GENETEST REVIEW Genetics in Medicine Familial Mediterranean fever—A review Mordechai Shohat, MD,1,2,3 and Gabrielle J. Halpern, MBChB1,2 TABLE OF CONTENTS Natural history..................................................................................................487 Recurrent fever.............................................................................................492 Common manifestations ............................................................................488 Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy Recurrent fever.........................................................................................488 syndrome ......................................................................................................492 Abdominal attacks ...................................................................................488 Pyogenic sterile arthritis, pyoderma gangrenosum, and acne ............492 Articular attacks........................................................................................488 Hyperimmunoglobulinemia D and periodic fever syndrome ..............492 Prodrome ..................................................................................................488 TNF receptor-associated periodic syndrome...........................................492 Pleural attacks...........................................................................................488 ELA2-related neutropenia...........................................................................493 Pericarditis.................................................................................................488 Blau syndrome .............................................................................................493 Amyloidosis...............................................................................................488 Amyloidosis...................................................................................................493 Rarer manifestations....................................................................................488 Abdominal pain............................................................................................493 Protracted febrile myalgia ......................................................................488 Arthralgia.......................................................................................................493 Erysipelas-like erythema..........................................................................488 Pleuritic pain.................................................................................................493 Vasculitides................................................................................................488 Atypical presentations and rare manifestations..........................................493 Reduced fertility .......................................................................................488 Recurrent monoarthritis..............................................................................493 Decreased atopy ......................................................................................489 Pleuritis ..........................................................................................................494 Chronic ascites and peritoneal malignant mesothelioma.................489 Recurrent pericarditis ..................................................................................494 Clinical diagnosis .............................................................................................489 Recurrent urticaria .......................................................................................494 Molecular genetics ..........................................................................................489 Meningitis .....................................................................................................494 Normal gene product .................................................................................489 Behc¸et disease ..............................................................................................494 Abnormal gene product .............................................................................489 Sequence variants........................................................................................490 Inflammatory bowel disease ......................................................................494 Molecular genetic testing...............................................................................490 Rheumatoid arthritis....................................................................................494 Targeted mutation analysis........................................................................490 Multiple sclerosis..........................................................................................494 Sequence analysis of select exons.............................................................490 Management ....................................................................................................495 Confirming the diagnosis and identification of the mutations................490 Evaluations after initial diagnosis ..............................................................495 In a proband.................................................................................................490 Treatment of manifestations......................................................................495 Carrier testing for at-risk relatives .............................................................490 Prevention of primary manifestations ......................................................495 Genotype-phenotype correlations ................................................................490 Prevention of secondary complications ...................................................495 Patients with only one identified mutation.............................................491 Surveillance...................................................................................................495 Other genomic alterations .........................................................................491 Agents/circumstances to avoid .................................................................495 Prevalence .........................................................................................................491 Newer therapies...........................................................................................495 Differential diagnosis.......................................................................................492 Testing of relatives at risk...........................................................................495 Abstract: Familial Mediterranean fever is inherited in an autosomal re- colchicine is required for homozygotes for the p.Met694Val muta- cessive manner. There are two phenotypes: types 1 and 2. Familial Med- tion or compound heterozygotes for p.Met694Val and another dis- iterranean fever type 1 is characterized by recurrent short episodes of ease-causing allele; this prevents the inflammatory attacks and the inflammation and serositis, including fever, peritonitis, synovitis, pleuritis, deposition of amyloid. Individuals who do not have the p.Met694Val and, rarely, pericarditis. The symptoms and severity vary among affected mutation and who are only mildly affected should be either treated individuals, sometimes even among members of the same family. Amy- with colchicine or monitored every 6 months for the presence of loidosis, which can lead to renal failure, is the most severe complication. proteinuria. Molecular genetic testing of the MEFV gene, the only Familial Mediterranean fever type 2 is characterized by amyloidosis as the gene currently known to be associated with familial Mediterranean first clinical manifestation of familial Mediterranean fever in an otherwise fever, can be offered to family members, especially when the asymptomatic individual. Routine treatment of end-stage renal disease, p.Met694Val allele is present, because renal amyloidosis can be including renal transplantation, is advised. Lifelong treatment with prevented by colchicine. Genet Med 2011:13(6):487–498. Key Words: familial Mediterranean fever, mutation, pyrin, protein- From the 1Raphael Recanati Genetic Institute, Rabin Medical Center; 2Felsen- uria, amyloidosis, colchicine stein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel; and 3 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. NATURAL HISTORY Gabrielle J. Halpern, MB, ChB, The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva 49100, Israel. Familial Mediterranean fever (FMF) has traditionally always E-mail: [email protected]. been regarded as being inherited in an autosomal recessive Disclosure: The authors declare no conflict of interest. manner, although some recent articles have reported a signifi- Submitted for publication August 31, 2010. cant number of patients with only one mutation who were diagnosed clinically as having FMF and responded well to Accepted for publication November 10, 2010. colchicine (see later).1–3 Published online ahead of print February 23, 2011. FMF is divided into two phenotypes, types 1 and 2. FMF DOI: 10.1097/GIM.0b013e3182060456 type 1 is characterized by recurrent short episodes of inflam- Genetics IN Medicine • Volume 13, Number 6, June 2011 487 Shohat and Halpern Genetics IN Medicine • Volume 13, Number 6, June 2011 mation and serositis including fever,