Hyper IgD syndrome

National Organization for Rare Disorders, Inc.

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  • hyperimmunoglobulinemia D with periodic fever

Disorder Subdivisions

  • None

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.

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 www.clinicaltrials.gov. 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

Email: prpl@cc.nih.gov

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: http://www.hids.net



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Autoinflammatory Alliance

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For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.