In short
X-linked lymphoproliferative syndrome is a rare genetic disorder that affects how the immune system responds to infections, particularly the Epstein-Barr virus. This condition primarily affects males and can lead to serious, life-threatening complications if left untreated.
What is X-linked lymphoproliferative syndrome?
X-linked lymphoproliferative syndrome (XLP), also known as Duncan syndrome, is a rare genetic condition where the immune system does not work properly. The immune system is made up of special cells, proteins, tissues, and organs that work together to protect our bodies from harmful germs, including bacteria, viruses, and fungi.
This condition is found almost exclusively in males. More than half of individuals with XLP experience an exaggerated immune response to the Epstein-Barr virus (EBV), a very common virus that eventually infects most humans. In some people, EBV causes infectious mononucleosis, commonly known as "mono".
Normally, after initial infection, EBV remains in certain immune system cells called B cells. However, the virus is generally inactive because it is controlled by other cells 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 cells called macrophages (a type of white blood cell that helps destroy germs).
Two types of XLP
XLP can be divided into two types based on its genetic cause and pattern of signs and symptoms: XLP1 (also known as classic XLP) and XLP2.
XLP type 1 is the most common type, accounting for approximately 60% of cases. It is caused by changes in the SH2D1A gene. This gene provides instructions for making a protein called signaling lymphocyte activation molecule (SLAM) associated protein (SAP). Without SAP, lymphocytes (white blood cells that fight infection) multiply unchecked in response to Epstein-Barr virus infection, and natural killer cells do not function properly.
XLP type 2 is less common and is clinically similar to type 1. It is caused by changes in the XIAP gene. People with XLP2 have not been known to develop lymphoma (cancer of immune system cells), are more likely to develop severe immune reactions without EBV infection, usually have an enlarged spleen, and may also have inflammation of the large intestine.
How common is this condition?
XLP1 is estimated to occur in about 1 per million males worldwide. XLP2 is even rarer, affecting about 1 per 5 million males.
What causes XLP?
XLP1 is caused by changes in the SH2D1A gene. Some gene changes impair SAP protein function, while 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 (cancers of lymphocytes) may develop when defective lymphocytes are not properly destroyed through a self-destruct process called apoptosis.
XLP2 is caused by changes in the XIAP gene. This gene provides instructions for making a protein that helps protect cells from undergoing apoptosis in response to certain signals. XIAP gene changes can lead to an absence of XIAP protein or decrease the amount of XIAP protein that is produced.
How is XLP inherited?
These conditions are "X-linked recessive." This means that the changed gene is on the X chromosome. X-linked disorders, such as XLP, are the result of changes in genes on the X chromosome and almost exclusively affect males.
Since males have one X chromosome and one Y chromosome, a genetic change on their X chromosome can cause X-linked lymphoproliferative disease. Females have two X chromosomes. In order to have XLP, they would need to have changes on both X chromosomes, which is rare. A female who has a change on one of her two X chromosomes also has a normal X chromosome, which compensates for the abnormal one. This means that in almost all situations, the female is healthy but is a "carrier". A male who inherits an X chromosome carrying a change does not have a second X chromosome to compensate, so may be affected by the disorder.
Most females with the genetic change are carriers. They do not have the disease themselves, but they can pass it on to their male children. However, there are increasing numbers of reports of affected females with unfavorable X-chromosome inactivation favoring the X chromosome with the genetic change who develop severe immune reactions, inflammatory bowel disease, and skin problems.
Sometimes changes can happen by chance (sporadically) and are not inherited from parents.
Signs and symptoms
X-linked lymphoproliferative syndrome is usually without symptoms until EBV infection develops. Children with X-linked lymphoproliferative disease often begin showing symptoms between 6 months and 10 years of age. Symptoms can vary from person to person and can be mild or severe.
Response to Epstein-Barr virus
One major risk for children with X-linked lymphoproliferative syndrome is that the immune system is unable to properly combat the Epstein-Barr virus. In individuals with a normal immune system, infection with Epstein-Barr virus causes a temporary illness known as "infectious mononucleosis". For children with a working immune system, a typical response to Epstein-Barr virus can include swollen lymph nodes (glands in the neck, under the arm, or in the groin), sore throat, high fever, lack of energy and tiredness, enlargement of the liver and/or spleen, and muscle aches and pains.
In patients with X-linked lymphoproliferative syndrome, Epstein-Barr virus can cause a life-threatening over-activation of the immune system. Most patients develop severe or fatal infectious mononucleosis with liver failure.
Hemophagocytic lymphohistiocytosis
This proliferation of immune cells often causes a life-threatening reaction called hemophagocytic lymphohistiocytosis (HLH). HLH is characterized as an acute illness with prolonged and high fever, low blood cell counts, and enlarged liver and spleen, which is often severe or fatal. 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. Death is generally secondary to liver failure or multisystem organ dysfunction.
Signs and symptoms of HLH include swollen lymph nodes (glands in the neck, under the arm, or in the groin), enlarged liver and spleen, liver, heart, spleen, and kidney damage, fevers, skin rashes, jaundice (yellowing of the eyes and skin), bone marrow problems, anemia (not enough healthy red blood cells), and digestive problems.
In some individuals with XLP, hemophagocytic lymphohistiocytosis or related symptoms may occur without EBV infection. Males with XLP2 are more likely to have HLH without EBV infection and recurrent episodes of HLH, which is not typically seen in those with XLP1.
Antibody deficiency
About one-third of people with XLP experience dysgammaglobulinemia, which means they have abnormal levels of some types of antibodies. Antibodies (also known as immunoglobulins) are proteins that attach to specific foreign particles and germs, marking them for destruction. Individuals with dysgammaglobulinemia are prone to recurrent infections.
In those with XLP1, low levels of antibodies can lead to varying degrees of immune dysfunction associated with lung damage and recurrent respiratory infections that, if untreated, may result in death. Hypogammaglobulinemia (lower than normal levels of antibodies) increases the risk of infection and can lead to recurrent infections. Survivors of initial infection may develop low antibody levels resembling that in common variable immunodeficiency.
Lymphoma and other complications
Cancers of immune system cells (lymphomas) occur in about one-third of people with XLP. Lymphoproliferative disease (malignant lymphoma) and other lymphoproliferative diseases are specific to XLP1 and often develop in childhood, usually following EBV exposure. To date, neither lymphoproliferative disease nor common variable immunodeficiency has been reported in males with XLP2.
Rarer findings in those with XLP1 can include aplastic anemia (inability to produce red blood cells), vasculitis (inflammation in the blood vessels), and lymphoid granulomatosis. Survivors of initial infection may develop aplastic anemia, enlarged spleen, or a combination of these conditions.
XLP2-specific features
Males with XLP2 are more likely to have enlarged spleen and gastrointestinal disease, including inflammation of the intestines and perirectal abscesses or abnormal connections between organs called fistulae. Rarely, individuals with XLP2 and inflammatory bowel disease have been reported to develop inflammatory liver disease, which can progress to fatal liver failure.
Prognosis
Without treatment, most people with XLP survive only into childhood. Death usually results from hemophagocytic lymphohistiocytosis. Approximately 75% of patients die by age 10 years, and all die by age 40 years unless treatment is provided.
Diagnosis
The diagnosis of X-linked lymphoproliferative syndrome should be considered in young males who have severe Epstein-Barr virus infection, hemophagocytic lymphohistiocytosis, a suggestive family history, or other common manifestations.
Genetic testing is the standard test for confirming the diagnosis (before and after EBV infection and symptoms develop) as well as the carrier state. The diagnosis of XLP1 or XLP2 can be established in a male who has a genetic change in SH2D1A (XLP1) or XIAP (XLP2) identified on molecular genetic testing. These males typically have low or absent SAP or XIAP protein expression, respectively, by flow cytometry.
However, genetic testing can take weeks to complete, so other testing is done if the diagnosis must be made earlier, such as flow cytometry to assess protein expression. Suggestive findings include decreased antibody responses to antigens (particularly to EBV nuclear antigen), impaired T-cell proliferative responses, decreased natural killer cell function, and an inverted ratio of certain T cell types. These findings are typical before and after Epstein-Barr virus infection. A bone marrow biopsy can help confirm hemophagocytic lymphohistiocytosis.
In survivors, laboratory and imaging tests are done yearly to check for lymphoma and anemia.
Genetic testing is done in relatives when a case or carrier is identified in a family. Screening before birth is recommended for people if a change that causes XLP has been identified in their family. Early screening of infant boys in families that have had children with XLP is critically important so that they can be treated before contracting an EBV infection.
Treatment
Treatment of X-linked lymphoproliferative syndrome is hematopoietic stem cell transplantation (also called bone marrow transplant). This involves replacing the patient's blood-forming cells with healthy ones from a donor. Approximately 80% of patients who receive a transplant survive. Transplantation is curative if done before Epstein-Barr virus infection or other disorders become irreversible.
Rituximab, a medication, can help prevent severe EBV infection before transplantation.
Gene editing and gene therapy have shown early promising results for patients with XLP. Some patients with less common cellular immunodeficiencies may need cellular reconstitution via hematopoietic stem cell transplantation or, perhaps, gene therapy.
The disease can be cured by bone marrow or cord blood transplantation. Early recognition is crucial since the disease can be cured by transplantation.
