ARTHRITIS & RHEUMATISM Vol. 44, No. 6, June 2001, pp 1416–1419 © 2001, American College of Rheumatology Published by Wiley-Liss, Inc. The Musculoskeletal Manifestations of Familial Mediterranean Fever in Children Genetically Diagnosed With the Disease Riva Brik, Marwan Shinawi, Leah Kasinetz, and Ruth Gershoni-Baruch Objective. Familial Mediterranean fever (FMF) is characterized by recurrent episodes of peritonitis, pleuritis, and synovitis. Its most common musculoskeletal manifestation is acute recurrent monarthritis, but other manifestations have also been described. We describe the articular and musculoskeletal manifestations in a group of patients who were found by genetic screening to be homozygous for the FMF gene. Methods. We surveyed 136 pediatric patients of Mediterranean extraction who were evaluated for a variety of musculoskeletal symptoms, and in whom genetic studies confirmed a diagnosis of FMF. Two groups of patients emerged: group 1 contained 107 patients who displayed a classic picture of FMF, and group 2 comprised 29 patients whose symptoms did not fulfill the criteria for a clinical diagnosis of FMF. Fifty-nine patients were Sephardic Jews and 77 were Arabs. The Jewish patients were all homozygous or compound heterozygous for the M694V mutation, while the Arab patients were homozygous or compound heterozygous for any 1 of the 5 mutations tested (M694V, V726A, M680I, M694I, and E148Q). Results. Acute episodes of monarthritis occurred in 42 (71%) of the Jewish children and 31 (40%) of the Arab children; 70% of these patients had the M694V mutation. Acute monarthritis occurred in 73 (68%) of the patients of group 1, but in none of the patients from group 2. Ten (34%) of the 29 patients from group 2 exhibited diverse musculoskeletal manifestations. Thirteen patients in our series (10%) presented with a variety of musculoskeletal symptoms, including febrile myalgia syndrome in 6 patients. Conclusion. Acute episodes of monarthritis are the most common musculoskeletal manifestation of FMF in children bearing the M964V mutation, which predominates among Sephardic Jews, although children with the M694V mutation may also present with diverse nonspecific musculoskeletal manifestations. Genetic screening for FMF appears indicated in the evaluation of unexplained musculoskeletal symptoms in children of Mediterranean extraction. Familial Mediterranean fever (FMF) is a recessive hereditary disorder that is particularly frequent in populations from the Mediterranean basin, with estimated carrier rates of 1:6 in North African Jews and 1:10 in Arabs (1,2). However, it is noteworthy that in a survey of 100 American FMF patients referred to the National Institutes of Health, 19% of the mutation-positive patients were of Italian ancestry, 21% were Ashkenazi Jews, 27% were Armenians, and 17% were Arabs; the rest were of non-Ashkenazi Jewish, Syrian, Cuban, Turkish, and Northern European heritage (3). The arthritis of FMF consists of acute attacks of pain and swelling of one articulation at a time, most frequently affecting the large joints of the lower extremities, although the shoulder, temporomandibular, or sternoclavicular joints may also be involved. These attacks usually subside within 2–3 days, and despite recurrent episodes of arthritis, there are no permanent sequelae in most of the cases (1,4). In ;5% of the patients, however, protracted arthritis develops, mostly in the hips or knees. Although complete recovery is the rule, disabling joint damage can occur and may, in some cases, even lead to joint replacement (5). A less common manifestation of joint involvement in FMF is spondylarthropathy, which is always HLA–B27 negative. These patients usually have unilateral or bilateral sacroiliitis, recurrent enthesitis, and inflammatory back or neck pain with minimal radiographic spinal involvement (6). Myalgia is also a common manifestation of FMF and occurs Riva Brik, MD, Marwan Shinawi, MD, Leah Kasinetz, MSc, Ruth Gershoni-Baruch, MD: Rambam Medical Center and TechnionIsrael Institute of Technology Faculty of Medicine, Haifa, Israel. Address correspondence and reprint requests to Riva Brik, MD, Department of Pediatrics, Rambam Medical Center, Haifa 31096, Israel. Submitted for publication July 17, 2000; accepted in revised form January 25, 2001. 1416 MUSCULOSKELETAL MANIFESTATIONS OF FMF IN CHILDREN in ;20% of patients (7). A unique syndrome has been described in patients with FMF, namely the protracted febrile myalgia syndrome, which is characterized by severe, disabling muscle pain and tenderness lasting several weeks, which responds only to treatment with corticosteroids (8). The diversity and the nonspecificity of the various clinical manifestations of FMF can often obscure the diagnosis. To date, the identification of the FMF gene and its various mutations enables the application of an accessible, noninvasive, sensitive molecular genetic test for an accurate diagnosis of this intriguing disease (9). Molecular testing provides an ultimate diagnosis of FMF in the absence of the full clinical syndrome, thus allowing the institution of colchicine therapy to prevent amyloidosis and to significantly reduce morbidity and disability from the disease. We describe the musculoskeletal features of a group of pediatric patients in whom genetic screening revealed homozygosity for the MEFV/FMF gene. We also report the apparent correlations between the musculoskeletal manifestations of the disease and the genotype of the patients. PATIENTS AND METHODS Our series consisted of 136 children (ages 2–18 years) of Mediterranean extraction (Israeli Arabs and Sephardic Jews) who, between January 1990 and December 1999, were referred to our Pediatric Rheumatology or Genetics clinics because of clinical symptoms suggestive of FMF, and a diagnosis of FMF was established by genetic studies. Patients were included in the study if they were homozygous or compound heterozygous for 1 of the 5 common mutations described in the FMF gene (M694V, V726A, M680I, M694I, and E148Q). The genetic studies were performed in our genetics laboratory. DNA was isolated from peripheral blood lymphocytes by standard procedures, and we used the polymerase chain reaction and restriction endonuclease digestion methods that were used in our previous works (10). The following data were recorded from the files of the 136 patients with FMF: ethnic origin, age at disease onset, and musculoskeletal manifestations at presentation (arthritis, myalgia, calf pain, erysipelaslike erythema, and miscellaneous manifestations). Of the 136 patients, 59 were Sephardic Jews and 77 were Arabs. The mean (6SD) age was 10.8 6 6.1 years. The patients were segregated into 2 groups: group 1 comprised patients who met the full clinical criteria for a diagnosis of FMF (11) (Table 1) , and group 2 contained patients in whom a diagnosis of FMF could not have been made based upon these criteria alone. One hundred seven children were suitable for inclusion in group 1 and 29 in group 2. Statistical analysis. Data were analyzed using the SPSS program (SPSS, Chicago, IL). Comparisons among different genotypes consisting of different combinations of mu- 1417 Table 1. (FMF)* Criteria for diagnosis of familial Mediterranean fever Criteria Major Typical attacks of 1. Peritonitis (generalized) 2. Pleuritis (unilateral) or pericarditis 3. Monarthritis (hip, knee, ankle) 4. Fever alone 5. Incomplete abdominal attacks Minor Incomplete attacks in the 1. Chest 2. Joint 3. Leg (exertional pain) 4. Favorable response to colchicine * Requirements for the diagnosis of FMF are the presence of 1 major criterion or 2 minor criteria. Typical attacks are defined as recurrent (3 at the same site), febrile ($38°C rectal temperature), and short (lasting 12 hours to days). Incomplete attacks are defined as painful and recurrent attacks differing from typical attacks in 1 or 2 features as follows: 1) temperature is normal or lower than 38°C, 2) attacks are longer or shorter than specified (but not shorter than 6 hours or longer than a week), 3) no signs of peritonitis are recorded during the abdominal attacks, 4) the abdominal attacks are localized, and 5) the arthritis involves joints other than those specified. Attacks not fulfilling this definition of typical incomplete attacks are not counted. tations were done by analysis of variance. Categorical variables were compared using the chi-square test. RESULTS Of the 136 FMF patients, 86 (63%) displayed musculoskeletal manifestations. Among the 107 patients whose clinical constellation conformed with the diagnosis of FMF (group 1), 73 (68%) had acute attacks of monarthritis and 3 had other musculoskeletal manifestations. Of the 29 children from group 2, 10 (34%) had a variety of musculoskeletal symptoms. The M694V mutation was detected in 42% of patients from group 1, and in 40% from group 2. Looking at the 2 ethnic groups separately, it was found that musculoskeletal manifestations occurred in 88% of the Sephardic Jews, but in only 44% of the Arab patients (P , 0.001). Of the 59 Sephardic Jewish patients, 42 (71%) had experienced recurrent attacks of monarthritis and 10 (17%) had miscellaneous musculoskeletal manifestations. These manifestations included protracted febrile myalgia syndrome in 6 children, .4 episodes of transient synovitis of the hip in 2 children, nonspecific myopathy documented by muscle biopsy in 1 child, and spondylarthropathy based on clinical and radiographic evidence of sacroiliitis in 1 child. This latter patient also had 1418 BRIK ET AL Table 2. Phenotype–genotype correlation in patients with familial Mediterranean fever and musculoskeletal symptoms Acute recurrent monarthritis Protracted febrile myalgia Nonspecific musculoskeletal symptoms Mutation Jews Arabs Jews Arabs Jews Arabs Total M694V/M694V M694V/other M680I/M680I V726A/other M694I/M694I V726A/V726A M680I/V726A E148Q/E148Q E148Q/other Total 33 9 – – – – – – – 42 1 8 3 2 3 5 4 2 3 31 5 1 – – – – – – – 6 – – – – – – – – – 0 3 1 – – – – – – – 4 – – – – – 1 1 1 – 3 42 19 3 2 3 6 5 3 3 86 protracted arthritis of the right hip and underwent hip replacement at the age of 18 years. All of the Sephardic Jewish patients who were observed to have these musculoskeletal manifestations were either homozygous (80%) or heterozygous for the M694V mutation. Of the 77 Arab patients, 31 (40%) experienced acute episodes of monarthritis and 3 patients had other musculoskeletal symptoms (2 had recurrent episodes of calf pain and pretibial swelling with normal results on laboratory tests and negative ultrasonographic findings, and 1 child had chronic arthritis of the right knee but showed no radiographic evidence of bony changes; this child had never had recurrent attacks of abdominal pain or any other features of FMF, but there was a history of FMF in his family). Among all of the Arab patients, the M694V mutation was detected in only 12% of the children; all but 1 of these Arab patients were heterozygous for the mutation. All 6 of the patients who had protracted febrile myalgia syndrome were Sephardic Jews. Five of the 6 patients were homozygous for the M694V mutation. The genotype–phenotype correlation among the patients from the 2 ethnic groups is presented in Table 2. Homozygosity for the M694V mutation, which is predominant among Sephardic Jews, was associated with a higher incidence of typical episodes of monarthritis as well as a higher incidence of diverse musculoskeletal manifestations (P , 0.001). Colchicine treatment resulted in clinical improvement in all patients, except in those patients with protracted febrile myalgia syndrome and in the patient who had spondylarthropathy. DISCUSSION Clinical and molecular genetic studies have recently defined several heritable disorders that present as self-limited episodes of serosal, synovial, or cutaneous inflammation. Two of these illnesses, namely FMF and hyperimmunoglobulinemia D with periodic fever syndrome, are inherited as autosomal-recessive traits (1,12). Recently, 6 mutations in tumor necrosis factor receptor 1 (TNFR1) were identified as the genetic defect causing the dominantly inherited periodic fever syndrome named TRAPS (TNFR1-associated periodic syndrome) (13). The cloning of the MEFV/FMF gene and the identification of the mutations causing FMF (14,15) have improved our ability to establish a rapid and accurate diagnosis of the disorder. The role of molecular diagnosis is especially significant in cases where the clinical manifestations are not typical or when a family history of the disease is lacking. Although the most common expression of musculoskeletal involvement in FMF is acute recurrent monarthritis of short duration, other manifestations have been described, including erysipelas-like erythema, muscle pain, or pain in the heels and the soles related to prolonged walking or standing (4). Additional rare manifestations include chronic joint disease in ,5% of patients, spondylarthropathy, fibromyalgia, and myopathy (5). Arthritis secondary to FMF is most frequently seen among North African Jewish patients, and occurs in ;75% of these patients. The frequency of arthritis is much lower in Iraqi Jews, Ashkenazi Jews, Armenians, and Turks (1). It was recently demonstrated that the incidence of arthritis is related to the presence of the V694V mutation (16). In our present study, which focused on the musculoskeletal manifestations of FMF, arthritis occurred in 71% of the Sephardic Jewish patients with musculoskeletal symptoms, all of whom carried the M694V mutation, whereas arthritis occurred in only 40% of the Arab patients, who carried mostly the V726A and M680I mutations. These findings are in accordance with those of previous reports on smaller numbers of patients (17). In a Turkish population survey, 44% of the FMF patients bearing the M694V mutation experienced recurrent arthritis, compared with only 9% of the patients bearing the M680I mutation (18). Our population of FMF patients consisted mainly of Sephardic Jews and of Arabs. We and others have shown that homozygosity for the M694V mutation is predominant among patients originating from North Africa, and is associated with a severe course and MUSCULOSKELETAL MANIFESTATIONS OF FMF IN CHILDREN prognosis of FMF (17). We have shown here that not only patients with a classic clinical pattern of the disease (group 1) bear the M694V mutation, but that this mutation is also found among patients with atypical and severe musculoskeletal manifestations, particularly protracted febrile myalgia syndrome. These observations are consistent with those of Langevitz et al, who found that among 15 patients with febrile myalgia syndrome, 12 were found to bear the M694V mutation (19). Our series included a group of patients (group 2) in whom the diagnosis of FMF could not have been made on the basis of the FMF clinical criteria alone, because of the nonspecificity of their musculoskeletal manifestations and the absence of characteristic clinical and laboratory findings. The awareness of possible FMF in these patients was aroused mainly by the recurrent and episodic nature of the symptoms and the Mediterranean heritage of the patients; the diagnosis could be established by genetic testing. In view of the frequent occurrence of FMF in the population at risk, our observations call for the inclusion of genetic screening for FMF in the investigation of children of Mediterranean extraction who display unexplained recurrent musculoskeletal manifestations. 1419 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. REFERENCES 1. Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet 1998;351:659–64. 2. Shinawi M, Brik R, Kepten I, Berant M, Gersoni B. 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