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Familial Mediterranean fever(FMF)

MedGen UID:
45811
Concept ID:
C0031069
Disease or Syndrome
Synonyms: Benign paroxysmal peritonitis; Familial Mediterranean Fever Type 1; Familial Mediterranean Fever Type 2; FMF; Periodic disease; Periodic peritonitis; POLYSEROSITIS, FAMILIAL PAROXYSMAL; POLYSEROSITIS, RECURRENT
SNOMED CT: Periodic disease (12579009); Paroxysmal polyserositis (12579009); Familial Mediterranean fever (12579009); Familial recurrent polyserositis (12579009); Familial paroxysmal polyserositis (12579009); Periodic polyserositis (12579009); Periodic peritonitis (12579009); Periodic familial peritonitis (12579009); MEF - Familial Mediterranean fever (12579009); Recurrent polyserositis (12579009); Benign paroxysmal peritonitis (12579009); FMF - Familial Mediterranean fever (12579009)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): MEFV (16p13.3)
 
Monarch Initiative: MONDO:0018088
OMIM®: 249100
Orphanet: ORPHA342

Disease characteristics

Excerpted from the GeneReview: Familial Mediterranean Fever
Familial Mediterranean fever (FMF) is divided into two phenotypes: type 1 and type 2. FMF type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to kidney failure, is the most severe complication, if untreated. FMF type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual. [from GeneReviews]
Authors:
Mordechai Shohat   view full author information

Additional descriptions

From OMIM
Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of fever and inflammation in the peritoneum, synovium, or pleura, accompanied by pain. Amyloidosis with renal failure is a complication and may develop without overt crises (French FMF Consortium, 1997). See also autosomal dominant FMF (134610), which is caused by heterozygous mutation in the MEFV gene.  http://www.omim.org/entry/249100
From MedlinePlus Genetics
Familial Mediterranean fever is an inherited condition characterized by recurrent episodes of painful inflammation in the abdomen, chest, or joints.  These episodes are often accompanied by fever and sometimes a rash or headache. Occasionally inflammation may occur in other parts of the body, such as the heart; the membrane surrounding the brain and spinal cord; and in males, the testicles. In about half of affected individuals, attacks are preceded by mild signs and symptoms known as a prodrome. Prodromal symptoms include mildly uncomfortable sensations in the area that will later become inflamed, or more general feelings of discomfort.

The first episode of illness in familial Mediterranean fever usually occurs in childhood or the teenage years, but in some cases, the initial attack occurs much later in life. Typically, episodes last 12 to 72 hours and can vary in severity. Episodes generally occur once a month, and in affected women of reproductive age, attacks often correspond with menstruation or ovulation. However, the length of time between episodes can range from days to years. During these periods, affected individuals usually have no signs or symptoms related to the condition. However, without treatment to help prevent attacks and complications, a buildup of protein deposits (amyloidosis) in the body's organs and tissues may occur, especially in the kidneys, which can lead to kidney failure.  https://medlineplus.gov/genetics/condition/familial-mediterranean-fever

Clinical features

From HPO
Abdominal pain
MedGen UID:
7803
Concept ID:
C0000737
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) and perceived to originate in the abdomen.
Arthralgia
MedGen UID:
13917
Concept ID:
C0003862
Sign or Symptom
Joint pain.
Chest pain
MedGen UID:
2992
Concept ID:
C0008031
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the chest.
Myalgia
MedGen UID:
68541
Concept ID:
C0231528
Sign or Symptom
Pain in muscle.
Episodic abdominal pain
MedGen UID:
814352
Concept ID:
C3808022
Finding
An intermittent form of abdominal pain.
Nephrotic syndrome
MedGen UID:
10308
Concept ID:
C0027726
Disease or Syndrome
Nephrotic syndrome is a collection of findings resulting from glomerular dysfunction with an increase in glomerular capillary wall permeability associated with pronounced proteinuria. Nephrotic syndrome refers to the constellation of clinical findings that result from severe renal loss of protein, with Proteinuria and hypoalbuminemia, edema, and hyperlipidemia.
Orchitis
MedGen UID:
18191
Concept ID:
C0029191
Disease or Syndrome
Testicular inflammation.
Renal amyloidosis
MedGen UID:
120633
Concept ID:
C0268382
Disease or Syndrome
A form of amyloidosis that affects the kidney. On hematoxylin and eosin stain, amyloid is identified as extracellular amorphous material that is lightly eosinophilic. These deposits often stain weakly for periodic acid Schiff (PAS), demonstrate a blue-to-gray hue on the trichrome stain and are typically negative on the Jones methenamine silver (JMS) stain. These tinctorial properties contrast with the histologic appearance of collagen, a major component of basement membranes, mesangial matrix and areas of sclerosis, which demonstrates strong positivity for PAS and JMS (See Figure 1 of PMID:25852856).
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
A degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate (less than 15 ml/min/1.73 m2) and other manifestations including increased serum creatinine.
Crohn disease
MedGen UID:
3664
Concept ID:
C0010346
Disease or Syndrome
A chronic granulomatous inflammatory disease of the intestines that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms. It primarily causes abdominal pain, diarrhea which may be bloody, vomiting, or weight loss, but may also cause complications outside of the gastrointestinal tract such as skin rashes, arthritis, inflammation of the eye, tiredness, and lack of concentration. Crohn's disease is thought to be an autoimmune disease, in which the body's immune system attacks the gastrointestinal tract, causing inflammation.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Chronic constipation
MedGen UID:
98325
Concept ID:
C0401149
Sign or Symptom
Constipation for longer than three months with fewer than 3 bowel movements per week, straining, lumpy or hard stools, and a sensation of anorectal obstruction or incomplete defecation.
Headache
MedGen UID:
9149
Concept ID:
C0018681
Sign or Symptom
Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.
Arthritis
MedGen UID:
2043
Concept ID:
C0003864
Disease or Syndrome
Inflammation of a joint.
Pleural effusion
MedGen UID:
10805
Concept ID:
C0032227
Disease or Syndrome
The presence of an excessive amount of fluid in the pleural cavity.
Pleuritis
MedGen UID:
10807
Concept ID:
C0032231
Disease or Syndrome
Inflammation of the pleura.
Erysipelas
MedGen UID:
41855
Concept ID:
C0014733
Disease or Syndrome
Increased susceptibility to erysipelas, as manifested by a medical history of repeated episodes of erysipelas, which is a superficial infection of the skin, typically involving the lymphatic system.
Leukocytosis
MedGen UID:
9736
Concept ID:
C0023518
Disease or Syndrome
An abnormal increase in the number of leukocytes in the blood.
Meningitis
MedGen UID:
6298
Concept ID:
C0025289
Disease or Syndrome
Inflammation of the meninges.
Pericarditis
MedGen UID:
18377
Concept ID:
C0031046
Disease or Syndrome
Inflammation of the sac-like covering around the heart (pericardium).
Peritonitis
MedGen UID:
14697
Concept ID:
C0031154
Pathologic Function
Inflammation of the peritoneum.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Neutrophilia
MedGen UID:
57729
Concept ID:
C0151683
Finding
Increased number of neutrophils circulating in blood.
Amyloidosis
MedGen UID:
272
Concept ID:
C0002726
Disease or Syndrome
The presence of amyloid deposition in one or more tissues. Amyloidosis may be defined as the extracellular deposition of amyloid in one or more sites of the body.
Elevated erythrocyte sedimentation rate
MedGen UID:
57727
Concept ID:
C0151632
Finding
An increased erythrocyte sedimentation rate (ESR). The ESR is a test that measures the distance that erythrocytes have fallen after one hour in a vertical column of anticoagulated blood under the influence of gravity. The ESR is a nonspecific finding. An elevation may indicate inflammation or may be caused by any condition that elevates fibrinogen.
Recurrent fever
MedGen UID:
811468
Concept ID:
C3714772
Sign or Symptom
Periodic (episodic or recurrent) bouts of fever.
Elevated circulating C-reactive protein concentration
MedGen UID:
892906
Concept ID:
C4023452
Finding
An abnormal elevation of the C-reactive protein level in the blood circulation.
Elevated circulating amyloid A concentration
MedGen UID:
1788190
Concept ID:
C5539521
Finding
The concentration of serum amyloid A in the blood circulation is above the upper limit of normal.
Aphthous stomatitis
MedGen UID:
20959
Concept ID:
C0038363
Disease or Syndrome
Oral aphthous ulcers typically present as painful, sharply circumscribed fibrin-covered mucosal defects with a hyperemic border.

Professional guidelines

PubMed

Tufan A, Lachmann HJ
Turk J Med Sci 2020 Nov 3;50(SI-2):1591-1610. doi: 10.3906/sag-2008-11. PMID: 32806879Free PMC Article
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Ann Rheum Dis 2019 Aug;78(8):1025-1032. Epub 2019 Apr 24 doi: 10.1136/annrheumdis-2019-215048. PMID: 31018962
Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G, Ozdogan H, Abu I, Gattorno M, Hawkins PN, Yuce S, Kallinich T, Bilginer Y, Kastner D, Carmona L
Ann Rheum Dis 2016 Apr;75(4):644-51. Epub 2016 Jan 22 doi: 10.1136/annrheumdis-2015-208690. PMID: 26802180

Curated

Orphanet, Familial Mediterranean fever, 2013

Recent clinical studies

Etiology

Bildirici AE
Int J Immunogenet 2023 Dec;50(6):273-280. Epub 2023 Oct 4 doi: 10.1111/iji.12640. PMID: 37794570
Bilici Salman R, Babaoglu H, Satiş H, Yapar D, Avanoglu Güler A, Karadeniz H, Ataş N, Haznedaroğlu Ş, Öztürk MA, Göker B, Tufan A
J Clin Rheumatol 2022 Jan 1;28(1):e77-e80. doi: 10.1097/RHU.0000000000001632. PMID: 33298810
Sotskiy PO, Sotskaya OL, Hayrapetyan HS, Sarkisian TF, Yeghiazaryan AR, Atoyan SA, Ben-Chetrit E
J Rheumatol 2021 Apr;48(4):608-614. Epub 2020 Oct 1 doi: 10.3899/jrheum.200574. PMID: 33004533
Ozdogan H, Ugurlu S
Presse Med 2019 Feb;48(1 Pt 2):e61-e76. Epub 2019 Jan 25 doi: 10.1016/j.lpm.2018.08.014. PMID: 30686512
Melikoglu MA, Senel K
Int J Rheum Dis 2017 Dec;20(12):2118-2121. Epub 2014 Apr 7 doi: 10.1111/1756-185X.12374. PMID: 24702830

Diagnosis

Lancieri M, Bustaffa M, Palmeri S, Prigione I, Penco F, Papa R, Volpi S, Caorsi R, Gattorno M
Int J Mol Sci 2023 May 31;24(11) doi: 10.3390/ijms24119584. PMID: 37298536Free PMC Article
Batu ED, Basaran O, Bilginer Y, Ozen S
Curr Rheumatol Rep 2022 Jun;24(6):206-212. Epub 2022 Apr 18 doi: 10.1007/s11926-022-01073-7. PMID: 35435612
Bilici Salman R, Babaoglu H, Satiş H, Yapar D, Avanoglu Güler A, Karadeniz H, Ataş N, Haznedaroğlu Ş, Öztürk MA, Göker B, Tufan A
J Clin Rheumatol 2022 Jan 1;28(1):e77-e80. doi: 10.1097/RHU.0000000000001632. PMID: 33298810
Tufan A, Lachmann HJ
Turk J Med Sci 2020 Nov 3;50(SI-2):1591-1610. doi: 10.3906/sag-2008-11. PMID: 32806879Free PMC Article
Kucuk A, Gezer IA, Ucar R, Karahan AY
Acta Medica (Hradec Kralove) 2014;57(3):97-104. doi: 10.14712/18059694.2014.47. PMID: 25649364

Therapy

Lancieri M, Bustaffa M, Palmeri S, Prigione I, Penco F, Papa R, Volpi S, Caorsi R, Gattorno M
Int J Mol Sci 2023 May 31;24(11) doi: 10.3390/ijms24119584. PMID: 37298536Free PMC Article
Kurup R, Galougahi KK, Figtree G, Misra A, Patel S
Heart Lung Circ 2021 Jun;30(6):795-806. Epub 2021 Jan 16 doi: 10.1016/j.hlc.2020.11.010. PMID: 33461916
Soriano A, Soriano M, Espinosa G, Manna R, Emmi G, Cantarini L, Hernández-Rodríguez J
Front Immunol 2020;11:865. Epub 2020 Jun 3 doi: 10.3389/fimmu.2020.00865. PMID: 32655539Free PMC Article
De Benedetti F, Gattorno M, Anton J, Ben-Chetrit E, Frenkel J, Hoffman HM, Koné-Paut I, Lachmann HJ, Ozen S, Simon A, Zeft A, Calvo Penades I, Moutschen M, Quartier P, Kasapcopur O, Shcherbina A, Hofer M, Hashkes PJ, Van der Hilst J, Hara R, Bujan-Rivas S, Constantin T, Gul A, Livneh A, Brogan P, Cattalini M, Obici L, Lheritier K, Speziale A, Junge G
N Engl J Med 2018 May 17;378(20):1908-1919. doi: 10.1056/NEJMoa1706314. PMID: 29768139
Finkelstein Y, Aks SE, Hutson JR, Juurlink DN, Nguyen P, Dubnov-Raz G, Pollak U, Koren G, Bentur Y
Clin Toxicol (Phila) 2010 Jun;48(5):407-14. doi: 10.3109/15563650.2010.495348. PMID: 20586571

Prognosis

Di Ciaula A, Iacoviello M, Bonfrate L, Khalil M, Shanmugam H, Lopalco G, Bagnulo R, Garganese A, Iannone F, Resta N, Portincasa P, Stella A
Eur J Intern Med 2023 Sep;115:79-87. Epub 2023 May 13 doi: 10.1016/j.ejim.2023.05.015. PMID: 37183082
Tezcan ME, Acer Kasman S, Şen N, Osken S, Yılmaz-Oner S
Rheumatol Int 2023 Jul;43(7):1313-1321. Epub 2023 Mar 6 doi: 10.1007/s00296-023-05290-w. PMID: 36879026
Tufan A, Lachmann HJ
Turk J Med Sci 2020 Nov 3;50(SI-2):1591-1610. doi: 10.3906/sag-2008-11. PMID: 32806879Free PMC Article
Finkelstein Y, Aks SE, Hutson JR, Juurlink DN, Nguyen P, Dubnov-Raz G, Pollak U, Koren G, Bentur Y
Clin Toxicol (Phila) 2010 Jun;48(5):407-14. doi: 10.3109/15563650.2010.495348. PMID: 20586571
Breathnach SM
J Am Acad Dermatol 1988 Jan;18(1 Pt 1):1-16. doi: 10.1016/s0190-9622(88)70001-8. PMID: 3279077

Clinical prediction guides

Tümerdem BŞ, Akbaba TH, Batu ED, Akkaya-Ulum YZ, Mutlu P, Ozen S, Balci-Peynircioğlu B
Int Immunopharmacol 2023 Nov;124(Pt B):111011. Epub 2023 Oct 14 doi: 10.1016/j.intimp.2023.111011. PMID: 37844462
Bilici Salman R, Babaoglu H, Satiş H, Yapar D, Avanoglu Güler A, Karadeniz H, Ataş N, Haznedaroğlu Ş, Öztürk MA, Göker B, Tufan A
J Clin Rheumatol 2022 Jan 1;28(1):e77-e80. doi: 10.1097/RHU.0000000000001632. PMID: 33298810
Ozen S, Lutz HL, Rivera VM, Reiff A, Batu ED, Anderson E, Salas Garcia M, Aldrovandi G, Akbaba TH, Pazarbasi İ, Bilginer Y, Balat A, Balci-Peynircioglu B, Gilbert JA, Dedeoglu F, Hausmann JS
Clin Exp Rheumatol 2021 Sep-Oct;39 Suppl 132(5):102-108. Epub 2021 Jul 5 doi: 10.55563/clinexprheumatol/olvbyd. PMID: 34251310
Padeh S, Berkun Y
Curr Opin Rheumatol 2016 Sep;28(5):523-9. doi: 10.1097/BOR.0000000000000315. PMID: 27286236
Sternick EB, Oliva A, Magalhães LP, Gerken LM, Hong K, Santana O, Brugada P, Brugada J, Brugada R
J Cardiovasc Electrophysiol 2006 Jul;17(7):724-32. doi: 10.1111/j.1540-8167.2006.00485.x. PMID: 16836667

Recent systematic reviews

Arnold DD, Yalamanoglu A, Boyman O
Front Immunol 2022;13:888392. Epub 2022 Jul 6 doi: 10.3389/fimmu.2022.888392. PMID: 35874710Free PMC Article
Yin X, Tian F, Wu B, Xu T
Cochrane Database Syst Rev 2022 Mar 29;3(3):CD010893. doi: 10.1002/14651858.CD010893.pub4. PMID: 35349164Free PMC Article
Indraratna PL, Virk S, Gurram D, Day RO
Rheumatology (Oxford) 2018 Feb 1;57(2):382-387. doi: 10.1093/rheumatology/kex353. PMID: 29029311
Akgul O, Kilic E, Kilic G, Ozgocmen S
Am J Med Sci 2013 Aug;346(2):137-41. doi: 10.1097/MAJ.0b013e318277083b. PMID: 23276893
Finkelstein Y, Aks SE, Hutson JR, Juurlink DN, Nguyen P, Dubnov-Raz G, Pollak U, Koren G, Bentur Y
Clin Toxicol (Phila) 2010 Jun;48(5):407-14. doi: 10.3109/15563650.2010.495348. PMID: 20586571

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