American Journal of Medical Genetics 44183-188 (1992)
Familial Mediterranean Fever: Analysis of Inheritance and Current Linkage Data Mordechai Shohat, Yehuda L. Danon, and Jerome I. Rotter Departments of Pediatrics and Medical Genetics (M.S.) and Department of Pediatric Immunology (Y.L.D.) Children Hospital, Beilinson Medical Center, and Felsenstein Medical Research Institute, Petah Tikua, and The Sackler School of Medicine, Tel Aviv University, Israel; Medical Genetics Birth Defects Center (J.I.R.), Departments of Medicine and Pediatrics, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, California Familial Mediterranean fever (FMF) is a genetic disorder characterized by recurrent attacksof fever and inflammation of serosal surfaces. Unlike many mendelian disorders, the mode of transmission has been subject to some controversy as segregation analysis studies have always demonstrated fewer “observed”than “expected”affected individuals. Despite efforts to map the gene causing FMF, no definite linkage has been yet identified. This review analyses the epidemiologic and genetic characteristics in order to evaluate critically the inheritance of the disease and provide a perspective on the current biochemical and molecular genetic studies whose aim is to locate the gene for this disease. 0 1992 Wiley-Liss, Inc.
KEY WORDS genetics, recurrent polyserositis, gene frequency, linkage studies INTRODUCTION Familial Mediterranean fever (FMF) is a genetic disorder described as early as 1908 [Janeway and Mosenthal, 19081, but was not recognized as a distinct disease until 1945 [Siegel, 19451. It is characterized by idiopathic, recurring, self-limited attacks of febrile serosal inflammation involving the peritoneum, synovium, or pleura [Heller et al., 1958; Eliakim et al., 1981;Sohar et al., 1967; Schwabe and Peters, 1974;Pras et al., 19821. The symptoms usually appear in the first 2 decades and produce a burden because of their lifelong chronicity and joint destruction in some patients. As the
Receivedor publication November 13, 1991; revision received February 18, 1992. Address reprint requests to Mordechai Shohat, M.D., Director, Medical Genetics, Beilinson Medical Center, 49 100 Petah Tikva, Israel. ~
0 1992 Wiley-Liss, Inc.
pathogenesis of FMF is unknown, and there is no specific objective biochemical abnormality, its diagnosis a t present is based entirely on clinical criteria [Eliakim et al., 19811. Amyloidosis is the most severe complication occurring in 2-60% of the patients depending on the ethnic group [Schwabe and Peters, 1974; Pras et al., 1982; Ozdemir and Cavit, 19691. Before the use of colchicine as a medication, the complication of amyloidosis led to end-stage renal failure, common in the second t o third decade of life [Pras et al., 1982;Zemer et al., 19861.
GEOGRAPHIC DISTRIBUTION Studies of family origin in large clinical series have pointed to the frequent occurrence of familial paroxysmal polyserositis in Mediterranean countries [Heller et al., 1958; Sohar et al., 19671.This distribution is mainly why the disease has also been named familial Mediterranean fever. Most patients are Jews, Armenians, Arabs, and Turks [Eliakim et al., 1981; Ozdemir and Cavit, 1969; Armenian and Khachadurian, 19731. Analysis of the racial and ethnic distribution suggests that FMF occurs both by geographic proximity and by common ancestry. Among the Jewish patients, 90% are of North African (Libya, Morocco, Tunisia) and Iraqi origin. The North African Jews are those whose ancestors were dispersed over various Middle Eastern countries, while the Iraqi Jews are descendants of the Babylonian Jews exiled to Mesopotamia some 2,600 years ago. Although part of the Spanish ancestors dispersed to Middle and Eastern Europe, the prevalence of FMF in Ashkenazi Jews is low. The disease has been reported frequently in Turks and Armenians, both of whom have major differences in ancestry, but have lived in close proximity. In Lebanon, the 2 communities that seem to be genetically the least similar, namely the Armenians and Shites, are the most affected with the disease [Armenian and Khachadurian, 1973; Lalouel et al., 19761. Among Arabs there is a high frequency in both Palestinian Arabs as well as Lebanese [Majeed and Barakat, 1989;Barakat et al., 19861. On the other hand, while the disease is common in North African Jews, its prevalence in the non-Jewish North Africans is low. This data suggest that the gene for FMF had or might still have a
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selective genetic advantage in the Mediterranean area. The high frequency in ethnic groups of multiple different origins that are now or have recently been in geographic proximity suggests the possibility that more than one mutation in this gene has occurred (analogous to the multiple mutations seen in the beta hemoglobin locus in Mediterranean populations with thalassemia). PREVALENCEANDGENEFREQUENCY Population based prevalence has been estimated for both Jews and Armenians [Sohar et al., 1967; Khachadurian and Armenian, 1974; Schwabe and Peters, 19741.These figures are an underestimation of the true frequencies since: 1)they were based on the number of patients referred to the clinic out of the total population, while the total population was not carefully screened; 2) 50-60% of the patients present only after age 10 years and even by age 20 a significant percent (20%) of the patients are not yet symptomatic [Eliakim et al., 1981;Sohar et al., 1967;Schwabe andPeters 1974; Siegel, 19641; 3) at the time these studies were carried out (especially those prior to 19701,FMF was not a well recognized entity and many patients were misdiagnosed a5 having other chronic inflammatory diseases; 4) reduced penetrance, especially in females, as will be discussed later (maletfemale ratio = 1.7).Assuming recessive gene inheritance (see below), the prevalence of 455 known cases among 900,000 non-Ashkenazi Jews in Israel represents a gene frequency of 1:45 and a homozygote frequency of 1:2,000 [Sohar et al., 19671.Based on the evaluation of a minimum of 150 cases of Armenian origin in a population of about 150,000 Armenians in Lebanon, Khachadurian and Armenian [19741have estimated a gene frequency of 1:32 and a homozygote incidence of 1:1,000. Schwabe and Peters [1974] determined the prevalence of the disease in 1974 for Fresno county Armenians at 100 per 90,000 population. A recent study by Rogers et al. [19891 has made an attempt to calculate the gene frequency in the Armenians, utilizing methods that would avoid previously mentioned pitfalls. They used information collected on uncles, aunts, and cousins of the probands. The mean estimate of the gene frequency was 0.073, which yields a carrier rate of about 117. This high gene frequency predicts a disease rate of 1in 187 among Armenians, which is consistent with (but likely more accurate than) the prior estimate of 1in 200-400 for Fresno County, California (based on autopsy data) [Schwabe and Peters, 19741. A recent study of the Jewish population in Israel, using the same method of gene frequency estimation through cousins and uncles as Rogers et al. [1989], revealed the following figures for carrier rate: 1/6 in North African Jews, 118 in Iraqi Jews, and 1/12 in the Ashkenazi Jewish population [Brener et al., 19911. There appears to be almost no FMF among Jews of Yemenite or Persian ancestry. INCIDENCE OF AMYLOIDOSIS Of interest is the different incidence of FMF amyloidosis among the various ethnic groups. This complication has been reported to occur in 60% of selected series of Turkish patients [Ozdemir and Cavit, 1969;
Ozer et al., 19711, 12-29% in non-Ashkenazi patients, but in only around 3% of Armenian patients [Schwabe and Peters, 1974; Armenian et al., 19731. The frequent occurrence of amyloidosis and its dramatic variation between ethnic groups raises a question relative to its inherent relationship to FMF and whether it is transmitted by the gene for FMF or as a separate genetic trait, as will be discussed further below. GENETIC AND INHERITANCE A genetic cause of FMF was suspected on the basis of familial aggregation and marked increased frequency among those of Mediterranean descent [Reimann et al., 19541. A recent twin study has provided definitive evidence for the genetic basis of FMF [Shohat et al., 19913. Full concordance for FMF was observed in all 10 monozygotic (MZ) twin pairs studied, while in the 11dizygotic (DZ) twin sets, concordance was found in only 3 pairs. While the familial nature of FMF has been well recognized, the mode oftransmission has been subject to some controversy [Heller et al., 1958; Sohar et al., 1967; Khachadurian and Armenian, 1974; Sohar et al., 1961; Reimann et al., 1954; Armenian, 1982; Naffah et al., 19751. Studies that have aimed to evaluate the inheritance of FMF were complicatedby significant ascertainment biases. Since there is no test available to identify heterozygotes in FMF, all studies by definition utilize a form of incomplete ascertainment. As a result, all studies were conducted on patients referred to clinics, and the more affected children a family contains, the more likely that family will be ascertained, which is characteristic of a “single” ascertainment study. In practice, since most studies were reported from central specialized FMF clinics, the ascertainment is more complete than in the true “single” type, but was still not fully truncate [Emery, 19861. In addition, since there is no biochemical defect known to be specific for FMF, the diagnosis is based on a combination of clinical signs. Patients who have a milder form of the disease and especially in the absence of family history, may not fit the criteria required for confirming the diagnosis of FMF [Eliakim et al., 19811; and therefore will be mistakenly regarded as not affected. Other factors that further reduce the observed number of affected siblings include late onset of the FMF symptoms [Siegel, 1945; Eliakim et al., 1981; Sohar et al., 1967; Schwabe and Peters, 19741, and the incomplete penetrance of FMF in at least 43% of the females carrying the responsible disease genes, as is suggested by a male to female ratio of 1.76:l [Eliakim et al., 19811. Nevertheless, a critical review and analysis of the accumulated data provide sufficient evidence to strongly suggest that FMF is an autosomal recessive trait in all ethnic groups studied. The following summarizes these supporting data and analyses: 1. Segregation studies: Although Heller et al. [1958] had initially interpreted their data as suggesting dominant inheritance, they were able to show in 2 later studies, that included a much larger group of cases and a more thorough study of family relationships, that FMF in non-Ashkenazi Jews is recessively inherited [Sohar
Genetics of FMF
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TABLE I. Segregation Ratio in FMF Sibships When None of the Parents Are Affected* No’ affected Expected Observed
No. families studied
Total no. siblings
22
?
Israel Lebanon
215 101
1,177 460
Arm
Lebanon
121
558
Naffah et al. [19751
Arm
Lebanon
43
113
40.8
Rogers et al. [19891
Arm
USA
53
151
69
Authors
Ethnicity
Country
Heller et al. [19581
NAJ
Israel
Sohar et al. [19671 Khachadurian and American [19741 Armenian [19821
NAJ Arm
?
20
AD
376 160
325 130
AR AR
193
163
Polygenic or AR AD
33
64 *Arm, Armenians; NAJ, non-Ashkenazi Jews; AD,autosomal dominant; AR, autosomal recessive.
et al., 1961,19671. The relatively lower “observed”than expected incidence in the non-Ashkenazi families (Table I) may be attributed to the reduced penetrance in females, onset of the disease in late childhood, and failure to diagnose milder forms of the disease. The results for the Arabs and for the Armenians from Lebanon caused some confusion about the mode of transmission in Armenians, as they have been interpreted to suggest both recessive [Khachadurian and Armenian, 19741 and dominant [Reimann et al., 1954;Naffah et al., 19751 and polygenic [Armenian, 19821 inheritance. Added to this confusion, there are several reports of families reportedly demonstrating an autosomal dominant inheritance, based on transmission of the disease in 2 or more consecutive generations [Nilsson and Flodesus, 19641. To investigate these issues, we have recently conducted a prospective family study of 64 Armenian index cases randomly ascertained a t the UCLA FMF clinic [Rogerset al., 19891. Fifty-three families containing 176 sibs in addition to the probands were analyzed by genetic segregation analysis. Upper and lower bounds of the segregation ratio were estimated, and ranged from .10f .03 to .18 ? .05 when only definitely affected sibs were classified as affected; .17 .04 to .27 2 .05 when considering “possibly affected” sibs as affected; and .19 ? .04 to .30 ? .05 when incomplete penetrance in females was corrected. Thus, these data are consistent with the recessive mode of inheritance and are able to reject autosomal dominant inheritance, in which the expected segregation ratio would be 0.5.
*
Proposed inheritance
Notes One family with 3 generations, 3 with 2 generations
Dominant transmission in 113 of families
AR
2. Evaluation of families with transmission of the disease in 2 or more generations consecutively: Table I1 summarizes the number of such sibships which have been reported in the previous family studies. About one in 15 of non-Ashkenazi Jewish families, and up to one in 10 in the Armenians were found to have transmission of the disease in 2 consecutive generations. A few families affected in 3 consecutive generations were observed [Sohar et al., 1967; Rogers et al., 19893 and in a single family from a small town in Lebanon [Reimann et al., 19541 vertical transmission was demonstrated even through 5 generations. The gene frequency can be used to estimate the expected prevalence of FMF in the Armenian population and the expected number of 2 generations affected, which equals 3q [Rogers et al., 19891. The probability of observing transmission of FMF through 3 consecutive generations is 7q2 [Rogers et al., 19891. As can be seen in Table 11, the “observed” number of families with 2 or 3 affected in consecutive generations, i.e., vertical transmission, was comparable with what is expected in an autosomal recessive condition, given the high gene frequency. Again, the relatively lower observed than expected number of such families may be explained by incomplete penetrance of the disease. The data are in agreement with the proposed autosomal recessive inheritance of FMF, and indicate that the parent-to-offspring transmission reported in Armenians and non-Ashkenazi patients represents a pseudo-dominant phenomenon (i.e., a mating between a homozygote and unrecognized heterozygote). The relatively fre-
TABLE 11. Expected vs. Observed Number of FMF Families With at Least One Affected Parent
Authors Sohar et al. 119611 Sohar et al. [19671 Khachadurian and Armenian [19741 Armenian [19821 Rogers et al. 119891
Gene freauencv 1:20 1:20 1:16
Heterozygote rate 1:lO 1:lO 1%
No, of families studied 123 215 120
1:16 1:16
1% 1:8
135 64
No. of sibships with affected parents Expected“ Observed 12 21 15
9 14 10
17
14 4
8
“ 2x gene frequency x number of families [Rogers et al., 19891. Gene frequencies were determined according tn Rogers et al. [19891 and Brener et al. [19911.
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quent occurrence of such families is readily explained by its high gene frequency in these ethnic groups. 3. Segregation ratio in FMF sibships where one of the parents is affected: The observed number of affected sibs among families with affected parents reported for the different ethnic groups is summarized in Table 111. To allow appropriate comparison with families without affected parents, we excluded the probands in the segregation ratio calculation. As can be seen, the segregation ratios in families with one parent affected was double that found for the rest of the families. As was explained before, incomplete penetrance in females, onset of the disease in late childhood, and failure to diagnose milder forms of FMF may be responsible for the difference from the expected 25% (normal parents) (Table I) and 50% (one parent affected) (Table 111) values. Thus, autosomal recessive inheritance seems to be strongly supported by all aspects of the family aggregation and population distribution so far examined.
THE BASIC DEFECT IN FMF-STUDIES AND THEORIES In spite of much investigation and many important advances, the pathogenesis of the disease has remained obscure and subject to much speculation. Previously proposed hypotheses include defects of fat and etiocholanolone metabolism, hypothalamic dysfunction, instability of leukocyte granules resulting in leakage of pyrogenic and inflammatory substances, an autoimmune or allergic pathogenesis, and vascular permeability and leakage. However, none of these hypotheses have been supported adequately by the available scientific evidence [Eliakim et al., 19811. A relatively recent hypothesis proposed by Aderka et al. [19821 raised the possibility that FMF may be caused by an exaggerated response to endogenous interferons. However, increased interferon activity was not detected in the peripheral blood of 8 FMF patients during acute attacks [Aderka et al., 19801. More recently, Matzner and Brzezinski [19841reported a deficiency of C5a inhibitor in the peritoneal fluid from patients with FMF during attacks and suggested that this may have a role in the pathogenesis. This hypothesis is certainly attractive, but until isolation and characterization of the inhibitor itself, this theory cannot be readily tested. We have recently presented a hypothesis that FMF may be a congenital disorder caused by deficiency of one of the lipocortin proteins [Shohat et al., 19891. The lipocortin family of proteins is thought to control the
biosynthesis of the potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid [Chang et al., 19871.A deficiency in one of these proteins could cause the uncontrolled inflammation seen in FMF [Shohat et al., 19891. We and others have tested the 5 lipocortin genes that have been cloned and previously mapped to chromosomes 4,9,10, and 15, using a candidate gene approach. Recombinations between FMF and the lipocortin 2, 3, and 5 (chromosomes 4q21-q31, 9q34.1q34.3, and 15q respectively) were observed [Ash et al., 19911. Lipocortin 1(chromosome 9p12-ql2) and 4 (chromosome 10) were excluded on the basis of regional screening with informative probes to their respective chromosomal regions [Gruberg et al., 19911. The immunological abnormalities in FMF [Eliakim et al., 19811 made the HLA region on the short arm of chromosome 6 an important area of investigation for possible association and/or linkage with FMF. However, no association was found between FMF and HLA-A and B antigens, CB,C4,and BF polymorphisms in both nonAshkenazi Jewish [Pras and Gazit, 1985; Schlesinger et al., 1984; Chaouat et al., 19771 and Armenian families [Shohat et al., 1990bl. Recently, formal parametric (lod score) linkage analysis excludes the immunogenetic region on chromosome 6 from linkage with FMF both in the Armenian and non-Ashkenazi Jewish populations [Shohat et al., 1990bl. Sack [19881 reported novel structural changes in the highly conserved serum amyloid A (SAA) gene family based on unusual polymorphisms found in 4 FMF patients, but in none of 20 controls. By formal linkage analysis a genetic linkage between the SAA gene structural locus and FMF was ruled out at a recombination distance of 6% or less (lod = -2.16) [Shohat et al., 1990~1. In addition, there was no association between SAA alleles and FMF amyloidosis, suggesting that this gene is not (marker) involved in determining this complication [Shohat et al., 1990~1. Another gene that could be associated with FMF amyloidosis is the serum amyloid P (SAP) gene. First, the SAP protein is the precursor of the amyloid P component which is found intimately associated with all types of amyloid fibrils [Cohen et al., 19831. Second, Woo et al. [1987] recently suggested that the 8.8 kb restriction fiagment length polymorphism (RFLP) (the A allele of the SAP gene) represents a genetic predisposition to reactive amyloidosis in juvenile rheumatoid arthritis. The results of a recent study that tested this association in FMF amyloidosis do not parallel the findings in juve-
TABLE 111. Segregation Ratios in FMF Sibships Where One of the Parents Is Affected Authors Sohar et al. [19611 Sohar et al. [19671 Khachadurian and Armenian [19741 Armenian 119821 Rogers et al. [19891
No. families with affected parents 9 14 10
Total no. Siblings 43 69 58
No. affected siblings 21
14 4
91 12
32 6
25 21
Segregation ratio (%) 49 36
36 35 50
Genetics of FMF nile rheumatoid arthritis and the 8.8 kb RFLP band does not represent a genetic predisposition to the reactive amyloidosis seen in FMF [Shohat et al., 1990~1. Interleukins play a central role in inflammatory reactions, and are therefore attractive candidate genes. IL-1 and IL-6 induce fever, acute-phase protein production, and lymphocyte activation, while IL-8 has strong neutrophil chemotactic activity. Gruberg et al. [19911have excluded all 3 genes. Similarly, genes encoding several structural and regulatory proteins in the complement cascade such as C3 (chromosome 19) and C5 locus (9q22-34)were excluded [Shohat et al., 1990a; Gruberg et al., 19911. An alternative approach t o delineating the disorder’s cause is to identify’hked genetic markers using a random probe approach. A comprehensive effort has recently been undertaken to map the FMF gene as a step in delineating its cause and pathogenesis. This includes investigation of the relationship between FMF and a panel of polymorphic phenotypic red cell and serum protein markers in patients and families with FMF as well as various DNA marker probes [Aksentijevich et al., 1991; Shohat et al., 1990al. Future goals should include examining those loci in which linkage could not be rejected. There are now sufficient markers that either a candidate gene approach [Lusis, 19881or a random linkage approach should lead to the localization of the FMF gene and its eventual identification [Wicking and Williamson, 19911.
ACKNOWLEDGMENTS This study was supported by grant #88-009811 from the US.-Israel Binational Science Foundation (BSF), Jerusalem, Israel and by the Cedars-Sinai Board of Governors’ Chair in Medical Genetics (J.1.R). REFERENCES Aderka D, Pras M, Bin0 T, Rosenberg H, Weinberger A, Pinkas J (1980): Absence of interferon activity during acute attacks of FMF. Biomedicine 33:95-96. Aderka D, Weinberger A, Pinkas J (1982): Familial Mediterranean fever: a congenital disorder of exaggerated response to endogenous interferon. Med Hypotheses 8:477-480. Aksentijevich I, Gruberg L, Balow JE, Dean M, Pras M, Kastner DL (1991): Linkage and analysis in Familial Mediterranean fever. 8th International Congress of Human Genetics, October 6-11, Washington DC, #1872. Am J Hum Genet 99:335. Armenian HK, (1982): Genetic and environmental factors in the aetiology of familial paroxysmal polyserositis. An analysis of 150 cases from Lebanon. Trop Geogr Med 34:183-187. Armenian HK, Khachadurian AK (1973): Familial paroxysmal polyserositis. Clinical and laboratory findings in 120 cases. J Med Liban 26:605-614. Ash S,Magal N, Danon Y,Ratter JI, Shohat M (1991): Evaluation of the lipocortin genes in familial Mediterranean fever. Isr J Med Sci (submitted for publication). Barakat M, Karnik AM, Majeed HA (1986): Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs: a study of 175 patients and review of the literature. Q J Med 60:837-847. Brener M, Shohat M, Pras M (1991): Familial Mediterranean fever: gene frequency according to the different ethnic groups in Israel. Isr J Med Sci (submitted for publication). Chang J, Musser JH, McGregor H. Phospholipase A2: function and pharmacological regulation. Biochem Pharmacol1987;36:2429-36. Chaouat Y, Tormen JP, Godeau P, Camus JP, Kahn MF, Ryckewaert A,
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Laula J E , Menkes CJ,Schmid J , Hors J. Marquerurs HLA chez les sujets atteints de maladie periodique. La Nouvelle Press Medicale 1977;6:2949-2953. Cohen AS, Shizahama T, Sipe JD, Skinner M (1983): Amyloidproteins, precursors, mediator and enhancer. Lab Invest 48:l-4. Eliakim M, Levy M, Ehrenfeld M (1981): “Recurrent Polyserositis.” New York: ElsevierNorth Holland Biomedical Press. Emery AEH (1986): “Methodology in Medical Genetics: An Introduction to Statistical Methods.” 2nd ed. New York: Churchill Livingstone. Gruberg L, Aksentijevich I, Balow J, Dean M, Kovo M, Pras M, Kastner DL (1991):Exclusion of candidate genes in familial Mediterranean fever. Human Gene Mapping #11. #27387, p. 274. Heller H, Sohar E, Sherf L (1958): Familial Mediterranean fever. Arch Intern Med 102:50-71. Janeway TC, Mosenthal HO (1908): Unusual paroxysmal syndrome, probability allied to recurrent vomiting, with a study of nitrogen metabolism. Trans Assoc Am Physicians 23504-518. Khachadurian AK, Armenian HK (1974): Familial paroxysmal polyserositis (Familial Mediterranean Fever). Incidence of amyloidosis and mode of inheritance. Birth Defects: Original Article Series 10(4):62-64. Lalouel JM, Lefrance G, Chaiban D (1976): Genetic differentiation among Lebanese communities. Acta Anthropogenet 1:15-20. Lusis AJ (1988): Genetic factors affecting blood lipids: the candidate gene approach (Rev.). J Lipid Res 29(4);397-429. Majeed HA, Barakat M (1989): Familial Mediterranean Fever (recurrent hereditary polyserositis)in children: analysis of 88 cases. Eur J Pediatr 148636-64 1. Matzner Y, Brzezinski A (1984):C5a-inhibitor deficiency in peritoneal fluids from patients with Familial Mediterranean Fever. New Engl J Med 311:283-290. Naffah J. Bitar E. Nasr W. Khouri K (1975): ktude aenetiaue de la polyskrite paroxystique ’familiale, a propos de 72 cis. No& presse Med 4:1031-1037. Nilsson WE, Flodesus S (1964): Nine cases of hereditary and nonhereditary periodic diseases. Acta Med Scand 175341-346. Ozdemir AI,Cavit S (1969): Familial Mediterranean Fever among the Turkish people. Am J Gastroenterol 51:311-316. Ozer FL, Kaplaman E, Zileli S (1971):Familial Mediterranean Fever in Turkey. A report of twenty cases. Am J Med 50:336-339. Pras M, Bronshpigel N, Zemer D, Gafni J (1982):Variable incidence of amyloidosis in Familial Mediterranean Fever among different ethnic groups. The Johns Hopkins Medical Journal 150:22-25. Pras M, Gazit E (1985): Familial Mediterranean Fever: no association of HLA with amyloidosis or colchicine treatment response. Isr J Med Sci 21:757-758. Reimann HA, Moadie J, Semerdjian S, Sahyoun PF (1954): Periodic peritonitis-hereditary and pathology; report of seventy-two cases. J Am Med Assoc 154:1254-1259. Rogers DB, Shohat M, Petersen GM, Bickal J , Congleton J , Schwabe AD, Fbtter J I (1989):Familial Mediterranean Fever in Armenians; autosomal recessive inheritance with high gene frequency. Am J Med Genet 34:168-172. Sack GH (1988): Serum amyloid A (SAA) gene variations in Familial Mediterranean Fever. Mol Biol Med 561-67. Schlesinger M, Ilfred DN, Zamir R, Brautbar C (1984): Familial Mediterranean Fever: no linkage with HLA. Tissue Antigens 24:65-66. Schwabe AD, Peters RS (1974): Familial Mediterranean fever in Armenians. Analysis of 100 cases. Medicine (Baltimore) 53:453-462. Shohat M, Korenberg JR, Schwabe AD, Rotter J I (1989): Hypothesis: Familial Mediterranean Fever - a genetic disorder of the lipocortin family? Am J Med Genet 173-176. Shohat M, Livneh A, Zemer D, Pras M, Sohar E (1991):Twin studies in familial Mediterranean fever. Submitted for publication to Am J Med Genet. Shohat M, Shohat T, Rotter JI, Schlesinger M, Petersen GM, Pribyl T, Sack G, Schwabe AD, Korenberg JR (1990~): Serum Amyloid A and P genes in Familial Mediterranean Fever. Genomics 8:83-89. Shohat T, Shohat M, Petersen GM, Sparkes RS, Langfield D, Bickal J, Korenberg JR, Schwabe AD, Rotter JI (1990a): Genetic marker
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family studies in FMF in Armenians. Clinical Genetics 38332-339. Shohat T, Shohat M, Tyan DB, Wang SJ, Sparkes RS, Schwabe AD, Rotter JI (1990b):Familial Mediterranean Fever - linkaae studies with genetic markers on chromosome 6. ?‘issue An‘tigen 35: 103-107. Siegel S (1945): Benign paroxysmal peritonitis. Ann Intern Med 23:l-21. Siegel S (1964): Familial paroxysmal polyserositis. Analysis of fifty cases. Am J Med 369393-918. Sohar E, Gafni J, Pras M, Heller H (1967): Familial Mediterranean
fever. A survey of 470 cases and review of the literature. Am J Med 43~227-253. Sohar E, Pras M, Heller J, Heller H (1961):Genetics of Familial Mediterranean Fever. Arch Intern Med 107:529-538. Wicking C, Williamson C (1991): From linked marker to gene. The Genomics book in the series on “how-to in genetics.” Trends Genet 7:288-293. Woo P, OBrien J, Robson M, Ansell BM (1987): A genetic marker for systemic amyloidosis in juvenile arthritis. Lancet 2:767-769. Zemer D, Pras M, Sohar E, Moda M, Cabili S, Gafni J (1986):Colchicine in the treatment and prevention of amyloidosisof Familial Mediterranean Fever. N Engl J Med 314:lOOl-1005.
Familial Mediterranean Fever: Analysis of Inheritance and Current Linkage Data Mordechai Shohat, Yehuda L. Danon, and Jerome I. Rotter Departments of Pediatrics and Medical Genetics (M.S.) and Department of Pediatric Immunology (Y.L.D.) Children Hospital, Beilinson Medical Center, and Felsenstein Medical Research Institute, Petah Tikua, and The Sackler School of Medicine, Tel Aviv University, Israel; Medical Genetics Birth Defects Center (J.I.R.), Departments of Medicine and Pediatrics, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, California Familial Mediterranean fever (FMF) is a genetic disorder characterized by recurrent attacksof fever and inflammation of serosal surfaces. Unlike many mendelian disorders, the mode of transmission has been subject to some controversy as segregation analysis studies have always demonstrated fewer “observed”than “expected”affected individuals. Despite efforts to map the gene causing FMF, no definite linkage has been yet identified. This review analyses the epidemiologic and genetic characteristics in order to evaluate critically the inheritance of the disease and provide a perspective on the current biochemical and molecular genetic studies whose aim is to locate the gene for this disease. 0 1992 Wiley-Liss, Inc.
KEY WORDS genetics, recurrent polyserositis, gene frequency, linkage studies INTRODUCTION Familial Mediterranean fever (FMF) is a genetic disorder described as early as 1908 [Janeway and Mosenthal, 19081, but was not recognized as a distinct disease until 1945 [Siegel, 19451. It is characterized by idiopathic, recurring, self-limited attacks of febrile serosal inflammation involving the peritoneum, synovium, or pleura [Heller et al., 1958; Eliakim et al., 1981;Sohar et al., 1967; Schwabe and Peters, 1974;Pras et al., 19821. The symptoms usually appear in the first 2 decades and produce a burden because of their lifelong chronicity and joint destruction in some patients. As the
Receivedor publication November 13, 1991; revision received February 18, 1992. Address reprint requests to Mordechai Shohat, M.D., Director, Medical Genetics, Beilinson Medical Center, 49 100 Petah Tikva, Israel. ~
0 1992 Wiley-Liss, Inc.
pathogenesis of FMF is unknown, and there is no specific objective biochemical abnormality, its diagnosis a t present is based entirely on clinical criteria [Eliakim et al., 19811. Amyloidosis is the most severe complication occurring in 2-60% of the patients depending on the ethnic group [Schwabe and Peters, 1974; Pras et al., 1982; Ozdemir and Cavit, 19691. Before the use of colchicine as a medication, the complication of amyloidosis led to end-stage renal failure, common in the second t o third decade of life [Pras et al., 1982;Zemer et al., 19861.
GEOGRAPHIC DISTRIBUTION Studies of family origin in large clinical series have pointed to the frequent occurrence of familial paroxysmal polyserositis in Mediterranean countries [Heller et al., 1958; Sohar et al., 19671.This distribution is mainly why the disease has also been named familial Mediterranean fever. Most patients are Jews, Armenians, Arabs, and Turks [Eliakim et al., 1981; Ozdemir and Cavit, 1969; Armenian and Khachadurian, 19731. Analysis of the racial and ethnic distribution suggests that FMF occurs both by geographic proximity and by common ancestry. Among the Jewish patients, 90% are of North African (Libya, Morocco, Tunisia) and Iraqi origin. The North African Jews are those whose ancestors were dispersed over various Middle Eastern countries, while the Iraqi Jews are descendants of the Babylonian Jews exiled to Mesopotamia some 2,600 years ago. Although part of the Spanish ancestors dispersed to Middle and Eastern Europe, the prevalence of FMF in Ashkenazi Jews is low. The disease has been reported frequently in Turks and Armenians, both of whom have major differences in ancestry, but have lived in close proximity. In Lebanon, the 2 communities that seem to be genetically the least similar, namely the Armenians and Shites, are the most affected with the disease [Armenian and Khachadurian, 1973; Lalouel et al., 19761. Among Arabs there is a high frequency in both Palestinian Arabs as well as Lebanese [Majeed and Barakat, 1989;Barakat et al., 19861. On the other hand, while the disease is common in North African Jews, its prevalence in the non-Jewish North Africans is low. This data suggest that the gene for FMF had or might still have a
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selective genetic advantage in the Mediterranean area. The high frequency in ethnic groups of multiple different origins that are now or have recently been in geographic proximity suggests the possibility that more than one mutation in this gene has occurred (analogous to the multiple mutations seen in the beta hemoglobin locus in Mediterranean populations with thalassemia). PREVALENCEANDGENEFREQUENCY Population based prevalence has been estimated for both Jews and Armenians [Sohar et al., 1967; Khachadurian and Armenian, 1974; Schwabe and Peters, 19741.These figures are an underestimation of the true frequencies since: 1)they were based on the number of patients referred to the clinic out of the total population, while the total population was not carefully screened; 2) 50-60% of the patients present only after age 10 years and even by age 20 a significant percent (20%) of the patients are not yet symptomatic [Eliakim et al., 1981;Sohar et al., 1967;Schwabe andPeters 1974; Siegel, 19641; 3) at the time these studies were carried out (especially those prior to 19701,FMF was not a well recognized entity and many patients were misdiagnosed a5 having other chronic inflammatory diseases; 4) reduced penetrance, especially in females, as will be discussed later (maletfemale ratio = 1.7).Assuming recessive gene inheritance (see below), the prevalence of 455 known cases among 900,000 non-Ashkenazi Jews in Israel represents a gene frequency of 1:45 and a homozygote frequency of 1:2,000 [Sohar et al., 19671.Based on the evaluation of a minimum of 150 cases of Armenian origin in a population of about 150,000 Armenians in Lebanon, Khachadurian and Armenian [19741have estimated a gene frequency of 1:32 and a homozygote incidence of 1:1,000. Schwabe and Peters [1974] determined the prevalence of the disease in 1974 for Fresno county Armenians at 100 per 90,000 population. A recent study by Rogers et al. [19891 has made an attempt to calculate the gene frequency in the Armenians, utilizing methods that would avoid previously mentioned pitfalls. They used information collected on uncles, aunts, and cousins of the probands. The mean estimate of the gene frequency was 0.073, which yields a carrier rate of about 117. This high gene frequency predicts a disease rate of 1in 187 among Armenians, which is consistent with (but likely more accurate than) the prior estimate of 1in 200-400 for Fresno County, California (based on autopsy data) [Schwabe and Peters, 19741. A recent study of the Jewish population in Israel, using the same method of gene frequency estimation through cousins and uncles as Rogers et al. [1989], revealed the following figures for carrier rate: 1/6 in North African Jews, 118 in Iraqi Jews, and 1/12 in the Ashkenazi Jewish population [Brener et al., 19911. There appears to be almost no FMF among Jews of Yemenite or Persian ancestry. INCIDENCE OF AMYLOIDOSIS Of interest is the different incidence of FMF amyloidosis among the various ethnic groups. This complication has been reported to occur in 60% of selected series of Turkish patients [Ozdemir and Cavit, 1969;
Ozer et al., 19711, 12-29% in non-Ashkenazi patients, but in only around 3% of Armenian patients [Schwabe and Peters, 1974; Armenian et al., 19731. The frequent occurrence of amyloidosis and its dramatic variation between ethnic groups raises a question relative to its inherent relationship to FMF and whether it is transmitted by the gene for FMF or as a separate genetic trait, as will be discussed further below. GENETIC AND INHERITANCE A genetic cause of FMF was suspected on the basis of familial aggregation and marked increased frequency among those of Mediterranean descent [Reimann et al., 19541. A recent twin study has provided definitive evidence for the genetic basis of FMF [Shohat et al., 19913. Full concordance for FMF was observed in all 10 monozygotic (MZ) twin pairs studied, while in the 11dizygotic (DZ) twin sets, concordance was found in only 3 pairs. While the familial nature of FMF has been well recognized, the mode oftransmission has been subject to some controversy [Heller et al., 1958; Sohar et al., 1967; Khachadurian and Armenian, 1974; Sohar et al., 1961; Reimann et al., 1954; Armenian, 1982; Naffah et al., 19751. Studies that have aimed to evaluate the inheritance of FMF were complicatedby significant ascertainment biases. Since there is no test available to identify heterozygotes in FMF, all studies by definition utilize a form of incomplete ascertainment. As a result, all studies were conducted on patients referred to clinics, and the more affected children a family contains, the more likely that family will be ascertained, which is characteristic of a “single” ascertainment study. In practice, since most studies were reported from central specialized FMF clinics, the ascertainment is more complete than in the true “single” type, but was still not fully truncate [Emery, 19861. In addition, since there is no biochemical defect known to be specific for FMF, the diagnosis is based on a combination of clinical signs. Patients who have a milder form of the disease and especially in the absence of family history, may not fit the criteria required for confirming the diagnosis of FMF [Eliakim et al., 19811; and therefore will be mistakenly regarded as not affected. Other factors that further reduce the observed number of affected siblings include late onset of the FMF symptoms [Siegel, 1945; Eliakim et al., 1981; Sohar et al., 1967; Schwabe and Peters, 19741, and the incomplete penetrance of FMF in at least 43% of the females carrying the responsible disease genes, as is suggested by a male to female ratio of 1.76:l [Eliakim et al., 19811. Nevertheless, a critical review and analysis of the accumulated data provide sufficient evidence to strongly suggest that FMF is an autosomal recessive trait in all ethnic groups studied. The following summarizes these supporting data and analyses: 1. Segregation studies: Although Heller et al. [1958] had initially interpreted their data as suggesting dominant inheritance, they were able to show in 2 later studies, that included a much larger group of cases and a more thorough study of family relationships, that FMF in non-Ashkenazi Jews is recessively inherited [Sohar
Genetics of FMF
185
TABLE I. Segregation Ratio in FMF Sibships When None of the Parents Are Affected* No’ affected Expected Observed
No. families studied
Total no. siblings
22
?
Israel Lebanon
215 101
1,177 460
Arm
Lebanon
121
558
Naffah et al. [19751
Arm
Lebanon
43
113
40.8
Rogers et al. [19891
Arm
USA
53
151
69
Authors
Ethnicity
Country
Heller et al. [19581
NAJ
Israel
Sohar et al. [19671 Khachadurian and American [19741 Armenian [19821
NAJ Arm
?
20
AD
376 160
325 130
AR AR
193
163
Polygenic or AR AD
33
64 *Arm, Armenians; NAJ, non-Ashkenazi Jews; AD,autosomal dominant; AR, autosomal recessive.
et al., 1961,19671. The relatively lower “observed”than expected incidence in the non-Ashkenazi families (Table I) may be attributed to the reduced penetrance in females, onset of the disease in late childhood, and failure to diagnose milder forms of the disease. The results for the Arabs and for the Armenians from Lebanon caused some confusion about the mode of transmission in Armenians, as they have been interpreted to suggest both recessive [Khachadurian and Armenian, 19741 and dominant [Reimann et al., 1954;Naffah et al., 19751 and polygenic [Armenian, 19821 inheritance. Added to this confusion, there are several reports of families reportedly demonstrating an autosomal dominant inheritance, based on transmission of the disease in 2 or more consecutive generations [Nilsson and Flodesus, 19641. To investigate these issues, we have recently conducted a prospective family study of 64 Armenian index cases randomly ascertained a t the UCLA FMF clinic [Rogerset al., 19891. Fifty-three families containing 176 sibs in addition to the probands were analyzed by genetic segregation analysis. Upper and lower bounds of the segregation ratio were estimated, and ranged from .10f .03 to .18 ? .05 when only definitely affected sibs were classified as affected; .17 .04 to .27 2 .05 when considering “possibly affected” sibs as affected; and .19 ? .04 to .30 ? .05 when incomplete penetrance in females was corrected. Thus, these data are consistent with the recessive mode of inheritance and are able to reject autosomal dominant inheritance, in which the expected segregation ratio would be 0.5.
*
Proposed inheritance
Notes One family with 3 generations, 3 with 2 generations
Dominant transmission in 113 of families
AR
2. Evaluation of families with transmission of the disease in 2 or more generations consecutively: Table I1 summarizes the number of such sibships which have been reported in the previous family studies. About one in 15 of non-Ashkenazi Jewish families, and up to one in 10 in the Armenians were found to have transmission of the disease in 2 consecutive generations. A few families affected in 3 consecutive generations were observed [Sohar et al., 1967; Rogers et al., 19893 and in a single family from a small town in Lebanon [Reimann et al., 19541 vertical transmission was demonstrated even through 5 generations. The gene frequency can be used to estimate the expected prevalence of FMF in the Armenian population and the expected number of 2 generations affected, which equals 3q [Rogers et al., 19891. The probability of observing transmission of FMF through 3 consecutive generations is 7q2 [Rogers et al., 19891. As can be seen in Table 11, the “observed” number of families with 2 or 3 affected in consecutive generations, i.e., vertical transmission, was comparable with what is expected in an autosomal recessive condition, given the high gene frequency. Again, the relatively lower observed than expected number of such families may be explained by incomplete penetrance of the disease. The data are in agreement with the proposed autosomal recessive inheritance of FMF, and indicate that the parent-to-offspring transmission reported in Armenians and non-Ashkenazi patients represents a pseudo-dominant phenomenon (i.e., a mating between a homozygote and unrecognized heterozygote). The relatively fre-
TABLE 11. Expected vs. Observed Number of FMF Families With at Least One Affected Parent
Authors Sohar et al. 119611 Sohar et al. [19671 Khachadurian and Armenian [19741 Armenian [19821 Rogers et al. 119891
Gene freauencv 1:20 1:20 1:16
Heterozygote rate 1:lO 1:lO 1%
No, of families studied 123 215 120
1:16 1:16
1% 1:8
135 64
No. of sibships with affected parents Expected“ Observed 12 21 15
9 14 10
17
14 4
8
“ 2x gene frequency x number of families [Rogers et al., 19891. Gene frequencies were determined according tn Rogers et al. [19891 and Brener et al. [19911.
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Shohat et al.
quent occurrence of such families is readily explained by its high gene frequency in these ethnic groups. 3. Segregation ratio in FMF sibships where one of the parents is affected: The observed number of affected sibs among families with affected parents reported for the different ethnic groups is summarized in Table 111. To allow appropriate comparison with families without affected parents, we excluded the probands in the segregation ratio calculation. As can be seen, the segregation ratios in families with one parent affected was double that found for the rest of the families. As was explained before, incomplete penetrance in females, onset of the disease in late childhood, and failure to diagnose milder forms of FMF may be responsible for the difference from the expected 25% (normal parents) (Table I) and 50% (one parent affected) (Table 111) values. Thus, autosomal recessive inheritance seems to be strongly supported by all aspects of the family aggregation and population distribution so far examined.
THE BASIC DEFECT IN FMF-STUDIES AND THEORIES In spite of much investigation and many important advances, the pathogenesis of the disease has remained obscure and subject to much speculation. Previously proposed hypotheses include defects of fat and etiocholanolone metabolism, hypothalamic dysfunction, instability of leukocyte granules resulting in leakage of pyrogenic and inflammatory substances, an autoimmune or allergic pathogenesis, and vascular permeability and leakage. However, none of these hypotheses have been supported adequately by the available scientific evidence [Eliakim et al., 19811. A relatively recent hypothesis proposed by Aderka et al. [19821 raised the possibility that FMF may be caused by an exaggerated response to endogenous interferons. However, increased interferon activity was not detected in the peripheral blood of 8 FMF patients during acute attacks [Aderka et al., 19801. More recently, Matzner and Brzezinski [19841reported a deficiency of C5a inhibitor in the peritoneal fluid from patients with FMF during attacks and suggested that this may have a role in the pathogenesis. This hypothesis is certainly attractive, but until isolation and characterization of the inhibitor itself, this theory cannot be readily tested. We have recently presented a hypothesis that FMF may be a congenital disorder caused by deficiency of one of the lipocortin proteins [Shohat et al., 19891. The lipocortin family of proteins is thought to control the
biosynthesis of the potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid [Chang et al., 19871.A deficiency in one of these proteins could cause the uncontrolled inflammation seen in FMF [Shohat et al., 19891. We and others have tested the 5 lipocortin genes that have been cloned and previously mapped to chromosomes 4,9,10, and 15, using a candidate gene approach. Recombinations between FMF and the lipocortin 2, 3, and 5 (chromosomes 4q21-q31, 9q34.1q34.3, and 15q respectively) were observed [Ash et al., 19911. Lipocortin 1(chromosome 9p12-ql2) and 4 (chromosome 10) were excluded on the basis of regional screening with informative probes to their respective chromosomal regions [Gruberg et al., 19911. The immunological abnormalities in FMF [Eliakim et al., 19811 made the HLA region on the short arm of chromosome 6 an important area of investigation for possible association and/or linkage with FMF. However, no association was found between FMF and HLA-A and B antigens, CB,C4,and BF polymorphisms in both nonAshkenazi Jewish [Pras and Gazit, 1985; Schlesinger et al., 1984; Chaouat et al., 19771 and Armenian families [Shohat et al., 1990bl. Recently, formal parametric (lod score) linkage analysis excludes the immunogenetic region on chromosome 6 from linkage with FMF both in the Armenian and non-Ashkenazi Jewish populations [Shohat et al., 1990bl. Sack [19881 reported novel structural changes in the highly conserved serum amyloid A (SAA) gene family based on unusual polymorphisms found in 4 FMF patients, but in none of 20 controls. By formal linkage analysis a genetic linkage between the SAA gene structural locus and FMF was ruled out at a recombination distance of 6% or less (lod = -2.16) [Shohat et al., 1990~1. In addition, there was no association between SAA alleles and FMF amyloidosis, suggesting that this gene is not (marker) involved in determining this complication [Shohat et al., 1990~1. Another gene that could be associated with FMF amyloidosis is the serum amyloid P (SAP) gene. First, the SAP protein is the precursor of the amyloid P component which is found intimately associated with all types of amyloid fibrils [Cohen et al., 19831. Second, Woo et al. [1987] recently suggested that the 8.8 kb restriction fiagment length polymorphism (RFLP) (the A allele of the SAP gene) represents a genetic predisposition to reactive amyloidosis in juvenile rheumatoid arthritis. The results of a recent study that tested this association in FMF amyloidosis do not parallel the findings in juve-
TABLE 111. Segregation Ratios in FMF Sibships Where One of the Parents Is Affected Authors Sohar et al. [19611 Sohar et al. [19671 Khachadurian and Armenian [19741 Armenian 119821 Rogers et al. [19891
No. families with affected parents 9 14 10
Total no. Siblings 43 69 58
No. affected siblings 21
14 4
91 12
32 6
25 21
Segregation ratio (%) 49 36
36 35 50
Genetics of FMF nile rheumatoid arthritis and the 8.8 kb RFLP band does not represent a genetic predisposition to the reactive amyloidosis seen in FMF [Shohat et al., 1990~1. Interleukins play a central role in inflammatory reactions, and are therefore attractive candidate genes. IL-1 and IL-6 induce fever, acute-phase protein production, and lymphocyte activation, while IL-8 has strong neutrophil chemotactic activity. Gruberg et al. [19911have excluded all 3 genes. Similarly, genes encoding several structural and regulatory proteins in the complement cascade such as C3 (chromosome 19) and C5 locus (9q22-34)were excluded [Shohat et al., 1990a; Gruberg et al., 19911. An alternative approach t o delineating the disorder’s cause is to identify’hked genetic markers using a random probe approach. A comprehensive effort has recently been undertaken to map the FMF gene as a step in delineating its cause and pathogenesis. This includes investigation of the relationship between FMF and a panel of polymorphic phenotypic red cell and serum protein markers in patients and families with FMF as well as various DNA marker probes [Aksentijevich et al., 1991; Shohat et al., 1990al. Future goals should include examining those loci in which linkage could not be rejected. There are now sufficient markers that either a candidate gene approach [Lusis, 19881or a random linkage approach should lead to the localization of the FMF gene and its eventual identification [Wicking and Williamson, 19911.
ACKNOWLEDGMENTS This study was supported by grant #88-009811 from the US.-Israel Binational Science Foundation (BSF), Jerusalem, Israel and by the Cedars-Sinai Board of Governors’ Chair in Medical Genetics (J.1.R). REFERENCES Aderka D, Pras M, Bin0 T, Rosenberg H, Weinberger A, Pinkas J (1980): Absence of interferon activity during acute attacks of FMF. Biomedicine 33:95-96. Aderka D, Weinberger A, Pinkas J (1982): Familial Mediterranean fever: a congenital disorder of exaggerated response to endogenous interferon. Med Hypotheses 8:477-480. Aksentijevich I, Gruberg L, Balow JE, Dean M, Pras M, Kastner DL (1991): Linkage and analysis in Familial Mediterranean fever. 8th International Congress of Human Genetics, October 6-11, Washington DC, #1872. Am J Hum Genet 99:335. Armenian HK, (1982): Genetic and environmental factors in the aetiology of familial paroxysmal polyserositis. An analysis of 150 cases from Lebanon. Trop Geogr Med 34:183-187. Armenian HK, Khachadurian AK (1973): Familial paroxysmal polyserositis. Clinical and laboratory findings in 120 cases. J Med Liban 26:605-614. Ash S,Magal N, Danon Y,Ratter JI, Shohat M (1991): Evaluation of the lipocortin genes in familial Mediterranean fever. Isr J Med Sci (submitted for publication). Barakat M, Karnik AM, Majeed HA (1986): Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs: a study of 175 patients and review of the literature. Q J Med 60:837-847. Brener M, Shohat M, Pras M (1991): Familial Mediterranean fever: gene frequency according to the different ethnic groups in Israel. Isr J Med Sci (submitted for publication). Chang J, Musser JH, McGregor H. Phospholipase A2: function and pharmacological regulation. Biochem Pharmacol1987;36:2429-36. Chaouat Y, Tormen JP, Godeau P, Camus JP, Kahn MF, Ryckewaert A,
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