Pediatric rheumatology review. New interest in an old disease: Familial Mediterranean fever

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1 Paraneoplastic RS3PE / F. Cantini et al. Pediatric rheumatology review SHORT REVIEW New interest in an old disease: Familial Mediterranean fever S. Ozen Seza Ozen, MD, Associate Professor, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey. Please address correspondence and reprint requests to: Dr Seza Ozen, Department of Pediatric Rheumatology and Nephrology, Hacettepe Universtiy Faculty of Medicine, Sihhiye Ankara, Turkey. sozen@gen.hun.edu.tr Received on August 25, 1999; accepted in revised form on October 12, Clin Exp Rheumatol 1999; 17: Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Key words: Familial Mediterranean fever, vasculitis. ABSTRACT Familial Mediterranean fever (FMF) is characterized by recurrent attacks of fever and serositis. Identifying the mutated gene has shed light on the pathogenesis of the disease. Typical attacks of FMF last 3 to 5 days. Arthritis is present in almost half of all patients and is localized to the ankle, knee or hip. Recently vasculitic features have been increasingly reported in FMF patients, and it may be speculated that vasculitis constitutes a feature of this disease. Genetic analysis is very important to confirm the diagnosis in patients with a European ancestry. However, at present the yield of genetic testing is not satisfactory; new sequencing techniques permitting more rapid screening and definition of all mutations are necessary. Colchicine is the drug of choice. A trial of colchicine may also help in the differential diagnosis with other periodic fever syndromes. Introduction Familial Mediterranean fever (FMF) is characterized by recurrent, self-limited attacks of fever and serosal inflammation (1-3). The constellation of symptoms was first described as a clinical entity some 50 years back (4). This periodic fever disease became increasingly recognized after the description of those first 10 cases. The disease was observed to be frequent in non-ashkenazi Jews, Arabs, Turks and Armenians. The diagnosis remained a clinical one for many years (5), and the lack of specific laboratory tests caused FMF to remain undiagnosed in many patients. The disease was also associated with a high mortality rate and the risk of renal amyloidosis. The first breakthrough was the introduction of colchicine treatment in 1972 (6). There are few drugs that have changed the fate of a rheumatic disease as much as colchicine has. A major advance in FMF was then introduced with gene hunting. Pedigree analysis had clearly shown that the pattern of inheritance in FMF is compatible with an autosomal recessive inheritance. Painstaking work allowed the mapping of the causative gene in 1997 (1, 2), after which the definition of the disease changed. FMF is now defined as a disease of the regulation of neutrophil inflammation caused by mutations in a gene designated as MEFV (1, 2). Interest in FMF grew after the characterization of the gene and its protein product. Identification of the mutations and carrier haplotypes suggested that the mutations originated in the eastern Mediterranean basin (1), and tracing back the ancestors through haplotype analysis suggests its origin in very ancient times (7, 8). Thus, the aforementioned ethnic groups acquired the disease more than 2000 years ago. Another important fact regarding FMF is that it is the first rheumatologic disease in which the causative gene has been identified. We already have strong data indicating that this protein is probably a transcription factor which acts to repress inflammation or to up-regulate an anti-inflammatory molecule (9). The delineation of this inflammatory pathway could provide an important tool to understand the pathogenesis of inflammation in many disease states. Epidemiology and genetics The frequency of FMF in the most commonly involved ethnic groups varies between 1/256 and 1/1075 (7, 9, 10). Definition of the mutations and tracing back haplotypes has suggested that the ancestors with the mutated gene came from the Eastern Mediterranean basin. The most common mutation, M694V, spread from the Eastern Mediterranean to Spain during the Babylonian captivity more than 2000 years ago. This mutation also spread to Turkey, Armenia, Iraq and sub- 745

2 PEDIATRIC REVIEW sequently to north Africa with the Sephardic expulsion of 1492 (7-9). Another mutation in this gene, the V726A mutation, spread from the same region in the following years, this time to Europe (7-9). The protein encoded by this gene is expressed in the neutrophils and in myeloid bone marrow precursors and is called pyrin or marenostrin (1, 2). This protein works inside the nucleus. It has been proposed that pyrin may act as an antiinflammatory protein (8, 9). Thus, when there is a mutation in MEFV, it produces an abnormal pyrin protein which is unable to properly suppress inflammation. The physiologic factors that uncover pyrin dysfunction and trigger the attack are unclear. At least 14 mutations have been identified for this gene, but 4 account for 85% of the mutations in populations where the disease is frequent (7-9). The high frequency of the disease in certain geographic areas and the number of mutations have led to the suggestion of a heterozygote advantage of the disease (11). Although there has been much speculation, we still lack conclusive data in this regard. Clinical manifestations and diagnosis FMF is characterized by brief attacks of fever and pain. The frequency of the attacks may be variable and the inciting factors are not always clear. Clinical observation has shown that infections and stress may be triggering factors. Patients can sometimes go for long periods without symptoms. The pediatric patient is severely ill during the episode and stops daily activities, is sent home by the teacher, and must be put to bed. Fever is usually more than 38 C. The level of fever should be recorded by the family. Abdominal pain is so severe that quite a few patients have undergone laparotomy and had their appendix removed. In cases of arthritis, usually the large joints of the lower extremities are involved. The most common presentation is a non-destructive, self-limited monoarthritis that is of short duration and resolves without sequelae. More rarely, a chronic destructive arthritis of the hip or sacroiliitis may occur (7). Pleuritis manifests as chest pain that can Familial Mediterranean fever / S. Ozen be extremely incapacitating. Pericarditis is very rare. In our series of over 600 children, 95% have presented with abdominal pain and 15% with chest pain, whereas half of them had arthritis/arthralgia. Joint complications seem to be more frequent in Jewish patients (5). It is very useful to determine the white blood cell count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and fibrinogen during the course of an attack, as these values will be raised, with remittance to normal levels within a few days after the cessation of the attack. There may be evidence of ongoing subclinical inflammation in patients during attack-free periods. Tunca et al. (12) have reported that even the first degree relatives of FMF patients, who are heterozygote for the mutation, have higher CRP and SAA levels compared to controls. Livneh et al. (13) from the Sheba Medical Center have suggested a detailed set of criteria for the diagnosis of FMF. The requirements for the diagnosis of FMF have been defined as the presence of: at least 1 major criteria; or at least 2 minor criteria; or 1 minor plus > 5 supportive criteria or 1 minor plus > 4 of first 5 supportive criteria. Typical attacks are defined by Livneh as recurrent (at least 3), febrile and short in duration (12 hours to 3 days). Incomplete attacks are defined as differing from typical attacks in 1 or 2 features as follows: (1) temperature < 38 C; (2) attack duration longer or shorter than a typical attack (but no less than 6 hours and no more than 7 days); (3) no signs of peritonitis during the attacks; (4) localized abdominal attacks; and (5) arthritis in a location other than the hip, knee, or ankle (Table I). In their study this set of criteria showed a high sensitivity and specificity. It is also in accordance with the diagnostic approach that we have used for the establishment of our FMF registry, which includes over 600 children (3). However, it remains to be validated in ethnic groups where FMF is not common. There are some less frequent symptoms in FMF. An erysipelas-like rash, sometimes with a violaceous color, is an important finding. It usually occurs just below the ankle or on the dorsum of the foot. This rash can be precipitated by stasis during a long journey or by strenuous exercise. It resembles cellulitis, sometimes with accompanying arthralgia, and fades away in 2-3 days. It has been reported in 7-40% of patients (7), but probably is more frequent when sought for. Protracted episodes of myalgia, spondyloarthropathy and scrotal attacks have been more and more frequently reported (14). Patients may present with severe myalgia that lasts longer than the normal duration of an attack. The erysipelas-like rash may accompany the protracted myalgia. More interestingly, we and others have reported increased frequencies of polyarteritis nodosa, Henoch Schonlein purpura and vasculitis-like features in these patients (15-17). Polyarteritis nodosa tends to present at a younger age in FMF patients. The patient usually exhibits constitutional symptoms, myalgia and hypertension. Thus, the presentation is usually of a classic polyarteritis with marked an- Table I. Suggested criteria for the diagnosis of FMF. Major criteria Typical attacks* 1. Peritonitis (generalized) 2. Pleuritis (unilateral) or pericarditis 3. Monoarthritis (hip, knee, ankle) 4. Fever alone 5. Incomplete abdominal attack Minor criteria Incomplete attacks* involving either or both of the following sites: 1. Chest 2. Joint 3. Exertional leg pain 4. Favorable response to colchicine Supportive criteria 1. Family history of FMF 2. Appropiate ethnic origin 3. Age < 20 yr at disease onset. Features of attacks: 4. Severe, requiring bed rest 5. Spontaneous remission 6. Symptom-free interval 7. Transient inflammatory response with 1 or more abnormal results for the following tests: white blood cell count, ESR, serum amyloid A, fibrinogen. 8. Episodic proteinuria/hematuria 9. Unproductive laparatomy or removal of white appendix 10. Consanguinity of parents * See text 746

3 Familial Mediterranean fever / S. Ozen eurysms in the renal artery. It is tempting to speculate that these vasculitic features constitute a manifestation of FMF per se (15, 18). Data on phenotype-genotype correlations are not conclusive. Dewalle et al. (19) have suggested that the presence of the M694V mutation, which is the most frequent mutation, is associated with more severe disease. Shohat et al. (20) have analyzed the association between amyloidosis and the haplotypes of FMF patients. They suggested that a specific core haplotype, with 153bp:104bp at markers D16S3370 and D16S2617, respectively, were associated with amyloidosis (20). However, the risk of amyloidosis is not confined to the most common mutations. Patients have been identified who do not carry the M694V mutation in either allele (8). One bias with the M694V mutation is that it represents the most frequent mutation of FMF in these groups. Thus, we need more data to identify the genetic predictors for the development of amyloidosis. The differential diagnosis (for example, with hyperimmunoglobulin D syndrome and autosomal dominant periodic fever syndromes in Irish patients) represents a problem, as will be discussed below (21-24). When one suspects FMF in a patient with a European ancestry, the yield of the genetic analysis is complicated and far from perfect. Since this is an autosomal recessive disease, confirmation of FMF by genetic analysis requires the presence of mutations on both alleles of the gene encoding for pyrin. This may be the same mutation (homozygote) or different mutations (compound heterozygote). When genetic analysis is carried out in a country where the disease is frequent, such as Israel or Turkey, the yield of the analysis is around 80%. In Turkish FMF patients we were able to define mutations in both alleles in 77% of the patients. In a recent report of an Armenian case series, mutated alleles were identified in 89% of the patients (25). However, when American patients with diverse ethnic backgrounds were analyzed, only 27.9% of the patients had 2 mutations and thus were genetically confirmed to have FMF (8). In an additional 26.7% only one mutation was identified. When a UK series of 27 patients of varied ethnic origin with probable or possible FMF were tested, only 62.9% had 2 mutations (26). However, the yield was higher in the probable FMF group. Varying ethnic background clearly is associated with the possibility of other periodic diseases or of novel mutations in the inflammatory cascade of pyrin or even other proteins. Unidentified new mutations in the gene coding for pyrin maybe present in these cases. Furthermore, another limiting factor of genetic analysis is the possibility of a second gene affecting perhaps another protein in this cascade. Linkage analysis in Turkish patients with typical FMF has suggested that there maybe another gene, perhaps another protein along the neutrophil inflammatory cascade, that is mutated (27). Thus, when new sequencing techniques are developed, permitting more rapid screening and the identification of all mutations, the yield of genetic testing will increase. Until then, FMF will remain a clinical diagnosis in a considerable number of cases. When genetic analysis for FMF is requested, the family should be informed of the results of the test. If the phenotype is highly suggestive in a heterozygote or negative case with typical attacks, a trial of colchicine may be recommended. A response to colchicine is suggestive of the diagnosis per se. This is especially advisable in a patient with a family history of amyloidosis. PEDIATRIC REVIEW Differential diagnosis FMF used to be a disease typical of certain countries. However, in a world characterised by constant movement and migrations, and with new developments related to the cloning of the gene, FMF is now becoming a more common problem. A patient from one of the four characteristic ethnic groups, who presents with typical recurrent (at least 4-5 times) attacks of fever, and pain lasting less than 3 days, does not represent much of a diagnostic challenge. However, when a European patient with a periodic fever is encountered, one is faced with a difficult task. We now know that FMF does occur in other ethnic groups, as well. In a US study of various ethnic groups, Samuels et al. (8) reported interesting results: among FMF patients applying for genetic studies, Italians were the third largest group, Ashkenazi Jews were the second, and diverse ethnic groups were represented. Thus, the differential diagnosis becomes very important. There are a number of important points to emphasize in the differential diagnosis of FMF with the other two principal hereditary periodic fever syndromes (7-9, 21-24). These two syndromes are hyperimmunoglobulin D (hyper-igd) syndrome and the periodic fever syndromes with an autosomal dominant form of inheritance (Table II). These points are: - In FMF, the duration of the attack is expected to be less than 3 days except for the aforementioned prolonged myalgia. In hyper-igd syndrome the attacks tend to be somewhat longer (3-7 days). In the disease formerly known as familial Hibernian fever (FHF), attacks may last from 1 day to several weeks. - The arthritis usually occurs in the hip, knee or ankle and is almost always monoarticular. However, arthralgias may also occur during the attacks. In hyper-igd syndrome the usual presentation is oligoarticular symmetric arthritis or arthralgia, while in FHF arthralgias are common. - One important point not mentioned in the criteria of Livneh et al. (13) is cutaneous involvement. The erysipeloid erythema of FMF is quite characteristic, if not pathognomonic for the disease (5). Cutaneous lesions are probably more common in hyper-igd syndrome and FHF; however, they are different in location and character. - Exertional leg pain is a sign of FMF. - A favorable response to colchicine is a feature of FMF, but not of hyper IgD or FHF. - Lymphadenopathy is not a feature of FMF. - In patients with FMF, careful questioning for the presence of amyloidosis in the family history should be included. - Vomiting and diarrhea are more frequent in hyper IgD syndrome, but may occur in FMF. Another disease which is important in the differential diagnosis in young children is the Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenopathy 747

4 PEDIATRIC REVIEW syndrome (PFAPA syndrome). This syndrome is characterized by episodes of the features contained in its name (28, 29). The attacks last for 4-5 days. However, the condition may be differentiated from FMF in that the symptoms are rapidly controlled by glucocorticoids (28, 29). Thus, a typical child with FMF will be the offspring of a consanguineous marriage, with self-limited attacks of fever and pain that remit spontaneously in 1-3 days. An erysipelas-like vasculitic rash, and a history of a relative with amyloidosis strongly support the diagnosis. In an out-patient setting, an algorithm for the probable diagnosis of FMF may be suggested as follows (from ref. 10): (1) the presence of fever plus abdominal and/or chest and/or joint pain; (2) the presence of at least 3 such attacks; and (3) a diagnosis of FMF or amyloidosis in a family member (10, 18). In patients who fulfill these criteria, we suggest that genetic analysis for mutations in the FMF gene should be carried out. The typical presentation of a child with hyper-igd syndrome would be oligoarticular arthritis, maculo-papular rash and lymphadenopathy during the fever attacks. We would suggest that IgD levels should be checked for in all patients with a European ancestry suffering from periodic attacks. A value >100 IU/ml would suggest hyper-igd syndrome. It should be kept in mind, however, that 10% of patients with FMF or FHF will also have elevated IgD levels (8). Thus, genetic analysis may be necessary in selected cases. The gene for hyper-igd syndrome has recently been cloned (21, 30). The typical presentation of FHF would be a patient with Irish/North European ancestry exhibiting arthralgias, tender erythematous lesions, lymphadenopathy, conjunctivitis, and myalgia during attacks. Recently, there has been an exciting development regarding the genetic locus of the autosomal recessive periodic fever diseases. These rare syndromes were previously referred to as familial Hibernian fever (23) or familial periodic fever (24). McDermott et al. (22) have shown that both are caused by mutations in TNF receptor 1 (TNFR-1). Thus, mutations in this gene, resulting in the impaired down-regulation of membrane TNFR-1, are responsible for the periodic inflammatory attacks. In a suspected case, genetic analysis for mutations in the TNF-receptor gene should be sought for. So far genetic analysis has proved to be highly informative. Treatment One of the milestones in the history of FMF was the introduction of colchicine for its treatment in 1972 (6, 31). Very few drugs have resulted in such a dramatic change in the course of a disease. Colchicine decreases the frequency and severity of attacks (3, 32). When a patient with FMF has recurrent attacks, however, it is crucial to evaluate his/her compliance with therapy. More importantly, colchicine prevents the most lethal complication of the disease, i.e. amyloidosis (3, 32). Zemer et al. (32) and our group (3) have shown that amyloidosis is almost entirely eliminated in patients who are on colchicine therapy. Those few patients who developed amyloidosis while on colchicine have admitted a failure to comply with therapy. It is astonishing that we are yet not certain how colchicine acts. Ben-Chetrit and Levy (31) have suggested that colchicine concentrates in neutrophils because of the absence of the P-glycoprotein efflux pump on their membranes. Then the high Familial Mediterranean fever / S. Ozen concentration of colchicine may exert an intracellular agonistic effect on pyrin. About 65% of patients respond with complete remission, and another 20-30% report a significant improvement of their attacks in terms of severity, duration and the presence of fever (7). Only 5-10% fail to respond, and in these patients it is not yet certain to what degree non-compliance may play a role. The physician must explain to the family and the patient(when appropriate) that colchicine is being prescribed in order to prevent amyloidosis, at least until we know more about the factors causing amyloidosis. Although the drug arrests mitotic and meiotic chromosomal segregation in vitro, no study to date has conclusively demonstrated that colchicine is responsible for trisomy 21 or other chromosomal defects in offspring (8, 33). Nevertheless, most physicians still recommend amniocentesis during pregnancy if either of the parents is taking colchicine. Sterility has also been suggested as a concern, but examples have been very rare in practice (31). Untreated attacks should be regarded as more substantial problems that may compromise fertility in both sexes. Testicular biopsies in two cases with azospermia have shown amyloidosis (31). Colchicine has a suppressive effect on the attacks, although it must be remembered that during an attack colchicine does not help to terminate it. Additional antiinflammatory drugs may be given together with the usual dose of colchicine during an attack. Indomethacine is the drug of choice in our center. Future concerns Mapping of the gene for FMF and other periodic diseases represented a very im- Table II. Differential diagnosis of the three most common periodic fever syndromes (modified from ref. 9). FMF Hyper-IgD syndrome Familial Hibernian fever Ethnic origin Jewish, Turkish, Armenian, Arab European (Dutch) Irish Prevalence As high as 1/ cases 24 cases Arthritis Monoarticular Oligoarticular, symmetric Arthralgia Cutaneous findings Occasional, erythema Common Common Lymphadenopathy Uncommon Common Common Tests before genetic analysis Response to colchicine suggestive Check serum IgD level Autosomal dominant inheritance suggestive 748

5 Familial Mediterranean fever / S. Ozen portant step forward in FMF. We are now able to make a definite diagnosis in many patients. Correct diagnosis saves the patient from unnecessary laboratory investigations, laparotomies, surgery, and medical expenses. However, important questions still remain, such as whether or not to treat asymptomatic subjects with genetically proven FMF. We still do not know what factors are operative in the development of amyloidosis, which is a lethal disease. Should one withhold colchicine from the sibling of a patient with amyloidosis, if he has genetically proven FMF but no symtomatic complaints at the time of diagnosis? In a homozygote sibling who has 2 mutations, colchicine may be advisable, especially if he/she also has a family history of amyloidosis. Amyloidosis clearly involves environmental factors, as well; it is known that Armenians living in the USA do not develop amyloidosis (8). What additional genetic and environmental factors may predispose a patient to amyloidosis need to be eludicated. Studying the pyrin cascade may shed light on other rheumatic diseases, as well. Currently a research group at the NIH has been concentrating on the role of pyrin. Why the inflammatory process stops may be as intriguing a problem as why the cascade starts. We also need to define the non-inflammatory triggers of the disease. New developments will help us to understand the inflammatory cascade more thoroughly. References 1. THE INTERNATIONAL FMF C ONSORTIUM: Ancient missense mutations in a new member of the RoRet gene family are likely to cause FMF. Cell 1997; 90: THE FRENCH CONSORTIUM: A candidate gene for FMF. Am J Hum Genet 1996; 59: SAATCI U, BAKKALOGLU A, OZEN S, BESBAS N: Familial Mediterranean fever and amyloidosis in children. Acta Paediatrica 1993; 81: SIEGAL S: Benign paroxysmal peritonitis. Ann Intern Med 1945; 23: SOHAR E, GAFNI J, PRAS M, HELLER H: FMF. 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