Case Report
Familial mediterranean fever in an Iranian patient with behcet disease Maryam Mobini (MD) *1
Abstract
1- Department of Internal Medicine, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, Iran.
Background: Familial Mediterranean fever (FMF) is the most prevalent disorder among the hereditary autoinflammatory syndromes. This disorder is characterized by fever and some painful attacks such as abdominal, chest or joint pain and potentially development of AA amyloidosis. Several vasculitis are more common in FMF than general population. There are some reports about association of FMF with Behcet Disease (BD). Case presentation: In this study, we describe a 27 year old patient with BD who suffered from attacks of fever, arthralgia, abdominal pain and genetic study confirmed the diagnosis of FMF. Conclusion: FMF should be considered in a patient with Behcet disease who is suffering from attacks of fever, arthralgia and abdominal pain. Keywords: Behcet disease, Familial Mediterranean fever, hereditary autoinflammatory syndrome. Caspian J Intern Med 2011; 2(4): 344-346.
* Correspondence: Maryam Mobini, Department of Internal Medicine, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Razi Street, Sari, Iran
E-mail: [email protected] Tel: 0098 151 2264044 Fax: 0098 151 2261700-4
Received: 9 Jan 2011 Revised: 10 July 011 Accepted: 27 Aug 2011
amilial Mediterranean fever (FMF) is the most prevalent hereditary F autoinflammatory syndromes with more than 10000 patients affected in the world (1). FMF is characterized by episodes of fever, usually lasting 1-3 days, with or without serositis, synovitis or rashes. The first clinical episodes usually occur in childhood or adolescence. Fever and abdominal pain as a dull ache to full blown peritonitis and patients often undergo exploratory laparoscopy. Repeated peritonitis may lead to adhesions. Acute monoarticular arthritis is most characteristic in FMF especially in the knee, ankle or hip. Characteristically, cutaneous lesion of FMF is erysipeloid erythema occurring on the dorsum of the foot, ankle or lower leg. The most serious complication of FMF is AA amyloidosis and before the use of colchicin, renal failure due to amyloidosis was the most common cause of death. Genetic study and clinical judgment maintain a central role in the diagnosis of FMF (2). Criteria for diagnosis of FMF include major criteria recurrent fever attacks with serositis or sinovitis, amyloloidosis without any other cause, a favor response to treatment by colchicin and minor criteria: recurrent fever attacks, eryseplus erythema, family history of FMF in first degree. Existence of 2 major and 2 minor criteria is necessary for diagnosis (3). Behçet's disease (BD) is a rare, chronic, multisystem inflammatory disorder. The prevalence of both BD and FMF is higher in the Middle Eastern and Mediterranean populations. There are some similarities in BD and FMF in pathogenesis and clinical manifestations. It was considered that MEFV mutations may act as a genetic susceptibility for BD especially for vascular manifestations and venous thrombosis, but other studies did not agree with this idea (4-8). In this report, we describe an Iranian patient with BD and FMF simultaneously and genetic study confirmed the compound heterozygote for MEFV.
Caspian J Intern Med 2(4): Autumn 2011 FMF and behcet in an Iranian patient
Case presentation A 27 year old man, from Mazandaran (north of Iran) was presented with attacks of fever, chills, arthralgia and arthritis 5 months ago. Each attack lasted for 3-4 days and had improved by taking diclofenac. He was considered to have been suffering from Behcet disease for 5 years, with oral and genital aphtus, pustular folliculitis and positive pathergy test according to international study group criteria for diagnosis of Behcet disease and was treated by colchicin. At this time, we added a low dose of prednisolone and azathioprine because of systemic and arthicular symptoms, but the symptoms continued and the patient complained of periodic attacks of fever as high as 39.5 centigrade, abdominal pain, diarrhea and arthralgia for 2-3 days every 2-3 weeks. Thus, we had to work up on the infectious and inflammatory bowel diseases. Laboratory data included: WBC: 5500/dl, Hemoglobin: 14.1 g/dl, Platelet: 244000/dl, ESR=25 mm/h, blood urea nitrogen=41mg/dl, creatinine=1mg/dl, AST=30 IU/L, ALT=36IU/L, ALP=183IU/L. Stool exam for parasites and blood, Wright and 2ME were negative and chest x-ray, barium enema and echocardiography did not show any abnormalities. Because of the occurrence of fever and diarrhea, colchicin and azathioprine were discontinued, the fever and abdominal pain became more severe but his diarrhea had stopped, thus colchicin was given again. At this time, his abdominal pain and fever improved significantly after administering colchicin. The genetic study for FMF showed compound heterozygote mutation E 148Q/P369S in MEFV gene and the result confirmed the diagnosis of FMF.
345
were compound heterozygote, and five were heterozygote and the most frequent genotype was M680I/M680I (6 patients, 16.7%) (12). In another study on 200 unrelated healthy Iranian Azeri turkish population, genotyping revealed that the carrier rate was 25.5%, with E148Q being the most common mutation (11.5%) followed by V726A (1.75%) (13). There are some periodic syndromes that can mimic FMF such as hyper IgD syndrome(autosomal recessive, mutation in MVK that encoding mevalonate kinase and present with abdominal and joint pain), TNF receptor associated periodic syndrome(autosomal dominant, with peritonitis and pleuritis, arthritis, rash, conjunctivitis) and familial cold autoinflamatory syndrome(autosomal dominant, with nausea, polyartheralgia, cold induced urticarial rash and conjunctivitis) but these kinds of autoinflammatory syndromes do not respond to colchicin and have different underlying genes (2). In this patient, we found compound heterozygote mutation E 148Q/P369S in MEFV gene. According to our data, this is the first report of Iranian patient with BD and FMF. Although FMF usually begins before 20 years old, we have seen this in our patient after the second decade of life. Another point in this patient was the simultaneous presentation of FMF and Behcet disease. In a study by Schwartz et al. between 1995 to 1997 on 4000 FMF patients, 39 cases with FMF-BD were found. FMF-Behcet diseases were of Iraqi/Turkish origin and responded less favorably to colchicin (14). Because some communities manifest diseases in BD and FMF with high carrier rate, it is suggested that FMF should be considered in patients with Behcet disease who are suffering from attacks of fever, arthralgia and abdominal pain.
Discussion FMF is the prototype of a group of inherited inflammatory disorders. Twenty- six patients with BD had one mutation in MEFV and M694V was the dominant mutation in these study groups (4, 10). Five mutations include V726A, M694V, M694I, M680I and E148Q account for 74% of FMF chromosomes from typical cases (Armenians, Arabs, Jews, and Turks) and the trend is that, genotypes including two mutations located codons 680 or 694 of the gene are associated with severe phenotypes, and E148Q being the mildest form of the disease (11). In a study performed on Iranian patients with FMF, from the 35 patients with mutations, ten were homozygote, 20
References 1. Simon A, Van Der Meer J WM, Drenth JPH. Familial autoinflamatory syndromes. In: Firestein GS, Budd RC, Harris ED, et al. Kelley's Textbook of Rheumatology. 8 th ed. Philadelphia: Saunders 2009; pp: 1863. 2. Ryan JG, Kastner DL. Periodic syndromes. In: Klipple JH, Stone JH, Crofford LJ, White PH. Primer on the rheumatic disease. 13th edition. New york: Springer 2008; pp: 462-3. 3. Daniel L, Kastner DL. Periodic syndromes. Klipple JH. Primer on the rheumatic disease. 12th ed. Atlanta, Arthritis foundation 2001; p: 194.
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4. Atagunduz P, Ergun T, Direskeneli H. MEFV mutations are increased in Behçet's disease (BD) and are associated with vascular involvement. Clin Exp Rheumatol 2003; 21: S35-7. 5. Rabinovich E, Shinar Y, Leiba M, et al. Common FMF alleles may predispose to development of Behcet's disease with increased risk for venous thrombosis. Scand J Rheumatol 2007; 36: 48-52. 6. Espinosa G, Arostegui JI, Plaza S, et al. Behçet's disease and hereditary periodic fever syndromes: casual association or causal relationship? Clin Exp Rheumatol 2005; 23: S64-6. 7. Aydin F, Akpolat T, Senturk N, Bagci H, Yasar Turanli A. Evaluation of pathergy test positivity in familial Mediterranean fever patients and comparison of clinical manifestations of FMF with Behçet's disease. Clin Rheumatol 2009; 28: 1331-5. 8. Ben-Chetrit E, Cohen R, Chajek-Shaul T. Familial mediterranean fever and Behçet's disease--are they associated? J Rheumatol 2002; 29: 530-4. 9. Louden BA, Jorizzo JL. Behcet's disease. In: Firestein GS, Budd RC, Harris ED, et al. Kelley's Textbook of
Caspian J Intern Med 2(4): Autumn 2011 Mobini M, et al
Rheumatology, 8th ed. Philadelphia: Saunders 2009; p: 1478. 10. Imirzalioglu N, Dursun A, Tastan B, Soysal Y, Yakicier MC. MEFV gene is a probable susceptibility gene for Behçet's disease. Scand J Rheumatol 2005; 34: 56-8. 11. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 2001; 9: 473-83. 12. Bidari A, Ghavidel-Parsa B, Najmabadi H, et al. Common MEFV mutation analysis in 36 Iranian patients with familial Mediterranean fever: clinical and demographic significance. Mod Rheumatol 2010; 20: 566-72. 13. Bonyadi M, Esmaeili M, Karimi A, Dastgiri S. Common Mediterranean fever gene mutations in the Azeri Turkish population of Iran. Genet Test Mol Biomarkers 2010; 14: 149-51. 14. Schwartz T, Langevitz P, Zemer D, et al. Behcet's disease in Familial Mediterranean fever: characterization of the association between the two diseases. Semin Arthritis Rheum 2000; 29: 286-95.
Familial mediterranean fever in an Iranian patient with behcet disease Maryam Mobini (MD) *1
Abstract
1- Department of Internal Medicine, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, Iran.
Background: Familial Mediterranean fever (FMF) is the most prevalent disorder among the hereditary autoinflammatory syndromes. This disorder is characterized by fever and some painful attacks such as abdominal, chest or joint pain and potentially development of AA amyloidosis. Several vasculitis are more common in FMF than general population. There are some reports about association of FMF with Behcet Disease (BD). Case presentation: In this study, we describe a 27 year old patient with BD who suffered from attacks of fever, arthralgia, abdominal pain and genetic study confirmed the diagnosis of FMF. Conclusion: FMF should be considered in a patient with Behcet disease who is suffering from attacks of fever, arthralgia and abdominal pain. Keywords: Behcet disease, Familial Mediterranean fever, hereditary autoinflammatory syndrome. Caspian J Intern Med 2011; 2(4): 344-346.
* Correspondence: Maryam Mobini, Department of Internal Medicine, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Razi Street, Sari, Iran
E-mail: [email protected] Tel: 0098 151 2264044 Fax: 0098 151 2261700-4
Received: 9 Jan 2011 Revised: 10 July 011 Accepted: 27 Aug 2011
amilial Mediterranean fever (FMF) is the most prevalent hereditary F autoinflammatory syndromes with more than 10000 patients affected in the world (1). FMF is characterized by episodes of fever, usually lasting 1-3 days, with or without serositis, synovitis or rashes. The first clinical episodes usually occur in childhood or adolescence. Fever and abdominal pain as a dull ache to full blown peritonitis and patients often undergo exploratory laparoscopy. Repeated peritonitis may lead to adhesions. Acute monoarticular arthritis is most characteristic in FMF especially in the knee, ankle or hip. Characteristically, cutaneous lesion of FMF is erysipeloid erythema occurring on the dorsum of the foot, ankle or lower leg. The most serious complication of FMF is AA amyloidosis and before the use of colchicin, renal failure due to amyloidosis was the most common cause of death. Genetic study and clinical judgment maintain a central role in the diagnosis of FMF (2). Criteria for diagnosis of FMF include major criteria recurrent fever attacks with serositis or sinovitis, amyloloidosis without any other cause, a favor response to treatment by colchicin and minor criteria: recurrent fever attacks, eryseplus erythema, family history of FMF in first degree. Existence of 2 major and 2 minor criteria is necessary for diagnosis (3). Behçet's disease (BD) is a rare, chronic, multisystem inflammatory disorder. The prevalence of both BD and FMF is higher in the Middle Eastern and Mediterranean populations. There are some similarities in BD and FMF in pathogenesis and clinical manifestations. It was considered that MEFV mutations may act as a genetic susceptibility for BD especially for vascular manifestations and venous thrombosis, but other studies did not agree with this idea (4-8). In this report, we describe an Iranian patient with BD and FMF simultaneously and genetic study confirmed the compound heterozygote for MEFV.
Caspian J Intern Med 2(4): Autumn 2011 FMF and behcet in an Iranian patient
Case presentation A 27 year old man, from Mazandaran (north of Iran) was presented with attacks of fever, chills, arthralgia and arthritis 5 months ago. Each attack lasted for 3-4 days and had improved by taking diclofenac. He was considered to have been suffering from Behcet disease for 5 years, with oral and genital aphtus, pustular folliculitis and positive pathergy test according to international study group criteria for diagnosis of Behcet disease and was treated by colchicin. At this time, we added a low dose of prednisolone and azathioprine because of systemic and arthicular symptoms, but the symptoms continued and the patient complained of periodic attacks of fever as high as 39.5 centigrade, abdominal pain, diarrhea and arthralgia for 2-3 days every 2-3 weeks. Thus, we had to work up on the infectious and inflammatory bowel diseases. Laboratory data included: WBC: 5500/dl, Hemoglobin: 14.1 g/dl, Platelet: 244000/dl, ESR=25 mm/h, blood urea nitrogen=41mg/dl, creatinine=1mg/dl, AST=30 IU/L, ALT=36IU/L, ALP=183IU/L. Stool exam for parasites and blood, Wright and 2ME were negative and chest x-ray, barium enema and echocardiography did not show any abnormalities. Because of the occurrence of fever and diarrhea, colchicin and azathioprine were discontinued, the fever and abdominal pain became more severe but his diarrhea had stopped, thus colchicin was given again. At this time, his abdominal pain and fever improved significantly after administering colchicin. The genetic study for FMF showed compound heterozygote mutation E 148Q/P369S in MEFV gene and the result confirmed the diagnosis of FMF.
345
were compound heterozygote, and five were heterozygote and the most frequent genotype was M680I/M680I (6 patients, 16.7%) (12). In another study on 200 unrelated healthy Iranian Azeri turkish population, genotyping revealed that the carrier rate was 25.5%, with E148Q being the most common mutation (11.5%) followed by V726A (1.75%) (13). There are some periodic syndromes that can mimic FMF such as hyper IgD syndrome(autosomal recessive, mutation in MVK that encoding mevalonate kinase and present with abdominal and joint pain), TNF receptor associated periodic syndrome(autosomal dominant, with peritonitis and pleuritis, arthritis, rash, conjunctivitis) and familial cold autoinflamatory syndrome(autosomal dominant, with nausea, polyartheralgia, cold induced urticarial rash and conjunctivitis) but these kinds of autoinflammatory syndromes do not respond to colchicin and have different underlying genes (2). In this patient, we found compound heterozygote mutation E 148Q/P369S in MEFV gene. According to our data, this is the first report of Iranian patient with BD and FMF. Although FMF usually begins before 20 years old, we have seen this in our patient after the second decade of life. Another point in this patient was the simultaneous presentation of FMF and Behcet disease. In a study by Schwartz et al. between 1995 to 1997 on 4000 FMF patients, 39 cases with FMF-BD were found. FMF-Behcet diseases were of Iraqi/Turkish origin and responded less favorably to colchicin (14). Because some communities manifest diseases in BD and FMF with high carrier rate, it is suggested that FMF should be considered in patients with Behcet disease who are suffering from attacks of fever, arthralgia and abdominal pain.
Discussion FMF is the prototype of a group of inherited inflammatory disorders. Twenty- six patients with BD had one mutation in MEFV and M694V was the dominant mutation in these study groups (4, 10). Five mutations include V726A, M694V, M694I, M680I and E148Q account for 74% of FMF chromosomes from typical cases (Armenians, Arabs, Jews, and Turks) and the trend is that, genotypes including two mutations located codons 680 or 694 of the gene are associated with severe phenotypes, and E148Q being the mildest form of the disease (11). In a study performed on Iranian patients with FMF, from the 35 patients with mutations, ten were homozygote, 20
References 1. Simon A, Van Der Meer J WM, Drenth JPH. Familial autoinflamatory syndromes. In: Firestein GS, Budd RC, Harris ED, et al. Kelley's Textbook of Rheumatology. 8 th ed. Philadelphia: Saunders 2009; pp: 1863. 2. Ryan JG, Kastner DL. Periodic syndromes. In: Klipple JH, Stone JH, Crofford LJ, White PH. Primer on the rheumatic disease. 13th edition. New york: Springer 2008; pp: 462-3. 3. Daniel L, Kastner DL. Periodic syndromes. Klipple JH. Primer on the rheumatic disease. 12th ed. Atlanta, Arthritis foundation 2001; p: 194.
346
4. Atagunduz P, Ergun T, Direskeneli H. MEFV mutations are increased in Behçet's disease (BD) and are associated with vascular involvement. Clin Exp Rheumatol 2003; 21: S35-7. 5. Rabinovich E, Shinar Y, Leiba M, et al. Common FMF alleles may predispose to development of Behcet's disease with increased risk for venous thrombosis. Scand J Rheumatol 2007; 36: 48-52. 6. Espinosa G, Arostegui JI, Plaza S, et al. Behçet's disease and hereditary periodic fever syndromes: casual association or causal relationship? Clin Exp Rheumatol 2005; 23: S64-6. 7. Aydin F, Akpolat T, Senturk N, Bagci H, Yasar Turanli A. Evaluation of pathergy test positivity in familial Mediterranean fever patients and comparison of clinical manifestations of FMF with Behçet's disease. Clin Rheumatol 2009; 28: 1331-5. 8. Ben-Chetrit E, Cohen R, Chajek-Shaul T. Familial mediterranean fever and Behçet's disease--are they associated? J Rheumatol 2002; 29: 530-4. 9. Louden BA, Jorizzo JL. Behcet's disease. In: Firestein GS, Budd RC, Harris ED, et al. Kelley's Textbook of
Caspian J Intern Med 2(4): Autumn 2011 Mobini M, et al
Rheumatology, 8th ed. Philadelphia: Saunders 2009; p: 1478. 10. Imirzalioglu N, Dursun A, Tastan B, Soysal Y, Yakicier MC. MEFV gene is a probable susceptibility gene for Behçet's disease. Scand J Rheumatol 2005; 34: 56-8. 11. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 2001; 9: 473-83. 12. Bidari A, Ghavidel-Parsa B, Najmabadi H, et al. Common MEFV mutation analysis in 36 Iranian patients with familial Mediterranean fever: clinical and demographic significance. Mod Rheumatol 2010; 20: 566-72. 13. Bonyadi M, Esmaeili M, Karimi A, Dastgiri S. Common Mediterranean fever gene mutations in the Azeri Turkish population of Iran. Genet Test Mol Biomarkers 2010; 14: 149-51. 14. Schwartz T, Langevitz P, Zemer D, et al. Behcet's disease in Familial Mediterranean fever: characterization of the association between the two diseases. Semin Arthritis Rheum 2000; 29: 286-95.
