Familial Mediterranean Fever (AR)

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.

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.

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.

Unknown

>= 40 % Unknown Unknown Unknown

Unknown

1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition?
Yes
No
2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways?
Yes
No

a. Patient Management

Yes
No

b. Surveillance or Screening

Yes
No

c. Circumstances to Avoid

Yes
No
3. Is there an intervention that is initiated during childhood (<18 years of age) in an undiagnosed child with the genetic condition?
Yes
No
4. Does the disease present outside of the neonatal period?
Yes
No
5. Is this condition an important health problem?
Yes
No
6. Is there at least on known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population?
Yes
No
Unknown