What is X-linked lymphoproliferative syndrome?
X-linked lymphoproliferative syndrome (XLP), which is also known as Duncan's syndrome, 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 100 families with XLP are known to exist worldwide. It is likely, however, that there are many more individuals whose disease is as yet unrecognised.

What are the features of the condition?
XLP 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. 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.

What are the symptoms?

  • Severe glandular fever
  • Lymphoma: Patients may be tired, anaemic and develop swollen glands
  • Hypogammaglobulinaemia: Patients may get frequent infections

What causes the condition?
The cause of the condition was only found in 1999, so there is much that we do not understand about it. It 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. In most families, the mistake is in a gene called SH2D1A. This gene normally makes a protein called SAP. Mistakes in the gene cannot be found in a number of individuals with the disease, and we are looking hard to find out which gene is responsible in these families.

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.

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 (SAP) 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. This can be a difficult procedure, requiring a prolonged hospital stay.

What is the outlook for people with the condition?
70% of individuals with XLP 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.

Source: Great Ormond Street Hospital NHS Trust, London.

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