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familial Mediterranean fever (FMF, recurrent polyserositis)

Recurrent systemic inflammatory disorder. Etiology: mutation in pyrin gene Epidemiology: (prevalence in parenthesis) 1) ethnic groups from the easterm Mediterranean basin a) Sephardic Jewish (0.1-0.4%) b) Ashkenazi Jewish (0.001%) c) Armenian (0.2%) d) Arabs (0.1%) e) Turkish (0.04%) 2) male:female ratio is 1.5-2.0: 1 3) generally presents during childhood or adolescence a) 65% < 10 years of age b) 90% < 20 years of age Pathology: 1) amyloidosis (if untreated) a) amyloid protein SAA produced as acute phase reactant deposits as amyloid protein AA in tissues b) kidney (renal failure) 1] renal vein thrombosis (30%) 2] nephrotic syndrome c) adrenal gland (adrenal failure) 2) autosomal dominant form is resistant to colchicine thus prone to AA amyloidosis 3) mortality from tuberculosis may be attenuated [4] Genetics: 1) autosomal recessive & autosomal dominant inheritance 2) autosomal dominant form is resistant to colchicine 2) disease maps to chromosome 16p -> mutation in pyrin gene (MEFV) 1] most mutations in exon 10 aa 680-761 2] M694V Met694 -> Val694 homozygotes may have most severe form of disease Clinical manifestations: 1) recurrent symptoms a) most episodes last 12-72 hours b) symptoms generally begin in childhood or adolescence c) 10% of cases present in adults [1] 2) episodic fever (38-40 C) 3) pelvic pain may mimic pelvic inflammatory disease 4) abdominal pain 5) chest pain 6) nausea 7) serositis a) peritonitis may be purulent but sterile [13] b) pleuritis: pleural effusion may occur c) pericarditis - pericardial tamponade & constrictive pericarditis is rare c) inflammation of the tunica vaginalis testis may mimic testicular torsion 8) arthritis (asymmetric) monoarthritis a) knees, ankles & wrists most frequently affected b) prolonged episodes of arthritis frequently involve the hip c) between attacks, joints are normal d) permanent damage to joints does NOT occur e) may resemble gout 9) myalgias not responsive to colchicine - may resemble fibromyalgia 10) rash (50% of patients) a) may occur as only manifestation other than fever b) generally occurs on legs, especially below the knee c) may resemble erysipelas or cellulitis 11) meningitis a) headache b) stiff neck Laboratory: 1) urinalysis a) proteinuria b) hematuria occurs in 5% 2) serum amyloid A (AA amyloid) is positive [1] 3) routine blood tests during acute attack are non-specific a) complete blood count (CBC) may show leukocytosis with a predominance of neutrophils b) serum C-reactive protein generally elevated c) erythrocyte sedimentation rate (ESR) generally elevated d) plasma fibrinogen may be elevated [13] 4) joint aspiration reveals inflammatory (purulent) joint -> up to 100,000 WBC/mm3 5) DNA testing: FMF Strip Assay, Pronto FMF [8] Radiology: non-specifc findings Differential diagnosis: 1) rheumatic fever 2) appendicitis 3) pseudogout 4) Lyme disease 5) nephrolithiasis 6) pericarditis 7) pleurodynia 8) lupus erythematosus 9) erysipelas or cellulitis 10) familial hibernian fever; TNF receptor-associated periodic syndrome (TRAPS) - febrile episodes generally last 7-21 days - conjunctivitis & periorbital edema [13] Complications: 1) misdiagnosis as surgical abdomen 2) death from nephrotic syndrome by age 50 if untreated 3) lower than expected incidence of cancer* [11] - cancer incidence lower than expected in both men & women (RR=0.66 & 0.75) 4) vasculitis (increased frequency) a) Henoch-Schonlein purpura [7] b) polyarteritis nodosa c) Behcet's disease [5] * excluding nonmelanoma skin cancer Management: 1) episodes of synovitis & serositis a) NSAIDs b) glucocorticoids 2) daily oral colchicine a) 0.6 mg PO BID b) effective in preventing flares & AA amyloidosis [1] c) autosomal dominant form is resistant to colchicine 3) etanercept, canakinumab [12] or anakinra [1] may be useful in patients not responding to colchicine 4) joint replacement is rarely needed 5) life expectancy is related to effects of amyloidosis 6) consultation with nephrologist &/or rheumatologist as indicated

Related

boutonneuse fever; Mediterranean spotted fever colchicine (Colcrys, Lodoco) fever

General

amyloidosis hereditary periodic fever syndrome; periodic fevers; recurrent fever syndrome; familial autoinflammatory disease

Database Correlations

OMIM correlations

References

  1. Medical Knowledge Self Assessment Program (MKSAP) 11,14,16,17,18. American College of Physicians, Philadelphia 1998,2006,2012,2015,2018.
  2. Ben-Cherit E, Levy M Familial Mediterranean fever. Lancet 351:659, 1998 PMID: 9500348
  3. Levneh A et al, Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40:1879, 1997 PMID: 9336425
  4. Tunca M, Ben-Chetrit E Familial Mediterranean fever in 2003. Pathogenesis and management.. Clin Exp Rheumatol 21:S53, 2003 PMID: 14727461
  5. Atagunduz P et al, MEFV mutations are increased in Behcet's disease (BD) and are associated with vascular involvement. Exp Rheumatol 21:S35, 2003 PMID: 14727457
  6. Mor A et al, Abdominal and digestive system associations of familial Mediterranean fever. Am J Gastroenterol 98:2594, 2003 PMID: 14687803
  7. Gershoni-Baruch R et al, Prevalence and significance of mutations in the familial Mediterranean fever gene in Henoch-Schonlein purpura. J Pediatr 143:658, 2003 PMID: 14615741
  8. Touitou I, Standardized testing for mutations in familial Mediterranean fever. Clin Chem 49:1781, 2003 PMID: 14578308 - Oberkanins C et al, Genetic testing for familial Mediterranean fever in Austria by means of reverse-hybridization teststrips. Clin Chem. 2003 Nov;49(11):1948-50 PMID: 14578333 - Tchernitchko D et al, Clinical evaluation of a reverse hybridization assay for the molecular detection of twelve MEFV gene mutations. Clin Chem 49:1942, 2003 PMID: 14578331
  9. http://www.emedicine.com/med/topic1410.htm has an excellent discussion
  10. Ben-Chetrit E, Touitou I. Familial mediterranean Fever in the world. Arthritis Rheum. 2009 Oct 15;61(10):1447-53 PMID: 19790133
  11. Brenner R, Ben-Zvi I, Shinar Y et al. Familial Mediterranean fever and incidence of cancer. Arthritis Rheumatol 2018 Jan; 70:127 PMID: 28992365 http://onlinelibrary.wiley.com/doi/10.1002/art.40344/abstract
  12. De Benedetti F, Gattorno M, Anton J et al Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med 2018; 378:1908-1919. May 17, 2018 PMID: 29768139 https://www.nejm.org/doi/full/10.1056/NEJMoa1706314
  13. NEJM Knowledge+ Complex Medical Care
  14. Mediterranean fever, familial http://ghr.nlm.nih.gov/condition=mediterraneanfeverfamilial