Abstract
Periodic fevers are characterized by prolonged periodic fever attacks, associated in some cases with peritonitis, pleurisy, arthritis, skinrash, conjunctivitis or systemic amyloidosis. Recently, the genetic cause of some entities was found and the group of periodic fever syndrome was roughly divided into autosomal recessive and autosomal dominant states.
Familial Mediterranean Fever (FMF) and Hyper IgD syndromes belong among autosomal recessive disorders. The genes for both entitieswere discovered 1997 and 1999, respectively, in the course of the Human Genome Project.
Gene modified in FMF is called MEFV and codes for protein pyrin, sometimes referred as manetostrin. Pyrin is expressed mainly in granulocytes and monocytes, the fever is caused by alteration in IL-1 regulation.
Hyper IgD syndrome is surprisingly caused by mutations in gene coding for mevalonate kinase, an enzyme involved in the cholesterol biochemical pathway. The detailed mechanism of fever pathogenesis is in that case unknown.
Autosomal dominant periodic fevers are grouped under the name TRAPS, TNF receptor-associated periodic syndromes. Individual case-reports known originally for example as Familial Hybernian Fever or Familial Periodic Fever are now included into the TRAPS group according to the genetical analysis in the affected families.
Mutated gene codes the subunit of the receptor for TNF, called now TNFSF1A. The probable cause of fever attacks is the diminished shedding of membrane bound receptor, causing low level of the soluble form which under normal circumstances might links with free TNF.
Blockade of TNF is thus one of the new possible therapeutical options. We followed over the last 5 years 12 children with periodic fever syndromes.
Even if the clinical characteristics differed among patients, all of them suffered from repeated attacks of fevers, lasting for at least one year. We systematically followed IgD and the level of mevalonic acid in children with suspected hyper IgD syndrome and soluble TNF receptor in children suspected for TRAPS.
Molecular diagnosis was until now performed in 5 children, hyper IgD syndrome was confirmed in 3 patients, critical exons 2, 3 and 4 ofTNFR1 gene were sequenced in another 2 children with clinically suspected TRAPS but no mutation was found in these patients.