Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Clinical manifestations and diagnosis of familial Mediterranean fever

Eldad Ben-Chetrit, MD
Section Editors
David S Pisetsky, MD, PhD
Lawrence S Friedman, MD
Deputy Editors
Monica Ramirez Curtis, MD, MPH
Shilpa Grover, MD, MPH, AGAF


Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder characterized by recurrent bouts of fever and serosal inflammation. This topic will review the clinical manifestations and diagnosis of FMF. The epidemiology, genetics, pathophysiology, and management of FMF and an overview of periodic fever syndromes and other autoinflammatory diseases can be found elsewhere. (See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis" and "Management of familial Mediterranean fever" and "Periodic fever syndromes and other autoinflammatory diseases: An overview".)


Familial Mediterranean fever (FMF) is characterized by sporadic, and in most cases, recurrent attacks of fever and serosal inflammation as manifested by abdominal and chest pain. Most patients with FMF experience their first attack in early childhood. The initial attack occurs before the ages of 10 and 20 years in 65 and 90 percent of cases, respectively [1]. However, in rare cases the initial attack can occur in individuals older than 50 years of age.

The onset of fever and pain (due to serositis at one or more sites) is usually abrupt, peaking soon after onset. Some patients have a stereotypic prodrome before their attacks [2]. Episodes last for one to three days and then resolve spontaneously. Patients are asymptomatic between attacks. The frequency of attacks is highly variable, even in a given patient. The intervals between episodes are irregular, ranging from one week to several months or years. Usually, FMF patients cannot describe a consistent triggering event. Nevertheless, vigorous exercise, exposure to cold, emotional stress, fatigue, surgery, and menstruation have been associated with an attack in some patients. During pregnancy, the course of FMF may worsen in about a third of the patients, improve in another third of patients, and remain unchanged in the rest [3].

Recurrent fever — Fever is one of the most constant characteristics of FMF and is present in almost all cases during attacks [4]. In the majority of FMF patients, the temperature rises from 38° to 40°C, although mild attacks may be accompanied by a subfebrile temperature (37.5° to 38°C). Typically, the duration of the fever is brief, lasting between 12 hours and three days. Fever may be the first and only symptom of FMF, especially in toddlers [5]. In FMF patients who are treated with colchicine, an acute attack may occur without fever.

Abdominal pain — In populations where FMF is common, 95 percent of the patients with FMF have episodic abdominal pain [1]. Abdominal pain and tenderness may initially be localized and then progress to become more generalized. Since the cause of the abdominal pain is inflammation of the peritoneum, signs of peritonitis such as guarding, rebound tenderness, rigidity, and an adynamic ileus are often present. These findings can be mistaken for an acute surgical abdomen leading to diagnosis delay and sometimes even to futile operations. (See "Evaluation of the adult with abdominal pain", section on 'Urgent/emergent evaluation and/or surgical abdomen'.)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Feb 17, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Sohar E, Gafni J, Pras M, Heller H. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 1967; 43:227.
  2. Lidar M, Yaqubov M, Zaks N, et al. The prodrome: a prominent yet overlooked pre-attack manifestation of familial Mediterranean fever. J Rheumatol 2006; 33:1089.
  3. Eviatar T, Zaks N, Kukuy OL, et al. The effect of pregnancy on disease course in FMF. Pediatr Rheumatol Online J 2013; 11(Suppl 1):A63.
  4. Ben-Chetrit E, Touitou I. Familial mediterranean Fever in the world. Arthritis Rheum 2009; 61:1447.
  5. Padeh S, Livneh A, Pras E, et al. Familial Mediterranean fever in children presenting with attacks of fever alone. J Rheumatol 2010; 37:865.
  6. Garcia-Gonzalez A, Weisman MH. The arthritis of familial Mediterranean fever. Semin Arthritis Rheum 1992; 22:139.
  7. Heller H, Gafni J, Michaeli D, et al. The arthritis of familial Mediterranean fever (FMF). Arthritis Rheum 1966; 9:1.
  8. Drenth JP, van der Meer JW. Hereditary periodic fever. N Engl J Med 2001; 345:1748.
  9. Lidar M, Doron A, Barzilai A, et al. Erysipelas-like erythema as the presenting feature of familial Mediterranean fever. J Eur Acad Dermatol Venereol 2013; 27:912.
  10. Majeed HA, Quabazard Z, Hijazi Z, et al. The cutaneous manifestations in children with familial Mediterranean fever (recurrent hereditary polyserositis). A six-year study. Q J Med 1990; 75:607.
  11. Bayram MT, Çankaya T, Bora E, et al. Risk factors for subclinical inflammation in children with Familial Mediterranean fever. Rheumatol Int 2015; 35:1393.
  12. Kucuk A, Gezer IA, Ucar R, Karahan AY. Familial Mediterranean Fever. Acta Medica (Hradec Kralove) 2014; 57:97.
  13. Kees S, Langevitz P, Zemer D, et al. Attacks of pericarditis as a manifestation of familial Mediterranean fever (FMF). QJM 1997; 90:643.
  14. Eshel G, Vinograd I, Barr J, Zemer D. Acute scrotal pain complicating familial Mediterranean fever in children. Br J Surg 1994; 81:894.
  15. Ertekin V, Selimoğlu MA, Alp H, Yilmaz N. Familial Mediterranean fever protracted febrile myalgia in children: report of two cases. Rheumatol Int 2005; 25:398.
  16. Langevitz P, Zemer D, Livneh A, et al. Protracted febrile myalgia in patients with familial Mediterranean fever. J Rheumatol 1994; 21:1708.
  17. Capron J, Grateau G, Steichen O. Is recurrent aseptic meningitis a manifestation of familial Mediterranean fever? A systematic review. Clin Exp Rheumatol 2013; 31:127.
  18. Rigante D, Lopalco G, Tarantino G, et al. Non-canonical manifestations of familial Mediterranean fever: a changing paradigm. Clin Rheumatol 2015; 34:1503.
  19. Ben-Chetrit E, Yazici H. Non-thrombocytopenic purpura in familial Mediterranean fever-comorbidity with Henoch-Schönlein purpura or an additional rare manifestation of familial Mediterranean fever? Rheumatology (Oxford) 2016; 55:1153.
  20. van der Hilst JC, Simon A, Drenth JP. Hereditary periodic fever and reactive amyloidosis. Clin Exp Med 2005; 5:87.
  21. HELLER H, SOHAR E, GAFNI J, HELLER J. Amyloidosis in familial Mediterranean fever. An independent genetically determined character. Arch Intern Med 1961; 107:539.
  22. Pras M. Amyloidosis of familial mediterranean fever and the MEFV gene. Amyloid 2000; 7:289.
  23. Tunca M, Akar S, Onen F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 2005; 84:1.
  24. Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet 1998; 351:659.
  25. Touitou I, Sarkisian T, Medlej-Hashim M, et al. Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis Rheum 2007; 56:1706.
  26. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 1997; 90:797.
  27. Medlej-Hashim M, Delague V, Chouery E, et al. Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects. BMC Med Genet 2004; 5:4.
  28. Berkun Y, Ben-Chetrit E, Klar A, Ben-Chetrit E. Peritoneal adhesions and intestinal obstructions in patients with familial Mediterranean fever--are they more frequent? Semin Arthritis Rheum 2007; 36:316.
  29. Granat M, Tur-Kaspa I, Zylber-Katz E, Schenker JG. Reduction of peritoneal adhesion formation by colchicine: a comparative study in the rat. Fertil Steril 1983; 40:369.
  30. Babior BM, Matzner Y. The familial Mediterranean fever gene--cloned at last. N Engl J Med 1997; 337:1548.
  31. Booty MG, Chae JJ, Masters SL, et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum 2009; 60:1851.
  32. Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997; 40:1879.
  33. Yalçinkaya F, Ozen S, Ozçakar ZB, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford) 2009; 48:395.
  34. Ozçakar ZB, Yalçınkaya F, Cakar N, et al. Application of the new pediatric criteria and Tel Hashomer criteria in heterozygous patients with clinical features of FMF. Eur J Pediatr 2011; 170:1055.
  35. Kondi A, Hentgen V, Piram M, et al. Validation of the new paediatric criteria for the diagnosis of familial Mediterranean fever: data from a mixed population of 100 children from the French reference centre for auto-inflammatory disorders. Rheumatology (Oxford) 2010; 49:2200.
  36. Samuels J, Aksentijevich I, Torosyan Y, et al. Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore) 1998; 77:268.
  37. Padeh S, Shinar Y, Pras E, et al. Clinical and diagnostic value of genetic testing in 216 Israeli children with Familial Mediterranean fever. J Rheumatol 2003; 30:185.