Hyper IgD syndrome (HIDS) associated with in vitro evidence of defective monocyte TNFRSF1A shedding and partial response to TNF receptor blockade with etanercept

• Published in: Clinical and experimental immunology Vol. 130; no. 3; pp. 484 - 488
• Main Authors: ARKWRIGHT, P. D., MCDERMOTT, M. F., HOUTEN, S. M., FRENKEL, J., WATERHAM, H. R., AGANNA, E., HAMMOND, L. J., MIRAKIAN, R. M., TOMLIN, P. I., VIJAYDURAI, P. I., CANT, A. J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-12-2002; Blackwell; Blackwell Science Inc
• Subjects: Antigens, CD - blood; Antigens, CD - genetics; Biological and medical sciences; Child, Preschool; Clinical Studies; DNA Mutational Analysis; Errors of metabolism; Etanercept; Familial Mediterranean Fever - drug therapy; Familial Mediterranean Fever - genetics; Familial Mediterranean Fever - metabolism; HIDS; Humans; Immunoglobulin G - therapeutic use; Leukocytes, Mononuclear - metabolism; Male; Medical sciences; Metabolic diseases; mevalonate kinase; Mevalonic Acid - urine; Miscellaneous hereditary metabolic disorders; Mutation; Pedigree; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Receptors, Tumor Necrosis Factor - antagonists & inhibitors; Receptors, Tumor Necrosis Factor - blood; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - therapeutic use; Receptors, Tumor Necrosis Factor, Type I; TNFRSF1A; TRAPS; Human; Enzyme; Transferases; Cytokine; Diseases of the osteoarticular system; Clinical form; Male; Case study; Mevalonate kinase; Chemotherapy; Treatment; Etanercept; Gene; Tumor necrosis factor; Familial recurrent polyseritis; Mutation; etanercept HIDS mevalonate kinase TNFRSF1A TRAPS; Child
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1046/j.1365-2249.2002.02002.x

Summary
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.