FMF is clinically diagnosed on the basis of typical attacks with an increased inflammatory response. Livneh et al from Israel, have suggested a set of criteria for diagnosis; however, these have not been validated in other ethnic groups.12 According to these guidelines, there are major and minor criteria as well as supportive criteria. The four major criteria include the typical attacks (≥3 of the same type; rectal temperature ≥38°C; lasting 12 to 72 hours) with peritonitis, pleuritis, monoarthritis (hip, knee, ankle), and fever alone. Minor criteria are defined as incomplete attacks, exertional leg pain, and favorable response to colchcine.12 The definite confirmation or the “gold standard” for diagnosis is the identification of two disease-causing mutations.
When the gene for FMF was identified in 1997, we thought that our problems with diagnosis were over and that we would rely on genetics for diagnosis. However, the experience in Israel and Turkey has shown that we are not able to identify two mutations (which is required to confirm the diagnosis in an autosomal recessive disease), in one-quarter to one-third of the patients. This may be due to the existence of mutations that are not routinely screened or the possibility of mutations in the promoter region of the pyrin gene. However, the explanation may be more complicated due to the contribution of other genetic factors. One also needs to consider the possibility of a wrong diagnosis with the presence of other periodic fever syndromes, discussed below. We were left with the question of what to do with the following type of patient, who has a finding of FMF but does not have genetic evidence of this disease.
Case 2: An 11-year-old boy was referred to us by the local physician with a probable diagnosis of FMF. The boy had had two attacks of fever and severe incapacitating abdominal pain and a recent attack of monoarthritis in the ankle. He occasionally complained of pain in his calf muscles with exercise. A cousin was on dialysis for secondary renal amyloidosis. The boy had no features suggestive of the other autoinflammatory syndromes. We tested him and found him to carry a M680I mutation in a single allele and no mutations in the other. Should we tell him to take colchicine thrice daily for the rest of his life?
This patient has a very strong history for FMF and there is a case of secondary amyloidosis in the family. Our approach would be to test his acute phase reactants and SAA levels and put him on a trial of colchicine. FMF is the only autoinflammatory disease that responds to colchicine. Thus, the trial period with colchicine would be followed by a period of withdrawal of the drug where we observe the symptoms and the SAA levels. We would then decide whether to accept this patient to have familial Mediterranean fever based on this data.
