Familial Mediterranean Fever Clinical Presentation

Updated: Sep 30, 2016
  • Author: John O Meyerhoff, MD; Chief Editor: Herbert S Diamond, MD  more...
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Presentation

History

The preeminent feature of familial Mediterranean fever (FMF) is the paroxysm, the classic onset of which occurs without warning, although some patients may be able to detect premonitory symptoms. The paroxysms usually last 48-96 hours, with peak intensity occurring within the first 12 hours. A plateau with resolution follows, usually occurring more slowly than the onset of symptoms.

In paroxysms, the person's temperature rises rapidly to 38-40°C (100.4-104°F). Temperature increases may occur before other manifestations. In mild attacks, fever may be the only manifestation.

Peritoneal symptoms

Almost all patients with FMF experience abdominal episodes. Abdominal pain develops, and may progress to peritonitis. Frequently the clinical presentation is consistent with appendicitis or cholecystitis, so patients commonly undergo appendectomies and cholecystectomies because the abdominal episodes of FMF are not recognized as such. The symptoms may also mimic renal colic.

In many cases, patients develop constipation during the attack and diarrhea after the attack resolves.

Even with recurrent attacks, adhesions are rare.

Pleural and pericardial symptoms

The frequency of pleural and pericardial attacks varies among ethnic groups, with 25-80% of patients reporting pleuritic episodes. Effusions occasionally occur. Pericarditis may develop, but tamponade and constrictive pericarditis are rare.

Synovial symptoms

The rate of synovial symptoms varies from 25-75% in reported series. The episodes may resemble gout in their acute onset and intensity. Knees, ankles, and wrists are the joints most commonly affected. An arthritis that resembles seronegative spondyloarthritis may also occur.

The joints are normal between attacks, and permanent damage is unusual.

Arthritic symptoms tend to last several days longer than abdominal symptoms. Episodes can be protracted.

Arthritis may be the only manifestation. FMF should be considered in patients with a family history of FMF or who live in an endemic area. [12]

Other manifestations

The following may also be features of FMF:

  • Dermatologic manifestations - As many as 50% of patients with FMF report erysipelaslike rashes on the lower extremities, particularly below the knees; rash and fever may be the only manifestations of attacks
  • Muscle symptoms - Severe myalgia may last 3-6 weeks; symptoms are consistent with fibromyalgia; these episodes do not respond to colchicine therapy
  • Pelvic symptoms - Female patients with FMF may have episodes of pelvic inflammatory disease
  • Scrotal attacks - In males, inflammation of the tunica vaginalis testis may mimic episodes of testicular torsion
  • Vasculitis - An increased frequency of Henoch-Schönlein purpura and polyarteritis nodosa is reported in persons with FMF, even in children; Behçet disease is also more common

Amyloidosis

In a patient of the appropriate ethnic group, the typical progression of amyloidosis in FMF is proteinuria, followed by nephrotic syndrome, and, inevitably, death from renal failure.

One third of patients with amyloidosis develop renal vein thrombosis. Nephrotic syndrome is reported in patients as young as 14 years. Despite the frequency and extent of amyloid deposits in the renal system, deposits in other organs are only rarely reported as significant.

In a retrospective study of 170 Armenian patients with FMF and suspected nephropathy, biopsy-proven amyloid A (AA) amyloidosis was found in 102 (60%). Recurrent arthritis was significantly associated with an increased risk of AA amyloidosis, and involvement of the joint synovial membrane, which is capable of active serum amyloid A production, was the main predictor of renal amyloidosis. [13]

Prolonged survival resulting from colchicine therapy, dialysis, and renal transplantation allows additional manifestations of amyloidosis to develop. Some patients have intestinal involvement, which may lead to malabsorption and death.

Some patients with a family history of FMF present with amyloid nephropathy without ever having experienced an amyloid attack. Furthermore, some patients with otherwise typical FMF may develop renal failure without previous proteinuria.

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Causes

FMF is a recessive genetic disease associated with missense and nonsense mutations in the MEFV gene, which is located on the short arm of chromosome 16. This gene codes for the protein known as pyrin or marenostrin.

Multiple mutations are located on the MEFV gene. Most of the mutations are in exon 10 of the gene between amino acids 680 and 761. One mutation in exon 1 at amino acid 148 may represent as many as one quarter of the known mutations. Although certain mutations are more common in particular ethnic groups, patients usually inherit different mutations from each parent.

Homozygotes for M694V (valine for methionine at position 694) may experience more severe disease and may be more likely to develop amyloidosis. Patients with V726A (alanine for valine at position 726) may be at a lower risk of developing amyloidosis, although one study suggests that the combination of V726A and E148Q may be particularly amyloidogenic. [6]

Other genes may be involved in FMF. This is supported by patients who meet criteria for FMF without identifiable mutations in MEFV and who have clinical manifestations that are indistinguishable from patients with MEFV mutations.

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Physical Examination

Temperatures can reach as high as 40°C (104°F), but, in most cases, rapid defervescence occurs within 12 hours. Other physical findings of FMF depend mostly on the serosal surface involved, as follows:

  • A boardlike or surgical abdomen is present with typical findings of peritonitis (ie, abdominal tenderness, decreased bowel sounds). Splenomegaly is common in response to the inflammation. Patients with pleural involvement may have shallow breathing and chest-wall tenderness, but friction rubs are rare.
  • Joints show typical inflammatory changes, with warmth, erythema, or swelling.
  • A well-demarcated, erythematous, warm rash, particularly below the knee, ranging from 15-50 cm 2 may develop and may be accompanied by swelling.
  • Patients with painful myalgia syndrome may have tender muscles.
  • Female patients with symptoms mimicking pelvic inflammatory syndrome may experience pain on cervical motion and may develop tender, enlarged ovaries.
  • Unilateral, erythematous, and tender swelling of the scrotum occurs in scrotal attacks. The typical manifestations of Behçet disease and Henoch-Schönlein purpura may be observed.
  • Amyloidosis is usually asymptomatic, with hypertension reported in 35% of patients late in the disease. Renal vein thrombosis may develop and manifests as loin pain.
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