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Hyper IgD syndrome

Synonyms of Hyper IgD syndrome

  • hyperimmunoglobulinemia D with periodic fever

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Hyper IgD syndrome (HIDS) is a rare inflammatory genetic disorder characterized by periodic episodes or "attacks" of fever associated with additional symptoms including joint pain (arthralgia), skin rash and abdominal pain. Most episodes last several days and occur periodically throughout life. The frequency of episodes and their severity vary greatly from case to case. HIDS is associated with decreased activity of the enzyme mevalonate kinase (MVK). Although many factors can set off a characteristic HIDS episode (e.g., minor infections), most episodes occur without a distinct precipitating event. HIDS is inherited as an autosomal recessive trait.


HIDS is characterized by recurrent episodes of fever of unknown origin. These episodes are accompanied by fatigue, chills, abdominal pain, swelling of affected lymph nodes (lymphadenopathy), a rash, joint inflammation (arthritis) and pain (arthralgia). Additional symptoms include nausea, diarrhea, vomiting, headaches, small ulcers in the mouth, and abnormal enlargement of the liver and spleen (hepatosplenomegaly). The skin rash associated with HIDS consists of reddish (erythematous) spots (macules) or bumps (papules).

The specific symptoms present during an episode and their severity vary from person to person. For an affected individual, the severity of individual episodes also varies. Episodes usually last for three to seven days, but can be shorter or longer. The frequency of episodes varies greatly. Some individuals have an episode every month, some more frequently and others less frequently. The frequency of episodes may also increase or decrease during a person's life. Between episodes individuals with HIDS do not display symptoms.

HIDS is often more severe in children. Affected children often have a high spiking fever that, in some cases, can cause convulsions. Children are also more likely to have an abnormally enlarged spleen (splenomegaly). Episodes occur more frequently in children than adults.

Individuals with HIDS have abnormally high levels of immunoglobulin IgD in the fluid portion (serum) of the blood (thus, the term hyper IgD). Immunoglobulins are proteins produced by certain white blood cells. There are five classes of immunoglobulins known as IgA, IgD, IgE, IgG, and IgM. Immunoglobulins play a role in defending the body against foreign substances or microorganisms by destroying them or coating them so they are more easily destroyed by white blood cells. While the specific function of other immunoglobulins is well-known, the specific function of IgD within the immune system is unknown.

Episodes of fever may be set off minor "triggers" such as emotional or physical stress. In children attacks often follow vaccination.


HIDS is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.

Investigators have determined that HIDS occurs as a result of disruption or changes (mutations) in a gene located on the long arm (q) of chromosome 12 (12q24). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 12q24" refers to band 24 on the long arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The mutated gene in HIDS encodes an enzyme known as mevalonate kinase (MVK). Due to this genetic mutation, individuals with HIDS have reduced activity of MVK. MVK is a key enzyme in the complex breakdown (metabolism) of cholesterol in the body. The exact role reduced MVK activity plays in the development of HIDS is unknown.

Affected Populations

HIDS affects males and females in equal numbers. Approximately 200 individuals worldwide are known to have the disorder. HIDS does not affect the lifespan of affected individuals or directly affect the growth or development of children. Most known cases of HIDS occur in individuals of western European heritage with approximately 60 percent occurring in Dutch or French individuals. HIDS was first described in 1984 by Dr. Jos van der Meer in the medical journal Lancet.

Related Disorders

Symptoms of the following disorders can be similar to those of HIDS. Comparisons may be useful for a differential diagnosis.

HIDS belongs to a group of disorders known as the periodic fever syndromes or hereditary autoinflammatory syndromes. This group includes familial Mediterranean fever, tumor necrosis factor TNF-receptor associated periodic syndrome (TRAPS), familial cold urticaria and Muckle-Wells syndrome.

Familial Mediterranean fever (FMF) is a rare, inherited, inflammatory disease characterized by recurrent attacks of fever and acute inflammation of the membranes that line the abdominal cavity (peritonitis) and/or the lungs (pleuritis); pain and swelling of the joints (arthritis); and/or the heart (pericarditis) and, in some cases, skin rashes. In addition, some affected individuals may experience a serious complication known as amyloidosis, which is characterized by abnormal accumulation of a fatty-like substance (amyloid) in various parts of the body. If amyloid accumulates in the kidneys (renal amyloidosis), it may impair kidney function potentially resulting in life-threatening complications. In most instances, but not exclusively, FMF affects persons of Mediterranean origin such as Sephardic Jews, Arabs, Armenians, and Turks. FMF is inherited as an autosomal recessive trait. The causative gene on the short arm of chromosome 16 has been cloned. (For more information on this disorder, choose "familial Mediterranean fever" as your search term in the Rare Disease Database.)

Standard Therapies

A diagnosis of a HIDS is made based upon a thorough clinical evaluation, identification of characteristic symptoms (e.g., lifelong recurrent fevers), and a variety of tests including blood tests to determine the levels of immunoglobulin D (IgD) in the blood, urine tests to detect the presence of mevalonate kinase, and DNA analysis to detect the genetic mutation associated with HIDS.

No specific treatment for HIDS exists. Treatment is directed toward the specific symptoms that are apparent in each individual. Various drugs including paracetamol (acetaminophen) have been used to treat affected individuals. Steroids, such as prednisone, have been used to treat some individuals. However, in other cases, such therapy led to an increase in the frequency of episodes.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010

For information about clinical trials sponsored by private sources, contact:

Researchers in the department of General Internal Medicine at the Radboud University Medical Center in Nijmegen, The Netherlands, have created a Web site to provide information and support for individuals with hyper IgD syndrome. The researchers have an acitve interest in HIDS and maintain the Nijmegen HIDS registry, a database that catalogues information on affected individuals. The Web site is located at:

Hyper IgD syndrome Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at

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Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:3245-7.

Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th ed. Elsevier Saunders. Philadelphia, PA; 2005:821.

Abreu TT. Periodic fever: the first Portuguese case-report of hyper-IgD syndrome (HIDS). Acta Med Port. 2004;17:391-4.

Scolozzi R, Boccafogli A, Vicentini L. Hyper-IgD syndrome and other hereditary periodic fever syndromes. Reumatismo. 2004;56:147-55.

Simon A, Bijzet J, Voorbij HA, et al. Effect of inflammatory attacks in the classical type hyper-IgD syndrome on immunoglobulin D, cholesterol and parameters of acute phase response. J Intern Med. 2004;256:247-53.

Simon A, Drewe E, van der Meer JW, et al. Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Clin Pharmacol Ther. 2004;75:476-83.

Houten SM, van Woerden CS, Wijburg FA, Wanders RJ, Waterham HR. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet. 2003;11:196-200.

Houten SM, Frenkel J, Rijkers GT, et al. Temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper-IgD and periodic fever syndromes. Hum Mol Genet. 2002;11:3115-24.

Cuisset L, Drenth JP, Simon A, et al. Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome. Eur J Hum Genet. 2001;9:260-6.

Drenth JP, Waterham HR, Kuis W, et al. Identification of the gene for hyper-IgD syndrome: a model of modern genetics. Ned Tijdschr Geneeskd. 2000;144:782-5.

Drenth JP, Cuisset L, Grateau G, et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet. 1999;22:178-81.

Drenth JP, Denecker NE, Prieur AM, van der Meer JW. Hyperimmunoglobulin D syndrome. Presse Med. 1995;24:1211-3.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2008/03/31 00:00:00 GMT+0

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