Familial Mediterranean fever

Abstract

Familial Mediterranean fever (FMF) is a genetic disorder restricted to certain ethnic groups and marked by the sporadic appearance of acute attacks and the insidious development of amyloidosis: in phenotype i the attacks appear first; in phenotype ii amyloidosis is the first manifestation. Four hundred seventy cases fulfilling our diagnostic criteria now constitute the series collected by the Tel-Hashomer Hospital unit; 357 additional cases were culled from the literature. Of our patients, 455 were Sephardic and ten Ashkenazic Jews (they are represented in approximately equal numbers in the over-all Israeli population); five were Arabs. In the cases reported in the literature, 181 patients were Sephardic and three Ashkenazic, eighty-seven were Armenians and thirty-six were Arabs from the Levant.

Genetic analysis of 229 complete pedigrees which yielded 350 of our cases indicated an autosomal recessive mode of inheritance. The calculated gene frequency in the Sephardic population is 0.22. Isolated pedigrees in which more than two generations were affected may be an indication of genetic heterogeneity.

The acute attacks, the hallmark of the disease, are self-limited febrile episodes lasting from twenty-four to forty-eight hours and recurring at irregular, unpredictable intervals, accompanied by evidence of peritonitis, pleuritis, synovitis or an erysipelas-like erythema. Peritoneal attacks were experienced by 95 per cent of our patients and were the presenting sign in 55 per cent. Pleural attacks occurred in 40 per cent of our patients. Synovial attacks were experienced by 78 per cent of our patients, in one-third of these as the presenting sign. They usually appeared as a monoarthritis. As a rule, the synovial attacks also were brief, subsiding within one to seven days, but they sometimes persisted for a month or, rarely, followed a protracted course for as long as one year. However, spontaneous complete functional recovery characteristically occurred. Erysipelas-like erythema affecting the leg or foot may be the only sign in a febrile attack or may accompany a synovial attack. Of uncertain significance are hematuria and Henoch-Schoenlein purpura, occasionally documented in cases of FMF without relation to a febrile episode.

Amyloidosis is the second major manifestation of FMF. It has been diagnosed in 125 (26.5 per cent) of our patients and in 28 per cent of those reported in the literature. In our series amyloidosis caused death in sixty-seven cases, as early as age five, and in 90 per cent before age forty, explaining the absence of older age groups in our patient population. Nephropathy, passing from a preclinical stage, diagnosable only by biopsy, through phases of proteinuria, nephrotic syndrome and uremia to death, dominated the clinical picture, except in one patient who died from intestinal malabsorption.

There was no relation between the appearance of attacks and amyloidosis. In 106 cases of FMF-phenotype I, amyloidosis was manifest or diagnosed over a time-range of from one to more than thirty years after the onset of attacks. In eight cases of FMFphenotype ii, amyloidosis preceded attacks, remaining the sole manifestation in three. The high proportion of patients showing both attacks and amyloidosis and the gamut of time-relationship between these two manifestations are best explained as expressions of a single pleiotropic gene. Treatment has been of no avail in shortening or preventing any of the forms of FMF attacks.

Necropsies in forty-two of our patients revealed pleural and peritoneal adhesions in some cases. Peritoneal adhesions were responsible for death via intestinal strangulation in two, in one of these without amyloidosis. Otherwise, amyloidosis was the only finding of significance. It was of the perireticulin type, affecting blood vessels of all organs and showing a characteristic pattern of parenchymal involvement. The latter consisted of massive replacement of renal glomeruli and adrenals, diffuse involvement of the spleen (“lardaceous”) and pulmonary alveolar septums, and remarkable sparing of hepatic sinusoids. The amyloid filaments showed no distinguishing electronmicroscopic features. Actively secreting fibroblasts and pathologic collagen fibrils were present in all specimens examined. The possibility that the metabolic defect underlying this hereditary disorder lies in the scleroprotein-producing system is suggested.