Hyper-IgD and periodic fever syndrome (HIDS) was originally described by Jos van der Meer in 1984 as a syndrome of recurrent incapacitating attacks of fever and a number of accompanying inflammatory symptoms, an acute phase response and elevated serum immunoglobulin D and A. Based on genotype and phenotype we now distinguish classic HIDS and variant HIDS – where classic HIDS is caused by mutations in the mevalonate kinase gene, while the cause of variant HIDS is still unclear. The phenotype of variant HIDS differs slightly from and is milder than that of classic HIDS.
Patients with HIDS have recurrent attacks of fever that usually start before the end of the first year of life. An attack is heralded by chills, followed by a sharp rise in body temperature, and lasts for four to six days, with gradual defervescence. It can be provoked by vaccination, minor trauma, surgery, or stress. Cervical lymphadenopathy and abdominal pain with vomiting, diarrhea, or both almost always accompany the attack. Symptoms that are common include hepatosplenomegaly, headache, arthralgias, arthritis of large joints, erythematous macules and papules, and even petechia and purpura. A minority of patients report painful, aphthous ulcers in the mouth or vagina. After an attack, patients are free of symptoms, although skin and joint symptoms disappear slowly. The attacks generally recur every four to six weeks, but the interval between them can vary substantially in an individual patient and from one patient to another. HIDS patients have febrile attacks throughout their lives, although the frequency of attacks is highest in childhood and adolescence. Patients may be free of attacks for months or even years. There have been no published reports of amyloidosis in association with HIDS. As a rule, attacks of arthritis do not lead to joint destruction, but there are exceptions.
HIDS is diagnosed on the basis of characteristic clinical findings and continuously high IgD values (more than 100 IU per milliliter). However, IgD values may be normal in very young patients (those less than three years old), and persistently low levels were reported in a patient with typical clinical findings and the genotype for the syndrome. More than 80 percent of patients have high IgA levels in conjunction with high IgD levels. During an attack, there is a brisk acute-phase response, with leukocytosis, high levels of serum C-reactive protein and serum amyloid A, and activation of the cytokine network.
Classical type HIDS is inherited as an autosomal recessive trait. The frequency of the susceptibility gene is low (ratio of persons with the gene to those without it, in The Netherlands, 1:350). Most HIDS patients are white and are from western European countries; some 60 percent are either Dutch or French.
A genome-wide search established the linkage of the susceptibility gene for HIDS to the long arm of chromosome 12. This information, along with the fortuitous detection of mevalonic acid in a urine sample obtained during a febrile attack in a HIDS patient, led to the identification of mutations in the gene for mevalonate kinase as the cause of the syndrome. Mevalonate kinase is a key enzyme in the cholesterol metabolic pathway and follows 3-hydroxy-3-methylglutaryl–coenzyme A reductase. In classic HIDS patients, the activity of mevalonate kinase is reduced to 5 to 15 percent of normal; as a result, serum cholesterol levels are slightly reduced, and during attacks, urinary excretion of mevalonic acid is slightly elevated.
Most patients are compound heterozygotes for missense mutations in the gene for mevalonate kinase. One mutation, V377I, is present in more than 80 percent of patients; the other mutations are less frequent. The V377I mutation results in a slight reduction of the stability of recombinant human mevalonate kinase protein and in the catalytic activity of the enzyme. Less than 1 percent of patients have a complete deficiency of mevalonate kinase, which is associated with mevalonic aciduria, a rare inherited disorder characterized by developmental delay, failure to thrive, hypotonia, ataxia, myopathy, and cataracts. In mevalonic aciduria, the disease-associated mutations are mainly clustered within a specific region of the protein.
How a deficiency of mevalonate kinase is linked to an inflammatory periodic fever syndrome is not yet exactly known.
Written by: Joost PH Drenth, MD PhD, and Anna Simon, MD PhD
For references: see literature.
Last update: October 27, 2004
