Familial Mediterranean fever

FMF is most commonly inherited in an autosomal recessive manner; affected individuals carry biallelic pathogenic variants in MEFV, and the recurrence risk for siblings of an affected proband is 25%. However, in approximately 25% of patients presenting with FMF symptoms, no second pathogenic variant can be identified across the entire coding region of the MEFV gene.  More recent studies indicate a gene dosage effect of MEFV variants and thus a semi-dominant inheritance. Heterozygous carriers who do not suffer from clinical FMF may exhibit a milder clinical course. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The clinical diagnosis is supported by the , which combine major criteria (typical recurrent febrile attacks with peritonitis, pleuritis or synovitis, AA amyloidosis, favourable response to colchicine) with minor and supportive criteria. Meeting the criteria establishes the clinical diagnosis. The provide an additional, prospectively validated framework for the classification of autoinflammatory recurrent fevers including FMF. No specific biochemical marker or imaging finding is diagnostic; acute-phase reactants are elevated during attacks but are non-specific.

Main differential diagnoses include:

• : autosomal dominant cold-induced attacks of fever, rash, and arthralgia or urticaria, deafness, and renal amyloidosis; NLRP3
• Hyperimmunoglobulinaemia D and (HIDS / mevalonate kinase deficiency): autosomal recessive recurrent fever syndrome with abdominal pain and arthralgia frequently indistinguishable from FMF; differentiation often depends on colchicine response and molecular testing; MVK
• : autosomal dominant recurrent fever syndrome with sterile peritonitis, arthralgia, myalgia, conjunctivitis and rash; distinguished by molecular testing; TNFRSF1A
• PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenopathy): periodic-fever episodes frequently indistinguishable from FMF; molecular testing and close clinical follow-up help establish the correct diagnosis; no causative gene identified to date

• Establishing the diagnosis through identification of the causative pathogenic variant(s).
• Confirming the molecular diagnosis enables specific and individualised surveillance and clinical management, including monitoring for AA amyloidosis, and is a prerequisite for targeted medical care decided by the treating physicians in consultation with the affected individual.
• Identification of the familial pathogenic variant(s) enables predictive testing of at-risk relatives within the framework of human-genetic counselling.

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