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Much progress has been made over the last two decades in elucidating the molecular mechanisms and pathogenesis of the hereditary fever syndromes. Patients with hereditary fever syndromes have recurrent febrile attacks that may be weeks, months, or years apart. The precipitants of these febrile episodes are not well characterized. There are three well-established periodic fever syndromes at this point.Familial Mediterranean Fever is an inherited autosomal recessive disease that is most common in people of eastern Mediterranean descent, such as Armenians, Sephardic Jews, Arabs, and Turks. It usually manifests before the age of 20 years, and patients typically present with periodic attacks of fever and serositis (peritonitis, pleuritis, or arthritis) that last for several days. The symptoms of serositis often predominate. Diagnosis is based on molecular genetic analysis, and this is important to establish because treatment with colchicine decreases the incidence of subsequent amyloidosis in these patients.The hyper IgD syndrome is seen in western Europeans, most commonly the Dutch and French, and is also inherited in an autosomal recessive pattern. During attacks, patients have chills and high fevers that typically last for 4 to 6 days. Cervical lymphadenopathy and abdominal pain with vomiting and diarrhea usually accompany attacks. In the large majority of patients, symptoms begin in the first year of life, although it is possible for a patient to evade diagnosis for many years. The serum IgD level is typically elevated in this syndrome and should be checked in a young person of European descent as part of a recurrent fever work-up. The genetic defect is in the mevalonate kinase enzyme of the cholesterol metabolism pathway. During attacks, levels of this enzyme are elevated in the urine and can be determined to corroborate with the diagnosis.The tumor necrosis factor receptor-associated periodic syndrome was first known as Familial Hibernian Fever, after its initial description in a large Irish family. It has since been seen in a number of ethnic cohorts. The syndrome is inherited in an autosomal-dominant pattern and usually manifests before the age of 20 years. Unlike the prior diseases, attacks can vary in length from 1 day to longer than 1 week. More than 80% of patients experience pain and tightness of local muscle groups. Abdominal pain, gastrointestinal symptoms, a macular rash, and painful conjunctivitis arc other prominent features. Genetic sequencing is the recommended method for definitive diagnosis. The disease is steroid responsive, but it is unclear whether treatment with etanercept, a tumor necrosis factor-a antagonist, will decrease the incidence of long-term complications.*157/348/5*