Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

GENE/GENE PANEL: MEFV
Condition: Familial Mediterranean Fever (AR)
GENEDISEASE PAIRS: MEFV249100
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Familial Mediterranean Fever (FMF) predominantly affects populations living in the southeastern Mediterranean region. Populations having a high prevalence (1/200-1/1000) include non-Ashkenazi Jews, Armenians, Turks, and Arabs. FMF is also seen in many other countries, although in much lower numbers.
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Clinical Features
(Signs / symptoms)
FMF is an autoinflammatory fever syndrome characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritic, and, rarely, pericarditis and meningitis. Attacks can vary in frequency (as often as once a week or every few years), typically last 1-4 days, and resolve spontaneously. Mild symptoms (myalgia, headache, nausea, dyspnea, arthralgia, low back pain, asthenia and anxiety) precede attacks and last about 17 hours in approximately 50% of patients. Attacks manifest as fever, diffuse or localized abdominal pain, constipation or diarrhea, arthralgias (in large joints), arthritis (in upper/lower limb/knee joints) chest pain caused by pleuritis and/or pericarditis, and skin eruption. Joint attacks can result in severe damage to the joint and permanent deformity may require joint replacement. The main long-term complication is amyloid A (AA) amyloidosis, which is common in untreated individuals, can lead to renal failure, and has a poor prognosis. Untreated individuals with FMF, especially those with multiple attacks and/or amyloidosis, are at higher risk for infertility.
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Natural History
(Important subgroups & survival / recovery)
Disease onset usually occurs before the age of 30 (approximately 90% before age 20) with an earlier onset corresponding to a more severe phenotype. Recurrent fever manifests during early childhood and may be the only manifestation. A Type 2 version of FMF has been described that is characterized by amyloidosis as the first clinical manifestation in an otherwise asymptomatic individual. However, some experts believe these cases are previously undiagnosed, milder forms of the disorder. In addition, a Type 3 phenotype has been recently described in which individuals with two pathogenic variants do not express any clinical manifestations. There are no long-term follow-up studies of patients with this phenotype, and thus their outcome cannot be predicted (e.g., development of secondary amyloidosis). Furthermore, no data exist to know whether these individuals have elevated acute phase reactants despite the lack of clinical manifestations.
 
Presentation of clinical features, particularly amyloidosis, can vary across genotypes, ethnicities, and geographical region. Patients who are homozygous for the M694V variant (or other pathogenic variants at position 680-694 on exon 10) or compound heterozygous with a M694V (or other pathogenic variant at position 680-694 on exon 10) and other pathogenic variant typically have a more severe phenotype, with an earlier age of onset and higher frequencies of arthritis and arthralgia than persons who are homozygous or compound heterozygous for other pathogenic variants. M694V mutations are also the most frequency genotype associated with amyloidosis. The association between M694V homozygosity and amyloidosis is less significant among Turkish patients compared to Armenians, Israelis, and Arabians. Amyloidosis is particularly common in the Jewish population of North African origin. In untreated individuals, amyloidosis can occur in 60% of individuals of Turkish heritage and in up to 75% of North African Jews. The age of onset of FMF attacks appears to be earlier in persons with amyloidosis than in those without amyloidosis. FMF-related manifestations of chest pain, arthritis, and erysipelas-erythema are more common in those with amyloidosis. Long periods between disease onset and diagnosis are associated with a high risk of developing amyloidosis. Patients in Western countries are less likely to develop amyloidosis, despite their ethnicities or genotype.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with FMF, the following evaluations are recommended:
 
• Physical examination to assess joint problems
 
• Urinalysis for the presence of protein. If proteinuria is found, further evaluation is required, including 24-hour urinary protein assay and renal function tests, and also, if indicated, rectal biopsy for the presence of amyloid.
 
• Medical genetics consultation. (Tier 4)
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Treatment with colchicine should be started as soon as a clinical diagnosis is made. Colchicine is very efficacious in preventing FMF attacks and associated amyloidosis. A systematic review on treatment of FMF identified three studies on the prophylactic use of colchicine (n=48). Overall, colchicine was found to consistently reduce the rate and severity of FMF attacks; however, these studies were found to be of low quality. In the first study (n=11), during the course of colchicine, compared to the course of placebo, patients reported fewer attacks (7 vs. 38 attacks, respectively; p<0.001) and milder attacks (p<0.002). In the second study (n=22), patients reported fewer attacks when on colchicine compared to receiving placebo (mean of 1.15 vs 5.25 per patient, respectively; p<0.01) during the first 2 months of treatment, though the risk ratio was not significant (risk ratio: 0.78 (95% CI: 0.49 to 1.23)). A third study (n=15), patients reported fewer attacks on colchicine compared to placebo (5 vs. 59 attacks, respectively; p<0. 002) with a risk ratio of 0.21 (95% CI: 0.05 to 0.95). (Tier 1)
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In addition, colchicine is the only current treatment for the prevention of secondary amyloidosis in FMF. A longitudinal study indicated that of the 960 patients on colchicine who had no evidence of amyloidosis, only 4 who adhered to the prophylactic schedule developed proteinuria, while 16 of the 54 who admitted non-compliance developed proteinuria. (Tier 2)
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Surveillance
Individuals homozygous for M694V who do not report symptoms, should be evaluated and followed closely in order to consider therapy. (Tier 2)
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For individuals with two pathogenic mutations for FMF who do not report symptoms, if there are risk factors for AA amyloidosis (e.g., country, family history, and persistently elevated inflammatory markers (particularly serum amyloid A protein)), close follow-up should be started and treatment considered. (Tier 2)
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All individuals with FMF, including those not currently being treated, those being treated with colchicine, and those receiving medication other than colchicine should undergo an annual physical examination, a urine spot test for protein, and an evaluation for hematuria. (Tier 3)
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Monitoring of acute-phase reactants (ESR and fibrinogen levels) at regular intervals during attack-free periods is recommended, particularly in those with the M694V variant. (Tier 3)
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Family Management
Routine genetic testing for MEFV mutations is not recommended in siblings of an index case. However, parents or siblings should be made aware of clinical signs of FMF in order to give them the possibility of seeking advice from a physician in case of suspected symptoms. In cases where the parents of a patient are very concerned about their other children, screening for acute phase reactants can be done. In case of elevated inflammatory markers on two successive blood tests in totally asymptomatic individuals, genetic testing should be considered, as elevated acute phase reactants may unveil a hidden disease. (Tier 2)
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Circumstances to Avoid
A single report has suggested that cisplatin worsens symptoms of FMF. (Tier 3)
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Cyclosporin appears to adversely affect renal transplant graft survival in individuals with FMF. It has also been reported to trigger FMF attacks, which responded well to colchicine in a previously asymptomatic individual with myelodysplastic syndrome who was heterozygous for the MEFV pathogenic variant M694I. (Tier 3)
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3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
 
Prevalence of Genetic Mutations
No information on the frequency of MEFV mutations in the general population was identified.
 
Pathogenic variants in MEFV are detected in more than 90% of all cases of FMF. The pathogenic variant M694V is found in more than 90% of affected Jewish persons of North African origin. (Tier 4)
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About 85% of patients of Mediterranean origin that meet clinical criteria have a mutation in both copies of the MEFV gene, with only one mutation identified in about 20% of affected cases. (Tier 3)
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Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on penetrance in a population defined by genotype alone was not identified. The following prevalence figures are based on individuals with a clinical diagnosis of FMF:
 
Abdominal attacks = 90%
 
Articular attacks = 75%
 
Cutaneous involvement = 7-40%
 
Protracted arthritic attacks = 5%
 
Prodrome = 50%
 
Pleural attacks = 45%. (Tier 4)
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Genetic and non-genetic factors appear to affect the rates of amyloidosis in FMF. A study of patients from 14 countries found amyloidosis in 260/2277 (11.4%) patients. The country of recruitment was the most important determinant of risk for development of amyloidosis, followed by the presence of homozygous M694V variants in Armenian, Israelis and Arabian patients. However, another study of 100 Armenian FMF patients living in the USA found no cases of amyloidosis, although M694V was demonstrated to be the most frequent MEFV mutation. (Tier 3)
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Information on the prevalence of mutations was not available.
 
 
 
Information on the prevalence of mutations was not available.
 
 
 
Information on the prevalence of mutations was not available.
 
 
 
Information on relative risk was not identified.
 
 
Expressivity
Symptoms and severity vary among affected individuals, even among members of the same family suggesting that manifestations are also influenced by other genes and/or environmental factors. (Tier 4)
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4. What is the Nature of the Intervention?
Nature of Intervention
Colchicine toxicity is a serious complication that should be given adequate consideration and be prevented. Colchicine is an alkaloid with a narrow therapeutic range. High concentrations may cause serious toxicity that can be life threatening. Complications of colchicine use occasionally include myopathy and toxic epidermal necrolysis-like reaction. Colchicine treatment may induce oligospermia/azoospermia. Other identified interventions include blood and urine tests, associated with low burden and risk.
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5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Symptoms associated with FMF (e.g., fever, pain) are not specific and may not direct the correct diagnosis.
 
 
 

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Recurrent serositis / Colchicine
2
3C
3A
2
10CA
Amyloidosis / Colchicine
2
2C
3B
2
9CB
Joint problems / Colchicine
2
3C
3A
2
10CA
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Giancane G, Ter Haar NM, Wulffraat N, Vastert SJ, Barron K, Hentgen V, Kallinich T, Ozdogan H, Anton J, Brogan P, Cantarini L, Frenkel J, Galeotti C, Gattorno M, Grateau G, Hofer M, Kone-Paut I, Kuemmerle-Deschner J, Lachmann HJ, Simon A, Demirkaya E, Feldman B, Uziel Y, Ozen S. Evidence-based recommendations for genetic diagnosis of familial mediterranean fever. Ann Rheum Dis. (2015) 74(4):635-41.
2. Witsch-Baumgartner M, Touitou I. Clinical utility gene card for: prototypic hereditary recurrent fever syndromes (monogenic autoinflammatory syndromes). Eur J Hum Genet. (2015) 23(8).
3. Familial Mediterranean fever. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=342
4. Wu B, Xu T, Li Y, Yin X. Interventions for reducing inflammation in familial mediterranean fever. Cochrane Database Syst Rev. (2015)
5. M Shohat. Familial mediterranean fever. 2000 Aug 08 [Updated 2016 Dec 15]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1227
6. Hentgen V, Grateau G, Kone-Paut I, Livneh A, Padeh S, Rozenbaum M, Amselem S, Gershoni-Baruch R, Touitou I, Ben-Chetrit E. Evidence-based recommendations for the practical management of familial mediterranean fever. Semin Arthritis Rheum. (2013) 43(3):387-91.
7. Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G, Ozdogan H, Abu I, Gattorno M, Hawkins PN, Yuce S, Kallinich T, Bilginer Y, Kastner D, Carmona L. Eular recommendations for the management of familial mediterranean fever. Ann Rheum Dis. (2016) 75(4):644-51.
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