Background

This rare disease is often a diagnosis of exclusion. Modern genetic analysis has revealed the genetic abnormalities responsible for the disease. It is characterized by short (1-3 days) attacks with fever, abdominal pain, arthralgia, chest pain, and amyloidosis. There is an erysipelas-like rash on the lower legs.

SYNONYMS	FMF
GEOGRAPHY	Armenian, Arab, Jewish, or Turkish
Familial Mediterranean fever: clinical and genetic characterization in a mixed pediatric population of Jewish and Arab patients. Brik R, Shinawi M, Kepten I, Berant M, Gershoni-Baruch R. Department of Pediatrics, Rambam Medical Center and Technion-Israel Institute of Technology Faculty of Medicine, Haifa, Israel.	Pediatrics 1999 May;103(5):e70 Abstract quote OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease which primarily affects non-Ashkenazi Jews, Armenians, Arabs, and Turks. The gene responsible for the disease (MEFV/FMF) has been recently identified. Four common mutations in exon 10 of the MEFV gene seem to account for 86% of the DNA variations identified in patients with FMF. We conducted a phenotype/genotype correlation study in a mixed population of Jewish and Arab children with FMF. STUDY DESIGN: Seventy patients clinically diagnosed as having FMF underwent molecular genetic studies using polymerase chain reaction and restriction endonuclease digestion methods to detect the presence of the four mutations (M694V, M680I, V726A, M694I). We then correlated the presence of each mutation with ethnic origin, age of onset, clinical manifestations, disease severity, and occurrence of amyloidosis. RESULTS: The M694V mutation, which is predominant in non-Ashkenazi Jews, was found in 92% of our Jewish patients and in only 30% of the Arab patients. All four mutations were identified among 94% of the Arab patients, but with no particular prevalence for any one of them. The presence of a homozygous M694V mutation was significantly associated with a more severe form of the disease: the clinical onset of the disease manifested at an earlier age; the number of attacks per month was higher; the global assessment by the treating physician and the severity of pain scored higher; and arthritis was more frequent. Only patients with the M694V mutation had a family history of amyloidosis. No association was found between the type of mutation and the predominance of fever, abdominal pain, pleuritis, skin eruption, or response to colchicine in the clinical picture. CONCLUSIONS: Homozygosity for the M694V mutation, predominant among North African Jews, is associated with a severe course and prognosis for FMF. This mutation is less common among Arabs and, when present, occurs almost only in heterozygous form. In Arab patients, the disease tends to run a milder course and seems to bear a better prognosis. The phenotype/genotype patterns that are evident from our study of a mixed series of Jewish and Arab children with FMF might provide a rational basis for counseling about the natural history of the disease and for clinical treatment of FMF patients and their families.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
Henoch-Schonlein purpura
Polyarteritis nodosa
The relation between familial Mediterranean fever and amyloidosis. Grateau G. Service de medecine interne, L'Hotel-Dieu, Paris, France.	Curr Opin Rheumatol 2000 Jan;12(1):61-4 Abstract quote Familial Mediterranean fever (FMF) is the most prevalent type of hereditary recurrent fever. Although the inflammatory attacks that characterize the disease may sometimes be debilitating, reactive amyloidosis remains the most serious manifestation of FMF. Daily treatment with colchicine can prevent both the attacks and amyloid deposition, but FMF-associated amyloidosis has not been eradicated and is still a cause of chronic renal failure in children and adults. The discovery of the gene responsible for FMF, Mediterranean fever gene (MEFV), and of associated mutations represents a major advance that now allows researchers to establish a strong, although nonexclusive association between one specific mutation, M694V, and the amyloid phenotype.

 

PATHOGENESIS	CHARACTERIZATION
Autosomal recessive
The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments. Mansfield E, Chae JJ, Komarow HD, Brotz TM, Frucht DM, Aksentijevich I, Kastner DL. Genetics Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH, Bethesda, MD 20892-1820, USA.	Blood 2001 Aug 1;98(3):851-9 Abstract quote Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever and intense inflammation. FMF attacks are unique in their sensitivity to the microtubule inhibitor colchicine, contrasted with their refractoriness to the anti-inflammatory effects of glucocorticoids. The FMF gene, MEFV, was recently identified by positional cloning; it is expressed at high levels in granulocytes and monocytes. The present study investigated the subcellular localization of the normal gene product, pyrin. These experiments did not support previously proposed nuclear or Golgi localizations. Instead fluorescence microscopy demonstrated colocalization of full-length GFP- and epitope-tagged pyrin with microtubules; this was markedly accentuated in paclitaxel-treated cells. Moreover, immunoblot analysis of precipitates of stabilized microtubules with recombinant pyrin demonstrated a direct interaction in vitro. Pyrin expression did not affect the stability of microtubules. Deletion constructs showed that the unique N-terminal domain of pyrin is necessary and sufficient for colocalization, whereas disease-associated mutations in the C-terminal B30.2 (rfp) domain did not disrupt this interaction. By phalloidin staining, a colocalization of pyrin with actin was also observed in perinuclear filaments and in peripheral lamellar ruffles. The proposal is made that pyrin regulates inflammatory responses at the level of leukocyte cytoskeletal organization and that the unique therapeutic effect of colchicine in FMF may be dependent on this interaction.
MEFV gene (16p13.3)	Cell 1997;90:797-807 Produces the Pyrin/marenostrin protein
MEFV mutations in multiplex families with familial Mediterranean fever: is a particular genotype necessary for amyloidosis? Tekin M, Yalcinkaya F, Cakar N, Akar N, Misirlioglu M, Tastan H, Tumer N. Department of Pediatrics, Ankara University School of Medicine, Turkey	Clin Genet 2000 Jun;57(6):430-4 Abstract quote Familial Mediterranean fever (FMF) is an autosomal recessive disease. It is characterized by recurrent febrile episodes in association with peritonitis, pleuritis, and arthritis. Progressive systemic amyloidosis is the most important complication of FMF that inevitably leads to chronic renal failure. Recently, the gene for FMF, MEFV, has been cloned and four missense mutations have been described: M694V, M680I, V726A, and M694I. Initial studies have suggested that the presence of the M694V mutation carries a significant risk for the development of amyloidosis. In this study, we present seven families, in which at least two individuals have been diagnosed with FMF and at least one with amyloidosis. Among 18 individuals, in whom molecular testing was performed for the four aforementioned mutations, ten had amyloidosis. None of these ten individuals was found to be homozygous for the M694V mutation. In three families, there were two sibs with amyloidosis. None of the sib-pairs with amyloidosis was found to have the same genotype. There were two or more sibs with the same genotype in four families. Only one sib from each family developed amyloidosis in these families. These results provide evidence that FMF patients without the M694V mutation are also at risk for the development of amyloidosis. Particular mutations themselves do not appear to be sufficient to explain the occurrence of amyloidosis in all cases with FMF.
Prevalence and significance of the familial Mediterranean fever gene mutation encoding pyrin Q148. Booth DR, Lachmann HJ, Gillmore JD, Booth SE, Hawkins PN. Centre for Amyloidosis and Acute Phase Proteins, Department of Medicine, Royal Free and University College Medical School, Royal Free Campus, London, UK.	QJM 2001 Oct;94(10):527-31 Abstract quote Familial Mediterranean fever (FMF) is caused by more than 25 mutations in the gene MEFV, which encodes pyrin (marenostrin), a protein implicated in the regulation of neutrophil activity. Pyrin Q148, is one of the five most common variants in populations in which FMF typically occurs. Our identification of the pyrin Q148 allele in several patients from ethnic groups in which FMF is not classically recognized who had longstanding fevers or AA amyloidosis prompted us to study the prevalence of pyrin Q148 in healthy British, Indian and Chinese subjects. The gene frequency was also sought in 50 British Caucasian patients with inflammatory arthritis, 25 of whom had AA amyloidosis, five Punjabi Indians with AA amyloidosis complicating inflammatory arthritis, and seven British Caucasian patients with uncharacterized longstanding fever syndromes. The allele frequency for pyrin Q148 was 21%, 15% and 0%, respectively, among Punjabi Indian, Chinese and Caucasian British controls, and was significantly increased among the patients with AA amyloidosis and the patients with obscure fever syndromes (p<0.01). Pyrin Q148 is a polymorphism and occurs widely in global terms, and, although it may cause FMF when associated with certain other MEFV mutations, homozygosity for Q148 alone must usually be insufficient to produce FMF in the populations studied. The association of pyrin Q148 with AA amyloidosis and with obscure chronic inflammatory diseases suggests the variant may augment inflammation non-specifically, which might have been beneficial during evolution, but could potentially exacerbate many chronic inflammatory disorders.
Familial Mediterranean fever: prevalence, penetrance and genetic drift. Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R. Institute of Human Genetics, Rambam Medical Center, Haifa, Isreal.	Eur J Hum Genet 2001 Aug;9(8):634-7 Abstract quote FMF is widely distributed in populations inhabiting the Mediterranean basin. It is mainly attributed to five founder mutations (M680I, M694V, M694I, V726A, E148Q) in the MEFV gene. The frequencies and distribution of these mutations in 146 FMF patients, of Arab and Jewish descent, were compared to that observed in 1173 healthy individuals of pertinent ethnic groups. Five mutations accounted for 91% of FMF chromosomes in our patients. Mutation M694V, predominant in North African Jews, was observed in all patients other than Ashkenazi Jews; mutation V726A was prevalent among all patients other than North African Jews; mutations M694I and M680I were mainly confined to Arab patients. Overall carrier rates, for four mutations (M680I, M694V, V726A, E148Q), were extremely high in our healthy cohort composed of Ashkenazi (n=407); Moroccan (n=243); Iraqi Jews (n=205); and Muslim Arabs (n=318); calculated at 1 : 4.5; 1 : 4.7; 1 : 3.5 and 1 : 4.3 respectively. The V726A allele prevalent among Ashkenazi and Iraqi Jews and Muslim Arabs (carrier rates: 7.4, 12.8 and 7.3%, respectively) was not found among Moroccan Jews. The M694V allele detected among Moroccan and Iraqi Jews and Muslim Arabs (carrier rates 11.1, 2.9 and 0.6%, respectively) was not observed among Ashkenazim. The overall frequency of mutations V726A and E148Q in Ashkenazim, Iraqi Jews and Arabs indicates that the bulk of individuals that comply with the genetic definition of FMF remain asymptomatic.

 

LABORATORY/RADIOLOGIC	CHARACTERIZATION
Recurrent hyperbilirubinaemia, a feature of familial Mediterranean fever: report of a child and review of the literature. Majeed HA, Halabi I, al-Taleb O. Department of Pediatrics, Faculty of Medicine, University of Jordon, Amman.	Ann Trop Paediatr 1998 Mar;18(1):13-5 Abstract quote Recurrent hyperbilirubinaemia was described as a feature of familial Mediterranean fever in the 1950s and early 1960s. However, over the last 33 years only one case has been published. We present a 12-year-old Arab boy who developed recurrent hyperbilirubinaemia in the course of familial Mediterranean fever. His response to colchicine was excellent. Review of the literature reveals that hyperbilirubinaemia of familial Mediterranean fever has a distinct clinical picture characterized by concurrent peritonitis, minimal jaundice and short duration. Factors contributing to the paucity of reports in recent literature are discussed.
Plasma fibronectin- and thrombospondin-adhesive molecules during acute attacks and attack-free periods of familial Mediterranean fever. Ertenli I, Kiraz S, Ozturk MA, Haznedaroglu IC, Celik I, Kirazli S, Calguneri M. Department of Rheumatology, Hacettepe University School of Medicine, Ankara, Turkey.	Rheumatol Int 2001 Aug;20(6):217-20 Abstract quote We assessed plasma concentrations of fibronectin (FN) and thrombospondin (TSP) during acute attacks and attack-free periods of patients with familial Mediterranean fever (FMF). Seven female and three male FMF patients (mean age 34+/-7 years) were enrolled in the study. Plasma samples were obtained during acute FMF attacks and after 3 months of freedom from attacks. Erythrocyte sedimentation rate, C-reactive protein, and white blood cell count were evaluated concurrently. Plasma levels of FN and TSP were assayed by enzyme-linked immunosorbent assay (ELISA). Both FN and TSP concentrations were found to increase during acute attacks. Levels of adhesive molecules decreased during attack-free periods (P < 0.05). Significant correlations were found between FN and TSP levels and the concentrations of acute-phase response indicators (P< 0.05). This study disclosed for the first time significantly higher increments in the plasma levels of FN and TSP during acute FMF attacks than in attack-free periods. Therefore, the two matrix glycoproteins may play precipitating and/or regulatory roles in the inflammatory processes of these attacks.
Increased urinary leukotriene E(4) during febrile attacks in the hyperimmunoglobulinaemia D and periodic fever syndrome. Frenkel J, Willemsen MA, Weemaes CM, Dorland L, Mayatepek E. Department of General Pediatrics, Wilhelmina Children's Hospital, KE.04.133.1, University Medical Center Utrecht, PO Box 85090, 3580AB Utrecht, Netherlands.	Arch Dis Child 2001 Aug;85(2):158-9 Abstract quote BACKGROUND: The hyperimmunoglobulinaemia D and periodic fever syndrome is a hereditary periodic fever, caused by deficiency of the enzyme mevalonate kinase. It is unclear how this defect leads to recurrent fever episodes. AIM: To assess the involvement of cysteinyl leukotrienes in the pathogenesis of fever attacks as reflected by urinary leukotriene E(4) (LTE(4)) excretion. METHODS: Urinary LTE(4) was measured in seven patients while febrile and afebrile. RESULTS: LTE(4) was raised during fever in all subjects (46-199 nmol/mol creatinine, mean 92; normal <40). Urinary LTE(4) was normal between attacks, as well as in normal children with fever as a result of miscellaneous causes. CONCLUSION: Our results suggest that cysteinyl leukotrienes play a role in the pathophysiology of this disorder. As no effective treatment is yet available, leukotriene receptor antagonists might offer a new therapeutic approach for patients with the hyperimmunoglobulinaemia D and periodic fever syndrome.

 

CLINICAL APPEARANCE/GROSS DISEASE	CHARACTERIZATION
Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Samuels J, Aksentijevich I, Torosyan Y, Centola M, Deng Z, Sood R, Kastner DL. Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892-1820, USA.	Medicine (Baltimore) 1998 Jul;77(4):268-97 Abstract quote Regarded as the most common and best understood of the hereditary periodic fever syndromes, familial Mediterranean fever (FMF) is a recessively inherited disease of episodic fever with some combination of severe abdominal pain, pleurisy, arthritis, and a characteristic ankle rash. The flares typically last for up to 3 days at a time, and most patients are completely asymptomatic between attacks; if untreated with prophylactic colchicine, some patients later develop amyloidosis and renal failure. The recent cloning of the FMF gene on the short arm of chromosome 16p, and the subsequent finding that its tissue expression is limited to granulocytes, has helped to explain the dramatic accumulation of neutrophils at the symptomatic serosal sites; the wild-type gene likely acts as an upregulator of an anti-inflammatory molecule or as a downregulator of a pro-inflammatory molecule. For nearly half a century, FMF was thought to cluster primarily in non-Ashkenazi Jews, Arabs, Armenians, and Turks, although the screening of the 8 known mutations in an American cohort has identified substantial numbers of people from the Ashkenazi Jewish and Italian populations in the United States who also have this disease. Nevertheless, the symptoms often go unrecognized and patients remain undiagnosed for years, not receiving the highly efficacious colchicine therapy; their histories often include multiple laparotomies, laparoscopies, and psychiatric evaluations. The combinations of clinical manifestations among FMF patients are quite heterogeneous, but our American cohort did not establish any connections between individual mutations and specific clinical pictures--as is seen in other diseases like cystic fibrosis, in which distinct genotypes target certain organ systems. Specifically, the data from our American series are insufficient to evaluate the hypothesis that the M694V/M694V genotype confers a more severe phenotype, or increases the risk of amyloidosis; but both our data and the recent literature (160) indicate that amyloidosis can occur in FMF patients with only 1 copy, or no copies, of the M694V mutation. It appears that specific MEFV mutations are probably not the sole determinants of phenotype, and that unknown environmental factors or modifying genes act as accomplices in this disease. Although we hope the discovery of the FMF gene will allow the diagnosis of FMF to become genetically accurate, the reality is that both clinical and genetic tools must still be used together unless mutations are identified on both of a patient's chromosomes. Physicians should be careful not to rule out the diagnosis in patients of high-risk ethnic backgrounds just because of atypical clinical features, as our data indicate that MEFV mutations are sometimes demonstrable in such patients. At the same time, physicians cannot yet rely solely on a genetic diagnosis because we have not yet identified a sufficient spectrum of mutations, and it is not currently feasible to examine every patient's full DNA sequence for the entire gene; screening an ethnically consistent and clinically positive patient for the 8 known mutations frequently identifies a mutation on only 1 chromosome, and genetic analysis of other classic cases will often reveal none of the 8 mutations. Still, our data suggest that ethnic background is an important predictor of finding 1 of the presently known mutations, and the knowledge of ancestries atypical for FMF can suggest the diagnosis of other hereditary periodic fever syndromes. As the list of FMF-associated MEFV mutations is expanded, and/or new sequencing technologies permit more rapid screening, the value and interpretation of genetic testing for FMF will become more straightforward. Moreover, as the pathophysiology of this disorder becomes less of a hypothesis and more of an understood entity, it is likely that treatment options will broaden beyond the use of daily prophylactic colchicine.
VARIANTS
The clinical patterns of myalgia in children with familial Mediterranean fever. Majeed HA, Al-Qudah AK, Qubain H, Shahin HM. Department of Pediatrics, Faculty of Medicine, University of Jordan.	Semin Arthritis Rheum 2000 Oct;30(2):138-43 Abstract quote OBJECTIVES: To study the frequency and clinical patterns of myalgia in a defined group of children with familial Mediterranean fever (FMF). METHODS: A prospective 4-year (September 1995-September 1999) study of children with FMF seen in the pediatric FMF clinic of Jordan University teaching hospital. Diagnosis of FMF was made according to published criteria. Once the diagnosis of FMF and myalgia was made, details about myalgia were collected by interview with the child and his/her parents and entered into a special study form. RESULTS: Of 264 children with FMF seen over the study period, 65 (25%) developed myalgia. Three clinical patterns of myalgia were identified: the spontaneous pattern, the exercise-induced pattern, and the protracted febrile myalgia syndrome (PFMS), seen in 8%, 81%, and 11% of patients, respectively. The three patterns differed in the severity of pain, height of fever, and duration of the episode. In 33 children with the exercise-induced myalgia, in which response to colchicine could be reliably assessed, a favorable response was achieved in 97%. Three children with the PFMS had a dramatic response to corticosteroids. CONCLUSIONS: Myalgia in children with FMF is common and can follow three different clinical patterns.
Familial Mediterranean fever--renal involvement by diseases other than amyloid. Tekin M, Yalcinkaya F, Tumer N, Cakar N, Kocak H, Ozkaya N, Gencgonul H. Ankara University Faculty of Medicine, Turkey.	Nephrol Dial Transplant 1999 Feb;14(2):475-9 Abstract quote BACKGROUND: In patients with familial Mediterranean fever (FMF) renal involvement is usually in the form of AA amyloidosis. There is increasing evidence that renal involvement may be due to diseases other than amyloid as well. METHODS: Amongst 302 children with FMF we observed and followed 28 with typical clinical and laboratory features of vasculitis. The diagnosis of FMF was established according to the Tel Hashomer criteria. RESULTS: Polyarteritis nodosa, protracted febrile attacks and Henoch-Schonlein purpura were diagnosed in 4, 13, and 11 patients, respectively. The presentation was often difficult to distinguish from FMF attacks, but protracted febrile attacks lasting several weeks, hypertension, thrombocytosis, and dramatic responses to corticosteroid therapy that were observed in many cases were different from what is observed in classical FMF. CONCLUSIONS: We suggest that FMF, perhaps as a consequence of impaired control of inflammatory responses, predisposes to vasculitis with renal involvement.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
General	Dermal neutorphilic infiltrate

 

PROGNOSIS AND TREATMENT

CHARACTERIZATION

Effects of colchicine on inflammatory cytokines and selectins in familial Mediterranean fever. Kiraz S, Ertenli I, Arici M, Calguneri M, Haznedaroglu I, Celik I, Pay S, Kirazli S. Hacettepe University, School of Medicine, Department of Internal Medicine, Ankara, Turkey.

Clin Exp Rheumatol 1998 Nov-Dec;16(6):721-4 Abstract quote OBJECTIVE: To evaluate whether basal levels of circulating cytokines and selectins exhibit a distinct profile in attack-free, non-colchicine taking familial Mediterranean fever (FMF) patients compared to normal healthy controls, and to determine the effect of colchicine treatment on these parameters. METHODS: Serum levels of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha, and soluble P-, E-, and L-selectin in attack-free, asymptomatic, non-colchicine using FMF patients (n = 11) and in normal controls (n = 10) were studied. Following 2 months of colchicine treatment the same parameters were evaluated again in the FMF patients. RESULTS: Before colchicine treatment the serum levels of all parameters except soluble P-selectin were significantly higher in FMF patients than in controls. After two months of treatment statistically significant decreases were observed in these parameters (p < 0.05). CONCLUSION: A distinct profile of IL-6, IL-8, TNF-alpha, and soluble E- and L-selectin levels was observed in FMF patients, which could reflect the presence of sustained inflammation in attack-free FMF patients. The effect of colchicine on these parameters suggests its therapeutic potential.

Medicine 1998;77:268-297.

Skin

Last Updated 11/10/2001

Send mail to psdermpath@earthlink.net with questions or comments about this web site.
Copyright © 2002 The Doctor's Doctor