Ab1804

Mevalonate kinase deficiency and Dutch type periodic fever
J. Frenkel¹, S.M. Houten², H.R. Waterham², R.J.A. Wanders², G.T. Rijkers³, J.L.L.Kimpen¹, R. Duran⁴, B.T. Poll-The⁴, W. Kuis³

Departments of General Pediatrics¹, Pediatric Immunology³, and Metabolic Disorders⁴, Wilhelmina Children's Hospital, University Medical Center, Utrecht; Department of Clinical Chemistry and Pediatrics², Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.

ABSTRACT
Dutch type periodic fever (DPF) is an autosomal recessive hereditary fever syndrome. Cases have been reported worldwide, the majority from France and The Netherlands. From infancy the patients suffer fever attacks that recur every 2-8 weeks, often precipitated by immunizations, infections or emotional stress. Fever lasts 2-7 days and can be accompanied by malaise, headache, diarrhea, abdominal pain, vomiting, skin rashes, arthralgia, arthritis, tender lymphadenopathy, hepatosplenomegaly, and oral and genital ulcers. Labarotory evaluation during fever shows granulocytosis and elevated acute phase reactants.
DPF is caused by a deficiency of the enzyme mevalonate kinase (MK). Besides DPF, the spectrum of MK deficiency includes a severe phenotype, mevalonic aciduria (MA). MA patients have less residual MK activity, leading to substantially higher urinary mevalonic acid excretion than in DPF. Mevalonic aciduria is characterized by mental retardation and dysmorphic features in addition to the clinical features of DPF. At the genomic level, several mutations of varying severity have been identified. The DPF phenotype is caused by one particular mild missense mutation. Most patients are compound heterozygotes for this mutation and a more severe mutation.
The mechanism by which MK deficiency leads to fever is not understood. The vast majority of DPF patients have persistently elevated serum IgD and can be classified as having hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). Conversely, most HIDS patients have MK deficiency and hence DPF, but the two disorders do not overlap entirely.

Key words
Fever, IgD, hypergammaglobulinemia, mevalonate kinase, mevalonic acid, familial Mediterranean fever, periodicity.

Please address correspondence and reprint requests to: Joost Frenkel, MD, Department of General Pediatrics, Wilhelmina Children's Hospital - University Medical Center Utrecht, Home mailbox KE.04.133.1, P.O. Box 85090, 3508AB Utrecht, The Netherlands.
Email j.frenkel@wkz.azu.nl