The symptoms of this syndrome usually first appear in during childhood or adolescence, with 90 % of patients having had onset by age 20 years [4] (see Table 43.1). FMF attacks are classically of short duration, lasting between 12 and 72 h, and consist of inflammation involving the peritoneum, pleura, joints, and/or skin. Patients may complain of severe abdominal pain that may be confused with the pain associated with appendicitis [5]. During an episode they often complain of constipation, secondary to the peritoneal inflammation leading to a temporary paralytic ileus, followed by diarrhea as the inflammation fades. Pleural pain is usually unilateral, occurring with decreased breath sounds. Arthralgia is more common than true arthritis [6]. Arthritis in adults is usually monoarticular; however, in children it may involve several joints with pain and large effusions [7]. Synovial aspirates are sterile but may demonstrate leukocyte counts as high as 100,000/mm³. Muscle pain occurs in about 20 % of patients and often appears in the lower extremities after physical exertion and subsides with rest. The most common skin manifestation is an erysipeloid erythematous rash on the dorsum of the foot, ankle, or lower leg. Findings less commonly seen in patients with FMF include episodes of unilateral acute scrotal pain in prepubescent boys. The latter is more often seen in children with Henoch-Schönlein purpura and polyarteritis nodosa. Between episodes patients are usually asymptomatic.

During attacks, increased levels of acute-phase reactant, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum amyloid A (SAA), and leukocytosis, are seen [5]. Persistent elevation of these acute-phase reactants between episodes predisposes the patient to the development of AA systemic amyloidosis, the most serious complication of FMF. Kidneys are usually the first organ involved with AA amyloidosis, and this is associated with proteinuria. Therefore it is prudent to obtain routine urinalysis at least yearly to look for proteinuria.

Testing for genetic mutations in the MEFV gene is a valuable adjunct to clinical diagnosis. More than 50 mutations have been described in MEFV (http://​fmf.​igh.​cnrs.​fr/​infevers/​) as well as a much larger number of sequence variants that are likely not pathogenic. The majority of FMF-related mutations are found in exon 10, and the most common mutations are the substitutions of valine or isoleucine for methionine at residue 694 (M694Vand M694I, respectively), the substitution of isoleucine for methionine at residue 680 (M680I) and the substitution of alanine for valine at residue 726 (V726A). A number of missense substitutions that are considered benign polymorphisms or mild mutations can be found in exon 2 of MEFV. The most notable is the substitution of glutamine for glutamic acid at residue 148 (E148Q). It is important to note that the frequency of E148Q is increased in the Indian population, and a corresponding increase of clinical FMF is not seen. FMF has been thought to be an autosomal recessive disease, thus two genetic mutations are typically found; however, 30 % of patients have only one demonstrable mutation [8]. A diagnosis of FMF should not be excluded based solely on the results of genetic testing; however a combination of clinical evaluation, family history, and genetic testing is the most sensible diagnostic approach.

Treatment with colchicine is highly effective for most patients in preventing febrile episodes and systemic amyloidosis. Daily therapy is more effective in controlling the attacks of FMF than intermittent treatment at the time of attacks. Daily therapy also has the added advantage of reducing the subclinical inflammation between episodes and potentially prevents or limits the development of amyloidosis. Colchicine is generally safe in children. Dosage should be started as low as possible (one half of a 0.6 mg tablet once daily in children) and slowly increased, titrating to maximize efficacy and minimize side effects, but usually not exceeding 1.8 mg/day in single or divided doses. This gradual increase in dose helps to prevent or lessen diarrhea, the most common side effect of colchicine. Some patients develop lactose intolerance due to colchicine, and a lactose-free diet may help to control the gastrointestinal symptoms. Intravenous colchicine is never indicated. Based on the role of pyrin in IL-1 activation, IL-1 inhibitors have been increasingly used in FMF patients who are unresponsive to or cannot tolerate therapeutic doses of colchicine. Studies using IL-1 inhibitors in FMF are underway.

The clinical manifestations of TRAPS are similar to those of FMF with episodic fever and inflammation with serosal, synovial, and cutaneous manifestations (see Table 43.1). Certain features distinguish TRAPS from other periodic fever syndromes including longer attacks (1–4 weeks or more) and eye (periorbital edema or conjunctivitis) and skin (macular areas of erythema) symptoms. The skin lesions are warm and tender and may resemble cellulitis and, when they occur on the limbs, may migrate distally. There may be associated myalgia due to inflammation of the underlying fascia. Clinical attacks may include peritoneal inflammation or pleurisy or both. Abdominal pain may resemble an acute abdomen. Arthralgia is more common than arthritis. It is estimated that 10–25 % of patients with TRAPS may develop amyloidosis.

Levels of acute-phase reactants (CRP, sedimentation rate, and SAA) are increased during flares, and most patients exhibit leukocytosis and thrombocytosis during a flare. Acute-phase reactants may remain elevated in between clinical attacks, suggesting an elevated level of baseline inflammatory activity. The specific diagnosis is defined by mutations in TNFRSF1A. The majority are single-nucleotide missense mutations in exons 2–4 encoding the first of second cysteine-rich extracellular domains (CDR1 and CDR2). Mutations at cysteine residues are associated with a more severe phenotype and a higher incidence of amyloidosis [10]. It is thought that these cysteine residues participate in assembly of disulfide bonds important for TNFR1 folding and disruption of these bonds affects protein folding.

Two TNFRSF1A variants, P46L and R92Q, have been identified in asymptomatic individuals and may be found at greater than 1 % frequency in healthy populations [11]. These variants do not lead to the same signaling abnormalities associated with more severe mutations, raising the question of whether they are mild mutations or functional polymorphisms.

Treatment depends on the severity of the underlying disease. For some patients with infrequent episodes, intermittent tapering doses of prednisone at the time of attacks may be effective and relatively safe [10]. For patients with more severe disease, etanercept (the recombinant TNF receptor antagonist), given weekly, is effective in preventing attacks in some patients [10]. Treatment with anti-TNF monoclonal antibodies (e.g., infliximab) has led to exacerbation of disease in some cases and should be avoided. IL-1 inhibition has also been shown to be an effective therapy in TRAPS. Colchicine usually has no effect on symptoms or the development of amyloidosis.