Centre for Arab Genomic Studies A Division of Sheikh Hamdan Award for Medical Sciences

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1 Centre for Arab Genomic Studies A Division of Sheikh Hamdan Award for Medical Sciences The Catalogue for Transmission Genetics in Arabs CTGA Database Familial Mediterranean Fever Alternative Names FMF Familial Mediterranean Fever, Autosomal Recessive Polyserositis, Recurrent Polyserositis, Familial Paroxysmal Record Category Disease phenotype WHO-ICD Endocrine, nutritional and metabolic diseases > Metabolic disorders Incidence per 100,000 Live Births OMIM Number Mode of Inheritance Autosomal recessive Gene Map Locus 16p13 Description Familial Mediterranean fever is an autosomal recessive disorder mostly prevalent in Mediterranean populations. It is characterized by recurrent selflimited episodes of fever, arthritis, serositis, and skin rash, with marked accumulations of polymorphonuclear leukocytes in affected areas during attacks. The most severe complication of the disorder is the development of amyloidosis, leading to nephrotic syndrome and end-stage renal disease. Two disease phenotypes have been identified, whether amyloidosis appears years after the appearance of the other clinical signs (phenotype I), or whether it is the first or the only familial Mediterranean fever presenting sign (phenotype II), which is less frequent. Estimates of the incidence of FMF in specific eastern Mediterranean populations range from 1 in 2000 to 1 in 100, depending on the population studied Molecular Genetics Familial Mediterranean fever is caused by mutation in the MEFV gene. Over 35 mutations have been discovered so far. The 5 most frequent mutations are M694V, M694I, V726A, M680I and E148Q. The FMF gene, encodes a 781-aa protein denoted pyrin, which is expressed primarily in neutrophils, eosinophils, and cytokine-activated monocytes. Epidemiology in the Arab World Bahrain Zayyani (1987) described some of the very first cases of FMF in the Arabian Peninsula. One of the cases was of a 37-year old Bahraini female, born to healthy, consanguineous parents, originating from Saudi Arabia. She presented with recurrent attacks of abdominal pain, accompanied with fever and vomiting, about twice a month. Earlier, repeated investigations with barium enemas, upper GI series, abdominal ultrasonography, and serum amylase determination did not yield any conclusive findings. Upon examination, her abdomen was slightly distended, with diminished bowel sounds. Upon palpitation of the abdomen, diffused tenderness, rebound, and guarding were elicited. Radiological examination of the abdomen showed dilated small bowel loops with air-fluid levels. The fever and abdominal pain subsided in 24 hrs. The patient was then tested for FMF using the metaraminol provocative test. Within three hours, the patient had a recurrence of her typical attack, confirming the diagnosis of FMF. The patient was then started on colchicine as oral medication. In the year subsequent to starting this treatment, she was found to have only one recurrence of her attack. Egypt One of the cases described by Zeyyani (1987) in her review of the very first cases of FMF in the Arabian 1

2 Peninsula, was a 28-year old Egyptian woman, with unrelated parents and no family history of the disease. She had been complaining of recurrent attacks of abdominal pain, pain in the chest and both knees, skin rash and fever, since 9-years of age. The attacks lasted three days and recurred three to four times a month. The patient had undergone two operations previously on the onset of attacks; one of them an appendectomy, and the other a right hemicolectomy. However, the abdominal pain persisted, and posthemicolectomy was accompanied with diarrhea. Upon examination during one of the attacks, direct and rebound tenderness was elicited all over upon palpitation of the abdominal rigidity. Radiological examination showed distension of the small and large bowel loops, and a small left pleural effusion. She was diagnosed with FMF, and was put on colchicine. Consequently, she had three recurrences in the following year. Dajani et al. (1987) described four Egyptian patients (three males and 1 female) residing in the UAE who were diagnosed as having periodic peritonitis, or familial Mediterranean fever. Their ages ranged between 26 to 50 years. Patients suffered from fever and acute self-limiting attacks of abdominal pain occurring at a frequency of 6-15 episodes/ year. Two of them underwent three abdominal operations and the other two patients had only one abdominal operation. Pleuritic chest pain was seen in three patients and one of them had a pleural rub during the attack. Three patients had peripheral joints involvement. Cervical spondylosis was observed in two cases and lactose intolerance in one patient. Metaraminol provocation was then performed three days after stopping maintenance colchicine therapy to confirm the diagnosis. Three of the patients were found to react positively to the metaraminol infusion by reproducing the attacks they experienced before. All of the patients had already shown a significant control of the illness by colchicine, whether during the acute attacks or during prophylactic maintenance therapy. Therefore, Dajani et al. (1987) concluded that the metaraminol provocation test would provide good support to the diagnosis of familial Mediterranean fever with a sensitivity index of 90%. The colchicine response, however, appeared more sensitive. Iraq Yuval et al. (1995) found 77 families, with 240 FMF patients, in which the disorder affected more than one generation. In 75 of these families, the occurrence of FMF in more than one generation was found to be consistent with a recessive mode of inheritance due to a high gene frequency and consanguinity of the parents. In 2 families, however, one of Ashkenazi and the other of Georgian Iraqi origin, in which FMF occurred in 4 consecutive generations, the transmission could be explained only by autosomal dominant inheritance. Pras et al. (1998) commented that North African Jews and Iraqi Jews were the 2 largest population groups suffering from FMF in Palestine. [See also: Libya > Damiels et al., 1995; Morocco > Aksentijevich et al., 1993] Jordan Rawashdeh and Majeed (1996) reviewed findings from the FMF pediatric patient population in northern Jordan (all children were of Jordanian, Palestinian, or Syrian origin). The 192 patients first presented between the age of 4 months and 16 years. The mean delay in diagnosis was 3.7 years and was increased for children who presented before the age of 2 years. Abdominal pain was the most common presenting symptom and occurred in 51%, while arthritis and pleuritis occurred in 26% and 23%, respectively. The investigators noted that family history was positive in 62% of the children, which was not surprising in this autosomal recessive disorder given the 64% consanguinity rate in northern Jordan. Minimum prevalence was given as 1 in 2,600 with an estimated gene frequency in the childhood population of 1 in 50 (calculated on the numbers of diagnosed patients). The authors warned that the frequency of FMF among Jordanian Arab children was greater than previously estimated. Kuwait In a study of FMF in Kuwait, Barakat et al. (1986) reported on an 11-year experience with 175 Arab patients. The most common manifestation was peritonitis (94%), followed by arthritis (34%) and pleurisy (32%). Amyloidosis, rashes, hepatosplenomegaly, and lymphadenopathy were rare. Barakat et al. (1986) referred to FMF as recurrent hereditary polyserositis. Lebanon Reimann et al. (1954) described 72 cases of FMF from Lebanon, most of them Armenian. In one remarkable family, survivors of the siege of Musa Dagh, 20 affected persons occurred in 5 generations, with 3 instances of skips in the pedigree. Reimann et al. (1954) suggested that the high gene frequency and 2

3 small breeding group could account for the findings as representing pseudodominant inheritance. Libya Dajani et al. (1987) described a 55 years old woman from Libya residing in the UAE who was diagnosed as having periodic peritonitis, or familial Mediterranean fever. The patient suffered from fever and acute self-limiting attacks of abdominal pain. She underwent two abdominal operations previously. Also, she had peripheral joints involvement and cervical spondylosis. Ultrasonological examination showed that the patient had gallbladder stones during an episode of abdominal pain, but cholecystectomy did not improve the symptoms. Metaraminol provocation was then performed three days after stopping maintenance colchicine therapy to confirm the diagnosis. It was found that the patient reacted positively to the metaraminol infusion by reproducing the attacks she experienced before. The patient had already shown a significant control of the illness by colchicine, whether during the acute attacks or during prophylactic maintenance therapy. Using extended pedigree data of 90 FMF probands, Daniels et al. (1995) calculated the FMF gene frequency in various ethnic groups in Palestine by analyzing the frequency in a total of 2,312 first cousins. The heterozygote frequencies were as follows: 1 in 4.9 (0.2 +/- 0.06) for the Libyan subgroup; 1 in 6.4 (0.16 +/- 0.03) for the subgroup from other North African countries; 1 in 13.3 (0.07 +/- 0.04) for the Iraqi subgroup; 1 in 11.4 (0.09 +/- 0.06) for the Ashkenazi subgroup; and 1 in 29.4 (0.03 +/- 0.03) for the remaining ethnic groups. The observed number of affected parents and affected offspring of probands was in agreement with the estimated gene frequency. Pras et al. (1998) commented that North African Jews were found to have more severe disease manifested by earlier age of onset, increase in frequency and severity of joint involvement, higher incidence of erysipelas-like erythema, and higher dose of colchicine required to control symptoms. Palestine Zeyyani (1987) described three Palestinian Arabs in her description of the very first cases of FMF from the Arabian Peninsula. Two brothers (32 and 37- years old) born to consanguineous parents presented with a history of recurrent attacks of fever, and abdominal pain, starting in the right lower quadrant and spreading to the whole abdomen. The attacks lasted for one to three days, and recurred once or twice every month. The elder brother had undergone an appendectomy during an attack. Radiographs showed distended small and large bowel. The younger brother underwent a metaramiol provocative test, which precipitated his attack within seven hours. FMF was thereby confirmed, and he was put on colchicine treatment. In the subsequent year, he had no recurrence of the attacks. His brother refused the metaraminol challenge. He was, however, put on colchicine too. During ten months of follow-up, he had one recurrence of the attack. Dajani et al. (1987) described three Palestinian male patients (two of them were brothers) residing in the UAE who were diagnosed as having periodic peritonitis, or familial Mediterranean fever. Their ages ranged between 35 to 45 years. Patients suffered from fever and acute self-limiting attacks of abdominal pain. They underwent an abdominal operation previously. Pleuritic chest pain was seen in the three patients and two of them had a pleural rub during the attack. Two patients had cervical spondylosis and one had peripheral joints involvement. Metaraminol provocation was then performed three days after stopping maintenance colchicine therapy to confirm the diagnosis. The patients were found to react positively to the metaraminol infusion by reproducing the attacks they experienced before. All of the patients had already shown a significant control of the illness by colchicine, whether during the acute attacks or during prophylactic maintenance therapy. [See also: Iraq > Pras et al., 1998; Jordan > Rawashdeh and Majeed, 1996; Libya > Damiels et al., 1995] Morocco Schwabe and Monroe (1988) described a 32-year-old non-ashkenazi Jewish man in whom meningitis first developed in Morocco at the age of 1 year. Between the ages of 26 and 31 years, he had 6 attacks of fever, frontal headache, nausea, and stiff neck, with positive Kernig and Brudzinski signs. Aksentijevich et al. (1993) observed different haplotypes associated with the disease in strong linkage disequilibrium in Moroccan and Iraqi Jewish families. This, together with the fact that Moroccans had a much more severe form of FMF, suggested that the two groups carry different allelic mutations. Using linkage disequilibrium mapping in the study of 65 Jewish, Armenian, and Arab families, Levy et al. 3

4 (1996) obtained a maximum lod score of 49.2 at a location 1.6 cm centromeric to D16S246. A specific haplotype using 3 markers was found in 76% of Moroccan and 32% of non-moroccan Jewish carrier chromosomes, but this haplotype was not overrepresented in Armenian or Arab FMF carriers. Since the Moroccan Jewish community represents a relatively recently established and genetically isolated founder population, Levy et al. (1996) analyzed the Moroccan linkage-disequilibrium data and placed the FMF susceptibility gene within cm of D16S246. Saudi Arabia Majeed and Barakat (1989) conducted a retrospective study to assess the clinical profile, course and complications of familial Mediterranean fever (recurrent hereditary polyserositis) seen in 88 children over a period of 11 years. The group included 48 children (55%) who had onset before the age of 5 years (mean 4.9 years). Peritonitis occurred in 85% of children, arthritis in 50%, pleuritis in 33% and erysipelas-like lesions in 16%. Two children developed renal amyloidosis, and one third of the children were subjected to unnecessary operative surgery, reflecting the diagnostic difficulties. The arthritis was mono-articular in 80% and polyarticular in 20% of children with arthritis, and was seronegative (rheumatoid factor and antinuclear antibodies). Human leucocyte antigen (HLA) typing for the B-27 antigen carried out in ten children with arthritis was negative. The synovial attack showed a wide variation in the clinical presentation, course and duration of arthritis, causing diagnostic difficulties. Of 45 children treated with colchicine, 42 children (93%) achieved a therapeutic response. [See also: Bahrain > Zeyyani, 1987] Syria Dajani et al. (1987) described two Syrian women residing in the UAE who were diagnosed as having periodic peritonitis, or familial Mediterranean fever. One of them was 24 years old and the other was 30 years old. The patients suffered from fever and acute self-limiting attacks of abdominal pain. The older patient had two abdominal operations previously, while the younger had only one. Peripheral joints involvement was observed in the older case. Metaraminol provocation was then performed three days after stopping maintenance colchicine therapy to confirm the diagnosis. The patients were found to react positively to the metaraminol infusion by reproducing the attacks they experienced before. All of the patients had already shown a significant control of the illness by colchicine, whether during the acute attacks or during prophylactic maintenance therapy. [See: Jordan > Rawashdeh and Majeed, 1996] United Arab Emirates See: Egypt, Libya, Palestine, and Syria > Dajani et al., References Aksentijevich I, Gruberg L, Pras E, Balow JE Jr, Kovo M, Gazit E, Dean M, Pras M, Kastner DL. Evidence for linkage of the gene causing familial Mediterranean fever to chromosome 17q in non- Ashkenazi Jewish families: second locus or type I error? Hum Genet. 1993; 91(6): PMID: Barakat MH, Karnik AM, Majeed HW, el-sobki NI, Fenech FF. Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs--a study of 175 patients and review of the literature. Q J Med. 1986; 60(233): PMID: Dajani AI, Awad SM, Jaber YI. Diagnosis of periodic peritonitis - Evaluation of metaraminol provocation test and colchicine therapeutic trial. Emirates Med J. 1987; 5: Daniels M, Shohat T, Brenner-Ullman A, Shohat M. Familial Mediterranean fever: high gene frequency among the non-ashkenazic and Ashkenazic Jewish populations in Israel. Am J Med Genet. 1995; 55(3): PMID: Levy EN, Shen Y, Kupelian A, Kruglyak L, Aksentijevich I, Pras E, Balow JE Jr, Linzer B, Chen X, Shelton DA, Gumucio D, Pras M, Shohat M, Rotter JI, Fischel-Ghodsian N, Richards RI, Kastner DL. Linkage disequilibrium mapping places the gene causing familial Mediterranean fever close to D16S246. Am J Hum Genet. 1996; 58(3): PMID: Majeed HA, Barakat M. Familial Mediterranean fever (recurrent hereditary polyserositis) in children: analysis of 88 cases. Eur J Pediatr. 1989; 148(7): PMID: Pras E, Livneh A, Balow JE Jr, Pras E, Kastner DL, Pras M, Langevitz P. Clinical differences between North African and Iraqi Jews with familial Mediterranean fever. Am J Med Genet. 1998; 75(2): PMID: Rawashdeh MO, Majeed HA. Familial Mediterranean fever in Arab children: the high prevalence and gene frequency. Eur J Pediatr. 1996; 155(7): PMID:

5 Reimann HA, Moadie J, Semerdjian S, Sahyoun PF. Periodic peritonitis; heredity and pathology: report of seventy-two cases. J Am Med Assoc. 1954; 154(15): PMID: Schwabe AD, Monroe JB. Meningitis in familial Mediterranean fever. Am J Med. 1988; 85(5): PMID: Yuval Y, Hemo-Zisser M, Zemer D, Sohar E, Pras M. Dominant inheritance in two families with familial Mediterranean fever (FMF). Am J Med Genet. 1995; 57(3): PMID: Zayyani NR. Familial Mediterranean fever in the Arabian Peninsula: Case reports and review of literature. Bahrain Med Bull. 1987; 9(3): External Links Contributors Ghazi O. Tadmouri: Abeer Fareed: Ghazi O. Tadmouri: Pratibha Nair: Ghazi O. Tadmouri: Related CTGA Records Familial Mediterranean Fever Gene Hyper-IgD Syndrome 5