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XLP & XIAP Info


What is X-linked lymphoproliferative syndrome?

X-linked lymphoproliferative syndrome (XLP),  is a genetic defect which causes the immune system to respond abnormally to some viral infections. This can result either in an underactive immune system (immunodeficiency) or an overactive immune system, which can cause as many problems.

How common is XLP?

XLP is extremely rare, and only about 150 families with XLP are known to exist worldwide. Around 80% of cases are XLP1 with the remaining 20% of cases being XLP2/XIAP, although we have noted an increase in XIAP cases in the last few years as diagnosis has got better. It is likely, however, that there are many more individuals whose disease is as yet unrecognised.

What are the features of the condition?

XLP1 can have many different symptoms, and we do not yet know what the full spectrum of the disease is. About a third of patients have a very severe episode of glandular fever (EBV - Epstein Barr Virus). Another third develop a cancer of their blood cells (lymphoma) and another third have low levels of immunoglobulin, the proteins in the blood that help fight infection. More rarely, individuals may have a severe form of anaemia or inflammation of small blood vessels (vasculitis). It is common for one individual to have several different symptoms over the course of their illness.

XLP2/XIAP affected boys are also susceptible to glandular fever, low levels of immunoglobulin and HLH (Hemophagocytic Lymphohistiocytosis) or VAHS (virus-associated hemophagocytoc syndrome). Most XIAP affected boys develop HLH related to the EBV infection, but in some cases they show HLH without having EBV as the obvious trigger.

What are the symptoms?

What causes the condition?

The cause of XLP1 was only found in 1999, and research into XIAP is in its infancy, so there is much that we do not understand about it. XLP is caused by a mutation, or mistake, in one of the genes on the X chromosome. This means that the cell does not get the right instructions it needs to work properly. For XLP1 the defective gene is the SAP (also known as SH2DIA or DSHP). For XLP2/XIAP the defective gene is the XIAP (also known as BIRC4).

Pathogenesis

We think that the immune system in XLP is unable to cope with some viral infections, in particular EBV. The immune system loses its normal tight regulation, and starts to malfunction.

How is the condition inherited?

The X chromosome is one of the sex chromosomes: females have two X chromosomes and males have one X and one Y. Each X chromosome carries one copy of the gene. If a male has a faulty gene on their X chromosome, they will have the disease. However, because the female has two X chromosomes, the normal gene on one X can compensate for the faulty one on the other. Thus, only males get the disease, and females may carry the disease but be unaffected. This is an “X-linked disease” and within a family tree you may be able to pick out other affected males. However please note that for XIAP that there are now reported cases where the female carrier has developed HLH, linked to the gene mutation.

Are all the children in the family affected?

No! If a mother carries the disease, each time she has a female child, there is a 50% chance that they will be a carrier. Each time that she has a male child there is a 50% chance that they will be affected by the disease.

How is the diagnosis made?

The diagnosis will be suggested by the pattern of illness in the child and their family. In most children we can confirm the diagnosis using a blood test. This will check if the protein that makes the cells work properly is present, and will also look for the “mistake” in the gene. In some families there may not be a mistake in this particular gene, and the diagnosis can be made on the clinical story alone.

What treatment can be given for the condition?

Initially treatment will be given for the symptoms that your child presents with, this may include anti-viral medicines, immunoglobulin therapy or steroids. Children may receive a variety of supportive treatments, such as immunoglobulin and antibiotics to keep them well in the short term. Bone marrow transplantation is the definitive treatment of choice at the present time for XLP1 and some XLP2/XIAP affected boys. This can be a difficult procedure, requiring a prolonged hospital stay.

What is the outlook for people with the condition?

70% of individuals with XLP1 die by the age of 10 years without any treatment. However, as we are learning more about the disease we are identifying adults with milder forms of the condition.


Footnotes


Also please see http://www.stjude.org/disease-summaries/0,2557,449_2164_6527,00.html