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.

Fig. 1

Pedigree of family showing the segregation of both the TNFRSF1A variant and MVK mutations. The normal gene sequences are represented as WT (wild-type). The proband (II-1), who has the P46L TNFRSF1A variant, is a compound heterozygote for MVK mutations (V377I and G211A) is the only symptomatic family member (shaded box).

Fig. 2

Clinical response of proband to etanercept therapy over a 12-month period. Filled boxes at the right of the figure indicate continuous treatment with etanercept at 0·4 and then 0·8 mg/kg/dose twice weekly. Arrows indicate extra etanercept boluses (0·8 mg/kg/dose).