Familial Mediterranean Fever

Familial Mediterranean Fever (FMF) or periodic disease is an autosomal recessive hereditary disorder that mostly affects Sephardi Jews, Turks, Armenians and Arabs. Thirteen to twenty per cent of individuals are carriers of the mutant gene in these populations. The first attacks of Familial Mediterranean Fever occur in childhood and only exceptionally after the age of 30.

The disease is characterised by attacks of fever and inflammation of the serosa, giving rise to pseudo-surgical abdominal pain, or joint or chest pain. The attacks can involve isolated and recurring fever, meningitis, myalgia or orchitis sometimes leading to testicular necrosis. Splenomegaly is only observed exceptionally. Skin reactions including erysipeloid lesions on the legs or back of the foot, purpuric lesions evocative of purpura rheumatica, subcutaneous nodules or diffuse erythema of the face, chest or palms are only observed rarely [1]. There have been reports of the disease occurring together with genuine systemic vasculitis. Familial Mediterranean Fever attacks occur unexpectedly but in some patients, they may be triggered by menstruation, stress, physical overexertion or cold.

The prognosis for patients with FMF depends on the possible onset of diffuse, particularly renal, AA amyloidosis, which increases the severity of the disease. Deaths from amyloidosis have even been described in young children. The incidence of amyloidosis varies depending on the ethnic groups: it was observed rarely in Armenians, in 60% of cases in Turks and in 25 to 40% of cases in Sephardi Jews before systematic and indefinite treatment with colchicine was introduced. 

The gene responsible for the disease located on the short arm of chromosome 16 has been identified and various mutations of the gene give rise to the disease [2]. Laboratory tests at the time of the attacks only reveal a non-specific inflammatory picture. A deficit in inhibitors of C5a has been transiently noted at the time of the attacks but the finding has not led to the development of a diagnostic test. Diagnosis is based on family investigation, the efficacy of colchicine and genetic testing.

The gene which has a full length of 14 kb codes for a new protein (marenostrin/pyrin) whose physiological role is still unknown. Four missense mutations grouped on a portion of exon 10 have been identified in 75% of patients; however, a dozen mutations have been identified to date. The most common are the M694V mutation which replaces methionine with valine, the V726A mutation (Druzes and Armenians), the M680I mutation (Armenians and Turks), the M694I mutation (which seems more specific to the Maghreb) and the E148Q mutation (Sephardi Jews). The presence of two identical mutations (homozygote) or two different mutations (double heterozygote) confirms the diagnosis [2].

When the diagnosis is clinically very probable (Table I) [3], direct genotyping can be used to determine whether the diagnosis improbable, but does not allow diagnosis by exclusion.

Differential diagnosis includes other diseases associated with recurring fevers, particularly Still’s disease, Behçet’s disease, hyper-IgD syndrome (mutation of a gene coding for mevalonate kinase) and autosomal dominant familial Hibernian fever caused by missense mutations in the gene encoding type I TNF (TRAPS: TNF receptor associated periodic syndromes) [2].