Pediatric Rheumatology Review - Mevalonate Kinase Deficiency and Dutch Type Periodic Fever

Aug 21, 2026

Dutch type periodic fever (DPF) is an autosomal recessive hereditary fever syndrome affecting infants with recurrent attacks every 2-8 weeks, often triggered by immunizations, infections, or emotional stress. Each fever episode lasts 2-7 days and may involve systemic symptoms and mucocutaneous, gastrointestinal, and joint manifestations. Laboratory evaluation during attacks shows granulocytosis and elevated acute-phase reactants. DPF results from mevalonate kinase deficiency, with genotype-phenotype links to related mevalonic aciduria.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages8

Reading Time20 min

AccessFree to download

Introduction

Disease characterization: clinical attacks and triggers

Etiology: mevalonate kinase deficiency and related disorders

Mechanistic considerations and immunologic patterns

Pediatric rheumatology review | Mevalonate kinase deficiency and Dutch type periodic fever | | --- | | J. Frenkel 1 , S.M. Houten2 , H.R. Waterham2 , R.J.A. Wanders2 , G.T. Rijkers3 ,
J.L.L.Kimpen 1 , 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. Joost Frenkel, MD; SanderM. Houten, MSc; Hans R. Waterham, PhD; Ronald J.A. Wanders, PhD; Ger T. Rijkers, PhD; Jan L.L. Kimpen; Ries Duran, PhD; BweeTien Poll-The, MD, PhD; and Wietse Kuis, MD, PhD. 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](Email j.frenkel@wkz.azu.nl) Clin Exp Rheumatol 2000: 18: 525-532.© Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2000. Key words: Fever, IgD, hypergammaglobulinemia, mevalonate kinase, mevalonic acid, familial Mediterranean fever, periodicity. 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 ofDPF. 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 hyperimmunoglobulinemiaD and periodic fever syndrome (HIDS). Conversely, most HIDS patients have MK deficiency and hence DPF, but the two disorders do not overlap entirely. Introduction The first reports of of children with recurrent febrile attacks in the presence of an abnormally high serum IgD concentration were published in 1984 (1) . The first detailed description of this disorder, was published by van der Meer et al. (2), who introduced the term hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). Most patients have been of Dutch extraction, although cases have been reported worldwide (3). Hence, the disease is also known as Dutch type periodic fever (DPF, MIM\#260920) . Inheritance is autosomal recessive. The first febrile crises usually occur in infancy and recur at varying intervals. The crises are typically triggered by infections and childhood immunizations. In addition to fever the patients often experience malaise, chills, headache, arthralgias, nausea, abdominal pain, and diarrhea, and show cutaneous rashes, hepatosplenomegaly, tender cervical lymphadenopathy, and frank arthritis (3) . Granulocytosis and elevated acute phase reactants during attacks are indicative of an acute inflammatory reaction, but a satisfactory explanation fo

FAQs

What triggers Dutch type periodic fever attacks?

Attacks often begin in infancy and recur every 2-8 weeks. Triggers include immunizations, infections, and emotional stress.

What symptoms and lab findings occur during fever episodes?

Fever lasts 2-7 days and can be accompanied by malaise, headache, gastrointestinal complaints, skin rashes, arthralgia or arthritis, lymphadenopathy, hepatosplenomegaly, and oral or genital ulcers. During attacks, granulocytosis and elevated acute-phase reactants are seen.

How is Dutch type periodic fever related to mevalonate kinase deficiency and mevalonic aciduria?

DPF is caused by mevalonate kinase (MK) deficiency. The broader MK deficiency spectrum includes mevalonic aciduria (MA), which reflects lower residual MK activity and features neurologic and dysmorphic findings in addition to DPF.

Aug 21, 2026

Upload by River Wang