Case 1: A 10-year-old girl presented to the outpatient department with arthritis of her left ankle, which appeared swollen and red and was very tender laterally. The mother of the girl said that her daughter had experienced similar attacks of arthritis in the recent years. These attacks would usually involve the ankle or knee and would subside in a few days along with the aspirin prescribed by the local physician. The girl’s initial attack had been diagnosed as septic arthritis and her subsequent attacks were diagnosed as acute rheumatic fever. However, the arthritis was not migratory and she continued to have arthritis despite the regular use of penicillin prophylaxis. According to the medical history, the patient had frequently presented to the pediatric clinic with “fever.” During these episodes, she used to stay in bed for a day or so but, despite extensive evaluation, no cause was found.
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Explore This IssueAugust 2008
This is a quite typical case presentation of familial Mediterranean fever (FMF). Despite prototypic manifestations, this condition is frequently misdiagnosed as another disease, such as acute rheumatic fever. FMF is generally diagnosed on the basis of clinical features characterized by recurrent attacks of inflammation: fever and serositis accompanied by elevated levels of acute phase reactants.1-3 Indeed, FMF and other autoinflammatory diseases are on the forefront of differential diagnosis when a child presents with recurrent attacks of arthritis or attacks of inflammation.
As shown by a remarkable series of genetic studies, FMF results from mutations in the gene coding for a protein called pyrin (for the Latin word for fever). The identification of this gene and understanding the functions of the protein opened a new chapter in rheumatology and has led to the molecular definition of a new group of conditions, the auto-inflammatory diseases. This group of rare disorders is characterized by unprovoked inflammatory episodes without high-titer autoantibodies.2 FMF is the most common autoinflammatory disease around the world and the mutations in its gene have the highest carrier rate for this group of diseases.4-6 The reason for such a high carrier rate has been the topic of great interest to investigators, because it suggests the possibility of a selective advantage for certain patterns of inflammatory responses.
FMF is most frequent among Jews (both Sephardim and Ashkenazi), Turks, Armenians, and Arabs. However, cases have been increasingly identified in people from south Italy and Greece.
Etiology and Pathophysiology
In FMF, it is thought that a mutated pyrin is associated with an abnormal activation of the interleukin-1 (IL-1) pathway, resulting in uncontrolled inflammation. This disease can have profound effects on the innate immune pathway.