title: Hyper IgD syndrome (HIDS) associated with in vitro evidence of defective monocyte TNFRSF1A shedding and partial response to TNF receptor blockade with etanercept.
abstract: Hereditary periodic fever syndromes comprise a group of distinct disease entities linked by the defining feature of recurrent febrile episodes. Hyper IgD with periodic fever syndrome (HIDS) is caused by mutations in the mevalonate kinase (MVK) gene. The mechanisms by which defects in the MVK gene cause febrile episodes are unclear and there is no uniformly effective treatment. Mutations of the TNFRSF1A gene may also cause periodic fever syndrome (TRAPS). Treatment with the TNFR-Fc fusion protein, etanercept, is effective in some patients with TRAPS, but its clinical usefulness in HIDS has not been reported. We describe a 3-year-old boy in whom genetic screening revealed a rare combination of two MVK mutations producing clinical HIDS as well as a TNFRSF1A P46L variant present in about 1% of the population. In vitro functional assays demonstrated reduced receptor shedding in proband's monocytes. The proband therefore appears to have a novel clinical entity combining Hyper IgD syndrome with defective TNFRSF1A homeostasis, which is partially responsive to etanercept.
authors.affiliation: Academic Unit of Child Health, St Mary's Hospital, Manchester, UK. peter_arkwright@lineone.net
authors.forename: P D
authors.initials: PD
authors.lastname: Arkwright
authors.forename: M F
authors.initials: MF
authors.lastname: McDermott
authors.forename: S M
authors.initials: SM
authors.lastname: Houten
authors.forename: J
authors.initials: J
authors.lastname: Frenkel
authors.forename: H R
authors.initials: HR
authors.lastname: Waterham
authors.forename: E
authors.initials: E
authors.lastname: Aganna
authors.forename: L J
authors.initials: LJ
authors.lastname: Hammond
authors.forename: R M
authors.initials: RM
authors.lastname: Mirakian
authors.forename: P I
authors.initials: PI
authors.lastname: Tomlin
authors.forename: P I
authors.initials: PI
authors.lastname: Vijaydurai
authors.forename: A J
authors.initials: AJ
authors.lastname: Cant
mesh_terms: D015703:Antigens, CD / Q000097:blood / Q000235:genetics*; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D000068800:Etanercept; D010505:Familial Mediterranean Fever / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000652:urine; D009154:Mutation; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics* / Q000627:therapeutic use*; D047888:Receptors, Tumor Necrosis Factor, Type I
chemical_list: D015703:Antigens, CD; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D000068800:Etanercept; D008798:Mevalonic Acid