Familial Mediterranean Fever

Excerpt

Clinical characteristics: Familial Mediterranean fever (FMF) is divided into two phenotypes: type 1 and type 2.

1. FMF type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to kidney failure, is the most severe complication, if untreated.

2. FMF type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual.

Diagnosis/testing: The diagnosis of FMF is established in a proband with Tel Hashomer clinical criteria of major and minor features. Major features include fever, abdominal pain, chest pain, joint pain, and skin eruption. Minor features include increased erythrocyte sedimentation rate (ESR), leukocytosis, and elevated serum fibrinogen. Identification of biallelic MEFV pathogenic variants on molecular genetic testing confirms the diagnosis. Up to 25% of individuals with FMF have only one MEFV pathogenic variant identified. A six-month trial of colchicine therapy can establish the diagnosis if molecular testing is inconclusive.

Management: Treatment of manifestations: Treatment of an acute episode is mainly supportive, including administration of intravenous saline for hydration and use of nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, or dipyrone for pain relief; treatment of febrile and inflammatory episodes with NSAIDs; routine treatment of end-stage kidney disease, including kidney transplantation.

Prevention of primary manifestations: Homozygotes for the p.Met694Val pathogenic variant or compound heterozygotes for p.Met694Val and another disease-causing allele require lifelong treatment with colchicine (1-2 mg/day orally in adults and 0.5-1 mg/day in children according to age and weight). Colchicine prevents the inflammatory attacks and the deposition of amyloid. Individuals who do not have the p.Met694Val pathogenic variant and who are only mildly affected (those with infrequent inflammatory attacks) should either be treated with colchicine or monitored every six months for the presence of proteinuria. Individuals who are homozygous or compound heterozygous for p.Glu148Gln should only be treated with colchicine if they develop severe inflammatory episodes and/or proteinuria as a result of amyloidosis. Symptomatic individuals with a heterozygous MEFV pathogenic variant may benefit from a trial of colchicine. Individuals who are unresponsive to colchicine may respond to intravenous colchicine or one of several other medications.

Surveillance: Annual physical examination, urine spot test for protein, and evaluation for hematuria for all affected individuals including those treated with colchicine; consider monitoring of acute-phase reactants (ESR and fibrinogen levels) at regular intervals during attack-free periods, particularly in those with the p.Met694Val pathogenic variant.

Agents/circumstances to avoid: Possible worsening of symptoms with cisplatin; possible adverse effect on kidney transplant graft survival with cyclosporin A.

Evaluation of relatives at risk: Offer molecular genetic testing to all first-degree relatives and other family members (regardless of symptoms) especially when the p.Met694Val allele is present because renal amyloidosis can be prevented with colchicine treatment.

Genetic counseling: FMF is usually inherited in an autosomal recessive manner, although recent studies have suggested that some heterozygotes manifest a spectrum of findings from classic FMF to mild FMF. For autosomal recessive FMF: In general, both parents of an affected individual with biallelic MEFV pathogenic variants are unaffected heterozygotes. However, in populations with a high carrier rate and/or a high rate of consanguineous marriages, it is possible that one or both parents have biallelic pathogenic variants and are affected. Symptomatic heterozygotes have also been reported. Thus, it is appropriate to consider molecular genetic testing of the parents of the proband to establish their genetic status. If both parents are heterozygotes, the risk to sibs of inheriting two pathogenic variants and being affected is 25%. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the MEFV pathogenic variants in the family are known.