Familial Mediterranean Fever (FMF)Dz

Last updated: November 5, 2014

Synonyms: Periodic fever, familial recurrent polyserositis.

ICD-9 Code: 277.31.
ICD-10: E85.0

Definition: FMF is an intermittent febrile disorder with inflammatory serositis, arthritis, and rash.

Etiology: FMF is an autosomal recessive disorder associated. The genetic defect is in the gene MEFV, which encodes pyrin, a 781-amino-acid protein that associates with the cytoskeleton in neutrophils and activated monocytes.

Twenty-eight mutations in this gene have been described, most in exon 10. Different mutations may be associated with variable prognoses and complications, such as amyloidosis. Heterozygous carriers of this gene are asymptomatic.

Pathology: Synovial biopsy shows nonspecific inflammation. Skin lesions show dense dermal infiltration with neutrophils and no evidence of vasculitis.

Demographics: Eastern Mediterranean persons (especially Armenians, Arabs, Turks, and Sephardic Jews) are most frequently affected. It is uncommon in other Mediterranean populations. In Iraqis and Sephardic Jews, the prevalence of FMF is between 1:250 and 1:1,000. The prevalence in Ashkenazi Jews is 1:73,000. The male:female ratio is 3:2. Less than half have a family history of FMF.

Cardinal Findings: Acute, recurrent, unpredictable attacks of fever, serositis (e.g., peritonitis, pleuritis), arthritis, and an erysipelas-like rash are seen. More than 80% of attacks begin before age 20, and initial attacks are very rare after age 40. Although fever and serosal attacks usually last 12 to 72 hours, arthritis may last for several weeks. Disease-free intervals may last days or months. Attacks may be precipitated by menses, stress, or physical exercise.
—Fever: The magnitude of fever varies.
—Serositis: Nearly all patients (>95%) have abdominal attacks at some time. Peritoneal attacks manifest as localized or generalized pain, abdominal distention, or signs of peritoneal inflammation. Constipation or diarrhea may accompany the attack. Pleural attacks occur in 25% to 50% of patients and tend to be unilateral and associated with a pleural rub and effusion on chest x-ray.
Arthritis: Seen in as many as 75% of patients, arthritis tends to be acute, very painful, and monarticular and typically affects the knee, ankle, and hip. Synovial effusion is usually detectable. Persistent synovitis is uncommon but may last for weeks or months. Such patients may have radiographic evidence of osteopenia or joint damage. Febrile myalgias may also be intense and last for weeks.
—Erysipelas-like rash: Seen in 20% to 46% of patients, rash may occur with fever, is usually on the anterior lower extremity, and may be uni- or bilateral. Lesions are sharply demarcated, erythematous, tender, and sometimes swollen. Purpura is less common.

Uncommon Findings: Pericarditis is rare. Scrotal edema and pain have been described.

Complications: Amyloidosis develops in 10% to 40% and is unrelated to severity or frequency of FMF. Such patients may exhibit proteinuria, renal failure, or intestinal malabsorption. Less than 5% of children manifest Henoch- Schönlein purpura. FMF may coexist with PAN.

Diagnostic Tests: Genetic testing for MEFV mutations is possible; however, the diagnosis can still be made on clinical grounds, particularly in high-risk populations. Leukocytosis, elevated ESR, and inflammatory synovial fluid are usually seen. A normochromic, normocytic anemia may be found. Transient albuminuria and microscopic hematuria may be seen during the febrile attacks. Sterile exudative peritoneal or pleural fluid, with a neutrophil predominance, is common. C5a-inhibitor and IL-8 may be decreased in serosal or joint fluid (these tests are not routinely available).

Differential Diagnosis: Acute appendicitis, porphyria, hereditary angioedema, systemic juvenile arthritis (Still disease), rheumatic fever, septic arthritis, and endometriosis or pelvic inflammatory disease in women should be considered. Other febrile syndromes should be considered.

Therapy: Symptomatic relief is the goal of therapy. Corticosteroids are ineffective. Colchicine prophylaxis (0.6 mg b.i.d. or t.i.d.) reduces the frequency of attacks, protects against amyloidosis, and stabilizes or lessens the proteinuria. Intravenous colchicine should be avoided.

Kastner DL. The hereditary periodic fevers. In: Hochberg MC, Silman AJ, Smolen JS, et al., eds. Rheumatology, 3rd ed. Edinburgh: Mosby, 2003:1717–1734.

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