Mevalonate kinase deficiency and Dutch type periodic fever

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 DPE, 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 DPE 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 lends 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.