History and exam

Key diagnostic factors

common

periodic fever

Temperature >100°F (38°C), usually lasting 12 to 72 hours but no longer than 1 week.

In very young children, the disease may begin with fever alone, but progresses to typical symptoms over time.[64]

abdominal pain

Most patients (95%) will recall having at least one episode. Usually precedes the fever and lasts longer. Varies from mild to severe (peritonitis), and localized to generalized with rigidity and rebound tenderness. Some of these patients have had more than one abdominal surgery for pseudo acute abdomen.[6][72]

altered bowel habit

Usually patients have constipation, but some, especially children, might have diarrhea.

acute joint pain/swelling

Attacks usually affect one large joint at a time in the lower extremities, but other joints (e.g., shoulder) could also be affected. Attacks typically last 2 to 3 days. Effusion develops in 75%. Usually there are no permanent sequelae despite multiple recurrences.[74]

response to colchicine

Unique among other hereditary periodic fever syndromes.[68] Can be used as a diagnostic test.

The diagnostic test with colchicine is considered positive if symptoms disappear with colchicine treatment and reappear after colchicine withdrawal.

uncommon

erysipelas-like skin lesions

Most characteristic skin manifestation. Occurs in 7% to 40% of cases.[77]

Tender, erythematous, elevated, well demarcated. Tender area measures 10 to 15 cm in diameter. Usually below the knee, often located on the ankle, and subsides within 24 to 72 hours with the resolution of the attack.

Other diagnostic factors

common

pleuritic chest pain

Pleurisy is present in 30% to 40% of patients. It is usually unilateral.[6]

It may also be an indicator of pericarditis, which is present in 0.5% to 1% of patients.

acute myalgia

Occurs in approximately 20% of patients. Usually only lasts 2 days.[73] Appears especially during or after physical exertion.

hepatosplenomegaly

Occurs in 15% to 20% of patients with transient elevation in liver enzymes. No clear relationship between FMF and liver disease but some suggested cryptogenic cirrhosis.[75][76]

history of appendectomy

Performed before adulthood in many patients due to the severity of abdominal pain localized to a specific quadrant in some cases.

abdominal scars

Diffuse mimicking of an acute abdomen occurs in many FMF patients. Some patients have had multiple abdominal exploratory surgeries.

uncommon

chronic joint pain

Present in 5% of patients.

Mostly affects the hip or knee. Rarely polyarticular. In some cases has resulted in joint replacement.[74]

pleural rub

May be an indicator of pericarditis, which is present in 0.5% to 1% of patients.

chronic myalgia/fibromyalgia

Occurs in rare cases.[74]

headache

Aseptic meningitis has been reported.[78]

neck stiffness

Aseptic meningitis has been reported.[78]

photophobia

Aseptic meningitis has been reported.[78]

acute scrotal pain + swelling

Occurs due to serositis of the tunica vaginalis. Can be confused with testicular torsion in prepubertal boys.[74]

visual disturbances

Blurred vision or complete or partial vision loss due to optic neuritis has been reported.[79]

Risk factors

strong

Mediterranean ancestry

Prevalence of FMF is 0.1% in people of Mediterranean descent.[11] It is also reported in Melungeon populations (triracial mix of European, sub-Saharan African, American Indian, and Mediterranean origins living mostly in the Appalachian region) within the US. Turkey and Armenia have the highest estimated FMF prevalence, at 1:1000 and 1:500, respectively.[12] The reported gene carrier frequency is 1:5 in non-Ashkenazi Jews, 1:16 in Arabs, 1:5 in Turks, and 1:7 in Armenians.[12]

age <20 years old

First attacks usually occur before 20 years of age (80% to 90% of cases).[13] Among pediatric populations, 20% occur before 2 years of age and 86% before 10 years of age.[16]

positive family history

FMF is a Mendelian recessively inherited genetic disorder common in people of Mediterranean descent. In some cases, FMF may appear sporadically and could go on to affect multiple generations. This is due to the high carrier rates of certain populations, which causes pseudodominant inheritance. Bouts of fever, polyserositis, skin rashes, and arthritis usually occur before 4 years of age but are not specific. The diagnosis is usually made retrospectively on the basis of recurrent febrile attacks and positive family history.[6] Genotyping of mutations of the Mediterranean fever gene in 1250 pedigrees of Armenian families with FMF proved to be autosomal recessive in 91.5% and pseudodominant in 8.5% of all families.[49] True dominant inheritance has also been described in some families.[31][32][33]

genetic mutation in MEFV gene

The gene responsible, Mediterranean fever, was identified by positional cloning and mapped to chromosome 16p13.3 with >80% of its mutations identified so far.[18][19] Patients homozygotic to M694V have an early severe disease, higher fever, splenomegaly and erysipelas-like erythema, acute monoarthritis, protracted myalgia syndrome, and are more likely to progress to renal amyloidosis.[21][26][50][51][52][53]

In a clinical context of FMF, the presence of two mutations on different alleles (homozygosity or compound heterozygosity) confirms the diagnosis.[54] When only 1 mutation is present, the diagnosis is unconfirmed; nevertheless, diagnosis should not be ruled out if the clinical presentation is typical, because some rare or unknown mutations do exist.[36][55] The registry of hereditary auto-inflammatory disorders mutations Opens in new window Those same ″true″ heterozygotes may display a complete clinical picture of FMF. It is also likely that some heterozygous patients, as in many recessive diseases, may have attenuated clinical signs. Incomplete presentations are more common in heterozygous patients, and heterozygosity may be a risk factor for various other inflammatory diseases (e.g., Crohn disease, Behcet disease, or multiple sclerosis).[56][57][58] Inheritance of other gene mutations affecting pyrin and inflammation may also cause symptoms.

country of origin: Armenia, Turkey, or the Mediterranean basin

In a large study that included 35 centers in 14 countries (2482 FMF cases including 260 with renal amyloidosis), country of recruitment, rather than the Mediterranean fever genotype, was the key risk factor for renal amyloidosis with a threefold increase in the risk, suggesting the importance of environmental factors in FMF pathogenesis.[59]

A further multicenter international registry study found that Eastern Mediterranean patients have a milder disease phenotype once they migrate to Europe, also reflecting the effect of environment on disease expression.[41]

weak

male sex

Accounts for 60% of cases. Male to female ratio among those with the renal complication amyloidosis is 2:1.[7][48]

psychological stress

Recognized by patients and physicians as a trigger for FMF attacks.[40]

viral illness

Recognized by patients and physicians as a trigger for FMF attacks.[40]

physical exertion

Recognized by patients and physicians as a trigger for FMF attacks.[40]

extreme exhaustion

Recognized by patients and physicians as a trigger for FMF attacks.[40]

use of vasoconstrictor sympathomimetics

Metaraminol and other drugs with similar mechanisms of action may trigger FMF attacks.[40]

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