Background information

What is the origin of the name?

This disorder is officially called “hyper-immunoglobulinemia D and periodic fever syndrome”. It was first described under this name in 1984. Within a short period of time, Prof. van der Meer and his colleagues saw a number of patients with strange, unexplained fever attacks, who all had high concentrations of IgD in their blood. It turned out that this had to be a disease that had not been described before. The disorder is often abbreviated to “hyper-IgD syndrome” or “HIDS”.

Other names in use

There are several other names in use for this disorder. Apart from Hyper-IgD and periodic fever syndrome or HIDS it is also known under the name Mevalonate Kinase Deficiency (MKD). This last name was coined after the discovery of the causative gene. Advantage is that the term IgD is no longer in the name, since this may confuse patients and doctors: not all patients have a high IgD, and it is also not a cause of the disease.

MKD encompasses the whole spectrum of disease from classical mevalonic aciduria (MVA) to HIDS. So patients who all have MKD can have very different symptoms, prognosis and treatment. The HIDS patients are then sometimes designated as “mild MKD” because they have a less severe defect in the enzyme. However, as patients will testify, symptoms of HIDS are often nothing like “mild”, thus this may give the wrong impression. Alternative would be to use the name MKD, and then make clear whether the patient has more the “HIDS-like phenotype” or “MVA-like phenotype”.

Lastly, some doctors prefer the name Mevalonate Associated Periodic Syndrome (MAPS). However, this is rarely used.

For this website (and in daily practice) we usually use HIDS or Hyper-IgD syndrome – but we may also use MKD, especially in scientific texts.

What is immunoglobulin D (IgD)?

Immunoglobulin D (IgD) is a protein produced by a certain type of white blood cells. A lot is known about other immunoglobulins (like IgG, IgA and IgM), they play an important role in the immune system. The function of IgD is still unclear. Patients with HIDS have a high concentration of this IgD in their blood.

There are a diversity of other diseases in which a high concentration of IgD can be found.

What is mevalonate kinase?

In 1999 it was discovered where exactly in the inherited information the fault lies in patients with HIDS. It turned out to be in a piece of DNA that contains information for the production of a specific protein called mevalonate kinase. This mevalonate kinase is a central enzyme in a number of metabolisms in the cell, which leads for example to cholesterol formation. In HIDS this mevalonate kinase does not function properly. Why this defect leads to fever attacks is not yet known.

Where is the predisposition located?

Our body is made up of little living units, which we call cells. Each cell has a nucleus in which are found 23 pairs of chromosomes. Chromosomes are largely made up out of DNA. This DNA contains all our inherited information, which determines all the characteristics of our body.

One pair of chromosomes contains one chromosome with inherited information from the mother and one from the father. Each separate chromosome of a pair contains information of identical characteristics. Everyone therefore has two copies for the predisposition of every characteristic.

Genes

A gene is a little piece of chromosome. It is built up out of DNA. One gene contains the information for one inherited predisposition. It is estimated that a human being has about 50.000 to 100.000 genes. Genes give a cell the information on what the function of that cell should be. Genes are for example responsible for blood types, color of the eyes, and the development of a cell into a muscle cell. There are also genes that control the production by the cell of substances that can inhibit or activate an inflammatory response.

Mutations

The DNA, that is, the inherited information, has to be copied a lot. This happens for example when reproductive cells are formed, but also when new cells for skin, blood or intestines are made. This copying can lead to mistakes. This happens very often. Some mistakes are recognized and corrected by mechanisms in the cell. Others remain. Most mistakes have no consequences, because they are located in a part of the DNA that is not used, or because the other chromosome of a pair, with the same information, compensates them. If such a mistake does have consequences, it is called a mutation. A gene containing a mutation often does not function properly.

From mutation to disease

HIDS is caused by mutations, that is small mistakes, in the inherited information, in one specific gene (called the mevalonate kinase gene). Both chromosomes of a pair with the gene must contain the mutation to get the disease. Someone who has a mutation in one copy of the gene and one copy without the mutation will not get fever attacks. Such a person is called a “carrier”.

So how about heredity?

Every child gets one copy of all his chromosomes from his father and one from his mother. A child will only get ill if both parents transmit a gene with the mutation to their child. This is called an “autosomal recessive” inheritance pattern. Which copy of the gene is transmitted by the parent to his or her child is purely coincidental. A person with HIDS has two HIDS-mutations. Both parents must therefore be a carrier of such a mutation. The risk of a child of parents who are both carriers to get the disease is 25% (1 in 4). In half of all cases, the child of such parents will be a carrier of the mutation. But a child does not always get the inherited predisposition. The inheritance of genes is purely coincidental – so it can also happen that for example 3 out of 4 children of such parents get the disease. Or none of the children.

What happens to children of a person with HIDS? Someone with HIDS, so who has 2 HIDS-mutations, has children together with someone without the inherited predisposition. These children will all be carriers of a HIDS-mutation. They will always get one gene with the mutation from the parent with HIDS and one normal gene of the healthy parents. The children in this case will therefore not be ill themselves.

The only way in which it can happen that someone with HIDS gets a child who also suffers from HIDS is when partner of the HIDS-patient is, by coincidence, carrier of a HIDS-mutation. In such a case there is a 50% chance that their child will get the disease. However, this is a very exceptional situation. At this moment, no family with HIDS is known in which this has happened, because the disease is so rare. A rough estimate is that at most about 1 in 500 persons in the Netherlands (which has a higher prevalence than other countries) are carrier of a HIDS-mutation. So for a Dutch patient marrying a Dutch partner, the chances of a child with HIDS are at most 1 in 1000.

For specific genetic counseling we advise patients to contact a genetic counselor.

Update: March 12, 2011

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