Objective. To characterize the frequency, clinical signs, and genotypic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a series of 394 patients of various ethnic origins who have recurrent inflammatory syndromes.Methods. Sequencing of the coding region of the TNFRSF1A gene was performed in 128 patients in whom there was a high suspicion of TRAPS, and denatured high-performance liquid chromatography was used to systematically screen for TNFRSF1A in 266 patients with recurrent inflammatory syndrome and no or only 1 Mediterranean fever gene (MEFV) mutation.Results. TNFRSF1A mutations were found in 28 (7.1%) of 394 unrelated patients. Nine (32%) of the 28 patients had a family history of recurrent inflammatory syndromes. In 13 patients, the length of the attack of inflammation was fewer than 5 days. Three of the mutations (Y20H, L67P, and C96Y) were novel. Two mutations, R92Q and (mainly) P46L, found in 12 and 10 patients, respectively, had lower penetrance compared with other mutations. TNFRSF1A mutations were found in patients of various ethnic origins, including those at risk for familial Mediterranean fever (FMF): Armenians, Sephardic Jews, and especially Arabs from Maghreb. Only 3 (10.7%) of the 28 patients had amyloidosis.Conclusion. TRAPS is an underdiagnosed cause of recurrent inflammatory syndrome. Its presence in the population of persons of Mediterranean ancestry and the short duration of the attacks of inflammation can lead to a fallacious diagnosis of FMF. Because an accurate diagnosis in patients with recurrent inflammatory syndromes is crucial for proper clinical management and treatment, genetic screening for TNFRSF1A is warranted.

Hepcidin is a 25-amino acid peptide involved in iron homeostasis in mice and humans. It is produced in the liver from a larger precursor, and it is detectable in blood and urine. In contrast to the human genome, which contains only one copy of the gene, the mouse genome contains 2 highly similar hepcidin genes, hepc1 and hepc2, which are, however, considerably divergent at the level of the corresponding mature 25-amino acid peptide. This striking observation led us to ask whether hepc1 and hepc2 performed the same biologic activity with regard to iron metabolism in the mouse. We recently described the severe iron-deficient anemia phenotype in transgenic mice overexpressing hepc1 in the liver. Here we report that, in contrast to the hepc1-transgenic mice, none of the 7 founder hepc2-transgenic animals suffered from anemia. They all developed normally with hematologic parameters similar to the nontransgenic littermates. Hepc2 transgenic mRNA level was found to be very high for all lines compared with the level of hepc1 transgene mRNA necessary to produce severe anemia. These data provide evidence that hepc2 does not act on iron metabolism like hepc1 and give clues for the identification of amino acids important for the iron-regulatory action of the mature 25-amino acid peptide. IntroductionHepcidin, a liver-specific regulatory peptide, was recently demonstrated to play a key role in regulating iron homeostasis. Although not demonstrated, hepcidin is likely acting on iron metabolism by limiting intestinal iron absorption and iron release from macrophages (for reviews, see Nicolas et al 1 and Ganz 2 ). This function is fundamental for maintaining iron homeostasis, in particular to avoid accumulation of excess iron that leads to organ dysfunction. This is the case in hereditary hemochromatosis (HH), a prevalent genetic disorder of iron hyperabsorption leading to hyperferremia, tissue iron deposition, and complications including cirrhosis, hepatocellular carcinoma, heart disease, endocrinopathies, and diabetes (for review see Fleming and Sly 3 ). Most patients with HH are homozygous for a missense mutation C282Y in the atypical major histocompatibility complex (MHC) class I molecule HFE. 4 A more severe form of the disease, known as juvenile hemochromatosis (JH), is characterized by rapid iron loading and clinical presentation of hypogonadism and cardiomyopathy at a young age. 5 The major responsible gene is linked to chromosome 1q21 but it has not yet been identified. Recently, 2 families with homozygous mutations of the hepcidin gene on chromosome 19 have been reported. 6 The affected individuals presented all the clinical signs of JH, which highlights the irreplaceable regulatory role of hepcidin in maintaining iron balance in humans. In mice, complete hepcidin deficiency has also been reported to be associated with a severe iron overload phenotype. 7 Interestingly, along with the uncommon JH due to complete hepcidin deficiency, partial hepcidin deficiency has been described in the most common form of HFE-related ...