to have more severe attacks and, in the pre-colchicine era, they had a high frequency of renal amyloidosis [42]. Patients with FMF who have Ashkenazi Jewish and Druze ancestry have a relatively low frequency of the M694V pathogenic variant and tend to have milder versions of FMF, with a low prevalence of amyloidosis [43,44].
●E148Q, R202Q, P369S, and R408Q – Genetic variants found in exons 2 (eg, E148Q, R202Q) and 3 (P369S, R408Q) are usually associated with less severe clinical presentations of FMF or even just mild nonspecific inflammatory manifestations. In Japan, where most pathogenic variants are in exons 2, 3, and 4, FMF tends to be milder with a lower prevalence of abdominal manifestations, a higher median age of onset, and a lower frequency of complications (eg, AA amyloidosis); disease is often easily controlled with low-dose colchicine [45].
However, reports exist of more severe or atypical disease associated with these variants. As an example, several studies showed that E148Q, P369S, and R408Q may exist together on a single allele (complex allele in Cis) and present with FMF-like disease or a periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA)-like syndrome [46-48]. Additional studies from Greece and Turkey reported that the R202Q mutation may be associated with the classic inflammatory phenotype of FMF [49,50], especially when patients have compound mutations involving R202Q [48].
It is still unclear whether the E148Q variant is truly pathogenic [51-53]. The E148Q variant has reduced penetrance and E148Q homozygotes are asymptomatic or may have a mild disease; amyloidosis is rare in such individuals. However, patients carrying the E148Q variant with an additional variant are almost always symptomatic. In one study, the penetrance of M694V/E148Q was found to be more than 17 times higher than that of M694V/-, suggesting an active role for the E148Q variant when combined with the M694V pathogenic variant [54]. Moreover, a subsequent study reported that E148Q in cis with M694V (complex allele), provided significant potentiation of inflammasome formation, enhancing FMF attack [55]. (See "Clinical manifestations and diagnosis of familial Mediterranean fever", section on 'Clinical manifestations'.)
Other factors — The incomplete penetrance and the varying expression of FMF suggest the presence of other genetic or environmental factors that influence the severity of the disease and its clinical manifestations:
●Modulation of clinical expression of MEFV gene – The segregation of different alleles of the major histocompatibility class I chain-related gene A (MICA) among FMF patients with different clinical features suggests that another gene may modulate the clinical expression of the MEFV gene. In one study that evaluated 151 affected patients and their family members for the presence of five common MICA alleles, the A-9 allele was strongly associated with early disease onset in M694V homozygotes, while the A-4 allele appeared to have a beneficial effect on the frequency of FMF attacks [56]. The possibility that another gene is tightly linked to MICA, and in linkage disequilibrium with the different MICA alleles, has not been excluded. The mechanism through which MICA, or another closely linked gene, influences the FMF phenotype is unclear.
●Genetic variants in related proteins – Heterogeneity among additional disease-modifying proteins may also contribute to the variable phenotypes among patients with identical MEFV genotypes [57]. This potential for variations in other disease-modifying proteins to impact the phenotype of FMF was illustrated in a study that evaluated the genotype of 137 Armenian patients from 127 families [58], which found that the serum amyloid A1 (SAA1) alpha homozygous genotype was associated with a sevenfold increased risk for renal amyloidosis compared with other SAA1 genotypes. In another study from Japan, SAA1 gene polymorphisms were also associated with susceptibility to FMF [59]. As another example, the Arg753Gln polymorphism in toll-like receptor 2 (TLR-2) may alter the innate immune response to pathogens and therefore may change the phenotype of FMF in geographic areas where bacterial insult is more common [60].
●Other factors – Epigenetic factors, microbiota, and host-microbiome interactions may also play a role in the phenotypic expression of FMF [61]. As an example, in a study that included 19 patients with FMF, there were differences in the composition of microbiota during attack and attack-free periods, as well as between patients with FMF and healthy controls [62].
PATHOGENESIS —
The MEFV gene encodes pyrin, a protein expressed predominantly in myeloid lineage cells as well as synovial fibroblasts and dendritic cells. Pyrin appears to act as a specific immune sensor (pattern recognition receptor [PRR]) for bacterial toxin modifications of Rho GTPases interaction. Pathogenic mutations in the MEFV gene cause a gain of function of the pyrin protein, which can start an inflammatory cascade in the absence of known or apparent provocation by a toxin or infection, resulting in an attack of familial Mediterranean fever (FMF).
Normal function of pyrin — Pyrin is a 781 amino acid protein that is expressed predominantly in the cytoplasm in cells of the myeloid lineage (among circulating cells) as well as synovial fibroblasts and dendritic cells [63]. Pyrin plays an important role in the innate immune system, which constitutes a primary defense against external pathogens and other harmful agents [64]. Pyrin's main function is sensing changes in the interaction between GTPases and Ras homolog gene family, member A (Rho A) [65], as outlined below:
●Physiologic conditions – Rho A peptide controls the activity of GTPases and other protein kinases. In physiologic conditions, Rho A-GTPase activates the serine-threonine protein kinases 1 and 2 (PKN1 and PKN2), which in turn bind and phosphorylate pyrin. Phosphorylated pyrin binds to inhibitory 14.3.3 proteins, which can trap pyrin and neutralize its activity [66]. This interaction retains pyrin in an inactive state where it does not induce inflammation.
●Inflammatory conditions – During inflammation, pyrin contributes to the formation of the inflammasome and perpetuates the inflammatory cascade. Specifically, following infectious or noninfectious triggers, the Rho A-GTPase system is downregulated and there is less phosphorylation of pyrin. Therefore, there is less trapping of pyrin by 14.3.3 peptides. Together with intracellular microtubules, this nonphosphorylated pyrin can recruit apoptosis-associated speck-like protein containing a CARD (ASC) peptide and procaspase, forming the pyrin inflammasome. The inflammasome activates procaspase to caspase, which in turn converts pro-interleukin 1 (IL-1) and pro-IL-18 into their active state. In parallel, caspase cleaves Gasdermin D (a pore-forming protein), causing cell membrane rupture (pyroptosis) and release of intracellular cytokines, which continue the inflammatory process [67].
This pathway may allow pyrin to serve as a PRR to indirectly detect pathogen virulence activity by responding to the downstream effects of pathogens on the Rho A-GTPase system [65]. This indirect action is in contrast to that of most mammalian PRRs, which directly recognize microbial or intracellular waste products. As an example, cytotoxin TcdB6-8 is a major virulence factor of Clostridioides difficile. This toxin inactivates Rho, thereby reducing the rate of pyrin phosphorylation by GTPases [68] and promoting an inflammatory process to fight the infection. The toxin also recruits ASC peptide and procaspase, which further contributes to the assembly of the pyrin inflammasome [65,68].
Inflammasome dysregulation in FMF — Pathogenic variants in the MEFV gene cause the gain of function of the pyrin protein without needing a strong external provocation (eg, from a pathogen) (figure 1). Following a seemingly minor trigger (eg, emotional stress, exposure to cold), the Rho-A and PKNs are mildly inactivated, meaning that pyrin is less phosphorylated. In patients with FMF, pathogenic variants in the MEFV gene further impair pyrin phosphorylation so that there is a significantly higher amount of active (nonphosphorylated) pyrin. This enables the construction of the pyrin inflammasome and propagates inflammation. In addition, pyrin encoded by the pathogenic variant in the MEFV gene does not require the critical reliance on intact microtubules for ASC assembly, further facilitating and enhancing the process of inflammasome formation [69]. The outcome of this process is the secretion of IL-1, IL-18, and other mediators of inflammation that enhance chemotaxis and neutrophilia, inducing an attack of FMF [68]. (See "Clinical manifestations and diagnosis of familial Mediterranean fever", section on 'Clinical manifestations'.)
This explanatory model of FMF is in contrast to the initial hypotheses about pathogenic variants in MEFV, which postulated that pyrin might normally attenuate the inflammatory process and that pathogenic variants in MEFV prevented this suppressive function, allowing FMF to flare [70].
An unsolved question in FMF is why the attacks spontaneously resolve within 72 hours. One explanatory hypothesis relates to the release of neutrophil extracellular traps (NET), which are web-like structures composed of nuclear or mitochondrial chromatin associated with different proteins, such as elastase, myeloperoxidase (MPO), cathepsin G, proteinase 3, and active IL-1 beta [71]. These NET structures that are observed in the first hours of FMF attacks, enhance inflammation and subside as the inflammatory attack resolves. The generation of NETs is restricted by a negative feedback mechanism, which helps stop the cycle of inflammation and may explain the self-limited nature of FMF attacks.
Dysregulation of the inflammasome due to mutated components also underlies other autoinflammatory diseases (eg, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and neonatal-onset multisystem inflammatory disease). (See "Cryopyrin-associated periodic syndromes and related disorders".)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Familial Mediterranean fever".)
SUMMARY
●Overview – Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder associated with pathogenic variants in the MEFV (Mediterranean Fever) gene, which encodes pyrin. It is characterized by recurrent bouts of fever and serosal inflammation. (See 'Introduction' above.)
●Epidemiology – FMF is most prevalent in individuals of Armenian, Turkish, Non-Ashkenazi Jewish, and Arab descent. However, FMF is not restricted to these groups and has been reported at a lower prevalence in other populations. (See 'Epidemiology' above.)
●Genetics
•MEFV gene and variants – FMF is usually considered an autosomal recessive disease related to biallelic pathogenic variants in the MEFV gene, which encodes pyrin. Five pathogenic founder mutations (M694V, M694I, M680I, V726A, and E148Q) account for approximately 75 percent of FMF chromosomes from typical cases in people with Armenian, Arabic, Jewish, and Turkish ancestry. Approximately 10 to 20 percent of individuals who meet diagnostic criteria for FMF have no MEFV pathogenic variant; there is controversy over whether such patients truly have FMF or another type of inflammatory condition. (See 'MEFV gene and variants' above.)
•Inheritance and penetrance – FMF is usually an autosomal recessive disease, with most affected individuals having biallelic pathogenic variants in the MEFV gene. Phenotypic expression of FMF has been reported in a subset of patients who carry only one MEFV pathogenic variant; however, more than 95 percent of those carrying a single MEFV variant are asymptomatic. (See 'Inheritance and penetrance of FMF' above.)
•Genotype-phenotype correlation – Patients fall into various phenotypic categories based on the presence of pathogenic or nonpathogenic variants in the MEFV gene and associated symptoms:
-"Phenotype 1" FMF – Individuals carrying one or more pathogenic MEFV variants who present with typical symptoms of FMF.
-"Phenotype 2" FMF – Individuals with biallelic pathogenic variants in MEFV who present with amyloidosis without a typical history of FMF attacks.
-"Phenotype 3" FMF – Asymptomatic individuals who carry two or more biallelic MEFV variants.
-Asymptomatic carriers – Asymptomatic individuals with one or more MEFV variants in cis (monoallelic).
Certain pathogenic variants are associated with specific disease manifestations. Patients who are homozygous for the M694V pathogenic variant have a severe form of the disease, with a higher likelihood of developing early disease onset, more frequent attacks, renal amyloidosis, high fever, arthritis, erysipelas-like skin lesions, and splenomegaly. In addition, patients who are M694V homozygotes require higher doses of colchicine to prevent attacks as compared with patients with other genotypes. (See 'Genotype-phenotype correlation' above.)
•Other factors – The incomplete penetrance and varying expression of FMF suggest the presence of other genetic or environmental factors that influence disease manifestations. Such factors may include variants in genes that modulate the expression of the MEFV gene or the structure of related proteins, epigenetic factors, microbiota, and host-microbiome interactions. (See 'Other factors' above.)
●Pathogenesis – The MEFV gene encodes pyrin, a protein expressed predominantly in myeloid lineage cells along with synovial fibroblasts and dendritic cells. Pyrin appears to act as a specific immune sensor (pattern recognition receptor [PRR]) for bacterial toxin modifications of Rho GTPases interaction. Pathogenic mutations in the MEFV gene cause a gain of function of the pyrin protein to start the cascade of inflammation even in the absence of provocation by a toxin or infection, resulting in an attack of FMF (figure 1). (See 'Pathogenesis' above.)
ACKNOWLEDGMENTS —
The UpToDate editorial staff acknowledges Peter M. Rosenberg, MD, and Stephen E Goldfinger, MD, who contributed to an earlier version of this topic review.
