Familial Mediterranean Fever (FMF) is an inherited autoinflammatory disease characterized by recurrent episodes of fever and serositis. This condition, deeply rooted in genetics and often manifesting across families, presents in two primary phenotypes: type 1 and type 2 FMF. Understanding the nuances of FMF, including its clinical presentations, diagnostic approaches, and management strategies, is crucial for affected individuals and their families. While “Familial Synonym” might not be a direct medical term, it highlights the importance of familial context in understanding and diagnosing genetic conditions like FMF, where shared genetic heritage plays a significant role in disease manifestation and prevalence within certain populations.
Clinical Characteristics of Familial Mediterranean Fever
FMF type 1 and type 2 represent the spectrum of clinical presentations of this genetic disorder.
FMF Type 1 is defined by recurring, short-lived inflammatory attacks. These episodes are marked by fever, peritonitis (inflammation of the abdominal lining), synovitis (joint inflammation), and pleuritis (inflammation of the lining of the lungs). Less frequently, individuals may experience pericarditis (inflammation around the heart) and meningitis (inflammation of the membranes surrounding the brain and spinal cord). The severity and specific symptoms can significantly vary, even among family members sharing the same genetic mutations. A major concern with untreated FMF type 1 is amyloidosis, a condition where abnormal protein deposits can lead to organ damage, most critically kidney failure.
FMF Type 2 is distinguished by the onset of amyloidosis as the first noticeable sign of FMF in an individual who otherwise appears asymptomatic. This form underscores the silent progression of the disease until a severe complication arises.
Diagnosis and Testing for Familial Mediterranean Fever
Diagnosing FMF involves a combination of clinical evaluation and genetic testing. The Tel Hashomer criteria are widely used clinical guidelines that aid in the diagnosis based on major and minor features.
Tel Hashomer Clinical Criteria:
- Major Features: These include recurrent episodes of fever, abdominal pain, chest pain, joint pain, and characteristic skin eruptions.
- Minor Features: These encompass laboratory findings such as elevated erythrocyte sedimentation rate (ESR), leukocytosis (increased white blood cell count), and elevated serum fibrinogen levels, all indicating inflammation.
Confirmation of FMF diagnosis often relies on molecular genetic testing to identify biallelic pathogenic variants in the MEFV gene. Biallelic means that both copies of the gene in an individual have mutations. However, it’s important to note that in up to 25% of FMF cases, genetic testing may only identify a single MEFV pathogenic variant. In cases where molecular testing is inconclusive, a six-month trial of colchicine therapy can be diagnostically helpful. A positive response to colchicine, which reduces the frequency and severity of attacks, can support the diagnosis of FMF.
Management and Treatment Strategies for FMF
The management of FMF focuses on treating acute attacks and preventing long-term complications, particularly amyloidosis.
Treatment of Manifestations: Acute FMF episodes are primarily managed with supportive care. This includes intravenous saline for hydration and pain relief using nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, or dipyrone. NSAIDs can also be used to manage febrile and inflammatory episodes. For individuals who develop end-stage kidney disease due to amyloidosis, routine treatment protocols, including kidney transplantation, are necessary.
Prevention of Primary Manifestations: Lifelong colchicine treatment is often required, especially for individuals homozygous for the p.Met694Val pathogenic variant or compound heterozygotes involving p.Met694Val and another disease-causing allele. Adults typically receive 1-2 mg of colchicine orally per day, while children’s dosage (0.5-1 mg/day) is adjusted based on age and weight. Colchicine is effective in preventing inflammatory attacks and the deposition of amyloid, thus significantly reducing the risk of kidney failure.
Individuals without the p.Met694Val variant and with milder FMF symptoms (infrequent attacks) may be managed with either colchicine or regular monitoring for proteinuria (protein in the urine), an early sign of kidney involvement. Those homozygous or compound heterozygous for p.Glu148Gln should only receive colchicine if they experience severe inflammatory episodes or proteinuria due to amyloidosis. Symptomatic individuals with a heterozygous MEFV pathogenic variant may also benefit from a colchicine trial. For patients unresponsive to standard colchicine, intravenous colchicine or other medications may be considered.
Surveillance and Agents to Avoid
Regular surveillance is critical for all FMF patients, including those on colchicine therapy. Annual physical examinations, urine protein tests, and hematuria (blood in urine) evaluations are recommended. Monitoring acute-phase reactants like ESR and fibrinogen levels during attack-free periods can be particularly useful for individuals with the p.Met694Val variant.
Certain agents and circumstances should be avoided in FMF patients. Cisplatin may potentially worsen FMF symptoms, and cyclosporin A may negatively impact kidney transplant graft survival.
Genetic Counseling and Family Screening
FMF is typically inherited in an autosomal recessive pattern. This means that an individual usually needs to inherit two copies of a mutated MEFV gene (one from each parent) to manifest the condition. However, recent research suggests that some heterozygotes (individuals with only one mutated copy) can also exhibit a spectrum of FMF symptoms, ranging from classic to mild forms.
In families with a history of FMF, molecular genetic testing is recommended for first-degree relatives and other family members, regardless of whether they are symptomatic. This is particularly important when the p.Met694Val allele is present in the family, as early colchicine treatment can prevent renal amyloidosis. Understanding the familial genetic background and offering genetic counseling are crucial steps in managing FMF risk within families. For families with known MEFV pathogenic variants, carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are available options.
Conclusion
Familial Mediterranean Fever is a genetic condition that requires a comprehensive understanding of its clinical variability, diagnostic approaches, and management strategies. The term “familial synonym,” while not a direct medical classification, emphasizes the critical role of familial context in genetic diseases like FMF. Early diagnosis, often guided by clinical criteria and confirmed by genetic testing, followed by appropriate management, particularly colchicine therapy, can significantly improve the prognosis and quality of life for individuals and families affected by FMF. Continuous surveillance and genetic counseling are essential components of long-term care and family planning in FMF.
