Familial Mediterranean fever (FMF)
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A 14-year-old of Sephardic Jewish ancestry has a 6-year history of recurrent 1-3 day episodes of high fever with severe abdominal pain mimicking peritonitis, sometimes with chest pain or monoarticular arthritis of the knee or ankle. Episodes resolve spontaneously and recur every few weeks. CRP and serum amyloid A (SAA) are markedly elevated during attacks and normalize between. Molecular testing identifies homozygous MEFV p.M694V variants.
Classically autosomal recessive (most cases); MEFV encodes pyrin (marenostrin), an inflammasome regulator expressed predominantly in neutrophils, monocytes, and synovial fibroblasts.
| Variant | Severity | Notes |
|---|---|---|
| p.M694V | Most severe; highest amyloidosis risk | Founder variant in Sephardic Jewish, Armenian, Turkish populations |
| p.M694I | Severe | Common in Arab populations |
| p.V726A | Milder | |
| p.M680I | Moderate | |
| p.E148Q | Mild / variable penetrance | Exact pathogenicity debated; sometimes a benign polymorphism |
| p.M694del, p.T577N | Dominant-acting | Heterozygotes can have full FMF phenotype |
Founder populations (carrier frequency 1 in 5 to 1 in 10 in some):
- Sephardic Jews
- Armenians
- Turks
- Arabs (Levant, North Africa)
- Italians (especially Sicilian, Calabrian)
Heterozygote phenotype: ~30% of obligate heterozygotes for severe variants have mild attacks ("incomplete penetrance" or pseudodominance). Many cases in the literature labeled "AD" reflect this rather than true dominant inheritance.
Pyrin is a sensor of bacterial RhoA inactivation that, when triggered, assembles a pyrin inflammasome with ASC and caspase-1, leading to IL-1β release. Disease-associated MEFV variants in the C-terminal B30.2 domain release pyrin from its tonic inhibition by RhoA-activated GTPases → spontaneous inflammasome assembly → unprovoked IL-1β surges → recurrent fever attacks. Colchicine works in part by stabilizing microtubule-dependent RhoA signaling and suppressing pyrin activation.
Attacks (paroxysms):
- Duration 1-3 days, self-limited
- High fever (often >38.5°C)
- Sterile serositis, choose any combination:
- Peritonitis (most common; severe abdominal pain, surgical-abdomen mimic; many patients have unnecessary appendectomies)
- Pleuritis (unilateral pleuritic chest pain)
- Pericarditis (less common)
- Monoarticular arthritis (knee, ankle, hip; large joint, oligoarticular)
- Erysipelas-like erythema: sharply demarcated red plaque, usually over the lower extremity, especially the dorsum of the foot/ankle
- Acute scrotum (orchitis) in boys
- Headache, aseptic meningitis in some
- Acute-phase proteins (CRP, SAA, ferritin, fibrinogen) markedly elevated during attacks; normalize between
- Onset usually before age 20 (>90%); childhood onset typical for severe variants
Subclinical inflammation between attacks: even asymptomatic patients often have low-grade elevation of acute-phase proteins, contributing to long-term amyloidosis risk
Long-term complication:
- AA (secondary) amyloidosis: chronic SAA elevation deposits in kidneys (nephrotic syndrome → renal failure), GI tract, heart, thyroid
- Highest risk: untreated p.M694V/M694V genotype, certain ethnic backgrounds (especially Armenian, Turkish, Arab), positive family history of amyloidosis, low colchicine adherence
- Colchicine prevents amyloidosis: this alone is the indication for lifelong colchicine in all FMF patients, regardless of attack frequency
Tel Hashomer / Livneh criteria (clinical):
Major: typical attacks of (1) peritonitis, (2) pleuritis or pericarditis, (3) monoarticular arthritis, (4) fever alone, (5) incomplete attack of abdominal type Minor: incomplete attacks of chest, joint, or leg pain on exertion + favorable response to colchicine Supportive: family history of FMF, ethnic background, age <20 at onset, severe attack requiring bedrest, spontaneous remission, asymptomatic intervals, transient lab inflammatory response, transient hematuria/proteinuria, unproductive laparotomy/appendectomy, parental consanguinity
Diagnosis requires ≥1 major or ≥2 minor or 1 minor + 5 supportive.
Molecular testing: MEFV panel/sequencing supports clinical diagnosis but does not replace it. A meaningful proportion of clinically diagnosed FMF patients have only one detectable MEFV variant or none.
Therapeutic trial of colchicine is part of the diagnostic process; clear response supports the diagnosis when criteria are borderline.
| Syndrome | Inheritance | Gene | Distinguishing features |
|---|---|---|---|
| TRAPS | AD | TNFRSF1A | Long attacks (1-3 weeks), periorbital edema, migratory myalgia |
| HIDS / MKD | AR | MVK | Onset <1 yr, attacks every 4-6 weeks, cervical lymphadenopathy, high IgD (variable) |
| CAPS (FCAS, MWS, NOMID/CINCA) | AD | NLRP3 | Cold-induced urticaria, sensorineural hearing loss, neonatal-onset multisystem disease |
| PFAPA | sporadic | none identified | Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis; pediatric, regular cycle, responds to single-dose steroid |
- Lifelong colchicine prophylaxis: first-line for all FMF patients
- Reduces attack frequency
- Prevents AA amyloidosis (the critical long-term outcome)
- Typical dose: 1.0-2.0 mg/day adults; weight-based in children
- Adherence is the dominant determinant of amyloidosis prevention
- Colchicine-resistant disease (~5-10%):
- IL-1 blockers: anakinra (daily SC), canakinumab (monthly SC); both effective
- Monitor for amyloidosis: annual urinalysis, periodic spot urine protein/creatinine, serum creatinine
- Renal biopsy if proteinuria develops (Congo red staining for amyloid)
- Pre-pregnancy counseling: continue colchicine through pregnancy and lactation (safe; stopping increases attack risk and amyloid risk)
- Avoid unnecessary surgery during attacks (peritoneal attacks are sterile)
FMF = "Fever, Mediterranean, Five-day max": short attacks (≤3 days) of fever + serositis + erysipelas-like rash; colchicine is the answer both to prevent attacks and prevent amyloidosis.