Familial Mediterranean fever (FMF) is an autoinflammatory disorder characterized by recurrent, self-limited episodes of fever accompanied by serositis, producing inflammation and pain in the abdomen, chest, joints, and muscles. Two clinical phenotypes are documented in GeneReviews: FMF type 1, defined by recurrent inflammatory episodes involving fever, peritonitis, synovitis, pleuritis, and rarely pericarditis or meningitis; and FMF type 2, in which AA-type amyloidosis manifests as the first clinical presentation in an otherwise asymptomatic individual. Certified disease subtypes include autosomal dominant FMF and autosomal recessive FMF.

According to GeneReviews prevalence data, FMF predominantly affects populations originating from the Mediterranean region, including North African Jews, Armenians, Turks, and Arabs, with the causative pathogenic variant found in more than 90 percent of affected individuals of North African Jewish origin. FMF is found across many global populations, though with considerable clinical variability. The certified prevalence estimate is 1 to 5 per 10,000 individuals. Onset is classified as juvenile in this packet.

FMF manifests in episodic inflammatory attacks spanning multiple organ systems. Phenotypes certified in this packet span very frequent (80–99%) and frequent (30–79%) frequency categories.

In the very frequent range, gastrointestinal and constitutional features include abdominal pain, constipation, nausea and vomiting, and fever. Musculoskeletal involvement at this frequency includes arthralgia and myalgia. Fatigue and asthenia are also documented in the very frequent or frequent range.

In the frequent range (30–79%), joint involvement includes arthritis and polyarticular arthritis. Chest involvement is reflected by pleuritis and chest pain. Gastrointestinal features at this frequency include diarrhea. Dermatological manifestations include erysipelas and erythema, each documented in 30–79% of affected individuals.

Hematological and inflammatory markers in the frequent range include increased total leukocyte count and hyperfibrinogenemia, consistent with episodic systemic inflammation. Sleep disturbance, oral leukoplakia, poor appetite, and irritability are certified in the frequent range. Neurological features in the frequent range include seizure and hypoesthesia. Proteinuria is documented in 30–79% of affected individuals, reflecting renal involvement.

Ascites is reported in 5–29% of affected individuals.

The certified packet does not include a structured causative-gene entry in the known-genes field; accordingly, no specific gene name is stated in this section. According to GeneReviews genetic counseling, familial Mediterranean fever is generally inherited in an autosomal recessive manner. For a subset of affected individuals, the family history is consistent with autosomal dominant inheritance, with heterozygous individuals manifesting findings across a phenotypic spectrum from mild to classic. Certified disease subtypes reflect this dual inheritance architecture. GeneReviews genotype-phenotype data documents that individuals with certain homozygous variant profiles have earlier onset, higher frequencies of arthritis and arthralgia, and greater risk of amyloidosis.

According to GeneReviews diagnostic guidance, FMF is suspected in individuals presenting with recurrent febrile episodes accompanied by peritonitis, synovitis, or pleuritis; recurrent erysipelas-like erythema; repeated laparotomies for acute abdomen with no pathology identified; amyloidosis of AA type developing after age 15 in untreated individuals even without a history of inflammatory attacks; a favorable response to continuous colchicine treatment; a first-degree relative with FMF; or membership in an at-risk ethnic population.

The minimum current clinical diagnostic standard referenced in GeneReviews is the Tel Hashomer clinical criteria. Molecular testing identifying biallelic pathogenic variants in the disease-associated gene can confirm the diagnosis when clinical features are inconclusive. A six-month colchicine therapy trial is described in GeneReviews as an approach that can support the clinical diagnosis. Evaluation following diagnosis includes physical examination for joint problems and urinalysis for proteinuria; if proteinuria is found, GeneReviews evaluation guidance specifies further assessment for amyloid, including 24-hour urinary protein measurement and kidney function testing.

Multiple FDA-approved therapies are certified in this packet. Colchicine is certified in three active formulations: COLCRYS (approved July 2009), MITIGARE (approved September 2014), and GLOPERBA (approved January 2019). ILARIS (canakinumab) is certified as an FDA-approved biologic therapy for FMF, approved June 2009.

According to GeneReviews management guidance, colchicine is used for the prevention of inflammatory attacks and for preventing amyloid deposition; GeneReviews specifies that colchicine is not effective as treatment during an acute FMF episode itself. GeneReviews describes acute episodes as managed with nonsteroidal anti-inflammatory agents and analgesics. End-stage kidney disease resulting from renal amyloidosis is addressed through renal replacement therapy; GeneReviews management notes that outcomes of live related-donor kidney transplantation in FMF-associated amyloidosis are similar to the general transplant population.

Agents identified in GeneReviews as warranting avoidance in affected individuals include cisplatin, which is reported to worsen FMF symptoms, and cyclosporin A, which is documented to adversely affect kidney transplant graft survival in individuals with FMF and may trigger inflammatory attacks.

Orphan-designation records are present for goflikicept and rilonacept, both designated for FMF; these records do not establish FDA approval or current availability for these agents in FMF.

The most severe documented complication of untreated FMF type 1 per GeneReviews is amyloidosis of AA type, which can progress to kidney failure. GeneReviews genotype-phenotype data notes that individuals with certain homozygous molecular profiles have higher risk for amyloidosis and reduced response to colchicine, while amyloidosis occurs less frequently in individuals with other variant profiles. GeneReviews surveillance guidance specifies that all individuals with FMF, including those not currently treated, undergo annual physical examination and urine monitoring for protein, with additional monitoring of acute-phase reactants at regular intervals during attack-free periods for individuals with higher-risk profiles.

Several active trial records are certified for familial Mediterranean fever, with 27 active records documented. Certified records include a long-running genetics and disease characteristics study at the National Human Genome Research Institute (NCT00001373); a Phase 4 study of anakinra in colchicine-resistant FMF in Chinese patients (NCT06666335, Swedish Orphan Biovitrum); observational studies examining efficacy and safety of various drug regimens in real-world FMF cases (NCT07077473); studies assessing cardiometabolic markers and advanced glycation end products in FMF (NCT07329556, NCT07439341); studies on dietary, exercise, and body composition interventions in FMF populations; and a quality of life and electrocardiographic study in children with FMF (NCT07128225). The research landscape digest for FMF documents 360 total classified publications, with epidemiology and natural history as the dominant research type and 67 review articles. Biomarker and recent trial publication activity are also represented.