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X-linked lymphoproliferative disease
(often shortened to XLP)
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Reviewed August 2010
What is XLP?
X-linked lymphoproliferative disease (XLP) is a disorder of the immune system and blood-forming cells that is found almost exclusively in males. More than half of individuals with this disorder experience an exaggerated immune response to the Epstein-Barr virus (EBV). EBV is a very common virus that eventually infects most humans. In some people it causes infectious mononucleosis (commonly known as "mono"). Normally, after initial infection, EBV remains in certain immune system cells (lymphocytes) called B cells. However, the virus is generally inactive (latent) because it is controlled by other lymphocytes called T cells that specifically target EBV-infected B cells.
People with XLP may respond to EBV infection by producing abnormally large numbers of T cells, B cells, and other lymphocytes called macrophages. This proliferation of immune cells often causes a life-threatening reaction called hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis causes fever, destroys blood-producing cells in the bone marrow, and damages the liver. The spleen, heart, kidneys, and other organs and tissues may also be affected. In some individuals with XLP, hemophagocytic lymphohistiocytosis or related symptoms may occur without EBV infection.
About one-third of people with XLP experience dysgammaglobulinemia, which means they have abnormal levels of some types of antibodies. Antibodies are proteins that attach to specific foreign particles and germs, marking them for destruction. Individuals with dysgammaglobulinemia are prone to recurrent infections.
Cancers of immune system cells (lymphomas) occur in about one-third of affected individuals.
Without allogeneic stem cell transplantation, in which a patient's diseased blood-forming cells (a type of stem cell) are replaced with stem cells from a healthy donor, most people with XLP survive only into childhood. Death usually results from hemophagocytic lymphohistiocytosis associated with EBV infection.
How common is XLP?
XLP is estimated to occur in about 1 per million males worldwide.
What genes are related to XLP?
Mutations in the SH2D1A and XIAP genes cause XLP. XLP caused by SH2D1A gene mutations is sometimes called classic XLP or XLP1. When the disorder is caused by XIAP gene mutations it may be known as XLP2. Because the frequency of the various features of XLP differ between the two types, and certain immune cell abnormalities identified in XLP1 have not been observed in XLP2, some researchers believe that these should actually be considered similar but separate disorders.
The SH2D1A gene provides instructions for making a protein called signaling lymphocyte activation molecule (SLAM) associated protein (SAP). This protein is involved in the functioning of lymphocytes that destroy other cells (cytotoxic lymphocytes) and is necessary for the development of specialized T cells called natural killer T cells. The SAP protein also helps control immune reactions by triggering self-destruction (apoptosis) of cytotoxic lymphocytes when they are no longer needed.
Some SH2D1A gene mutations impair SAP function. Others result in an abnormally short protein that is unstable or nonfunctional, or prevent any SAP from being produced. The loss of functional SAP disrupts proper signaling in the immune system and may prevent the body from controlling the immune reaction to EBV infection. In addition, lymphomas may develop when defective lymphocytes are not properly destroyed by apoptosis.
The XIAP gene provides instructions for making a protein that helps protect cells from undergoing apoptosis in response to certain signals. XIAP gene mutations can lead to an absence of XIAP protein or decrease the amount of XIAP protein that is produced. It is unknown how a lack of XIAP protein results in the signs and symptoms of XLP, or why features of this disorder differ somewhat between people with XIAP and SH2D1A gene mutations. For example, affected individuals with XIAP gene mutations have not been known to develop lymphoma; they may also develop hemophagocytic lymphohistiocytosis with or without EBV exposure or with another virus called cytomegalovirus.
How do people inherit XLP?
This condition is generally inherited in an X-linked recessive pattern. The genes associated with this condition are located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of an associated gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of an associated gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
Rarely, a female carrying one altered copy of the SH2D1A or XIAP gene in each cell may develop signs and symptoms of this condition.
Where can I find information about diagnosis or management of XLP?
These resources address the diagnosis or management of XLP and may include treatment providers.
General information about the diagnosis and management of genetic conditions is available in the Handbook. Read more about genetic testing, particularly the difference between clinical tests and research tests.
To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.
Where can I find additional information about XLP?
You may find the following resources about XLP helpful. These materials are written for the general public.
You may also be interested in these resources, which are designed for healthcare professionals and researchers.
What other names do people use for XLP?
What if I still have specific questions about XLP?
Where can I find general information about genetic conditions?
The Handbook provides basic information about genetics in clear language.
These links provide additional genetics resources that may be useful.
What glossary definitions help with understanding XLP?
allogeneic ; allogeneic stem cell transplantation ; apoptosis ; bone marrow ; cell ; chromosome ; familial ; fever ; gene ; immune response ; immune system ; infection ; inheritance ; lymphocyte ; lymphoma ; molecule ; mutation ; proliferation ; protein ; recessive ; sex chromosomes ; stem cells ; susceptibility ; syndrome ; virus ; X-linked recessive
You may find definitions for these and many other terms in the Genetics Home Reference Glossary.
See also Understanding Medical Terminology.
References (11 links)
The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook.