X-linked lymphoproliferative syndrome (XLP) is an inherited disorder of the immune system that affects males. XLP is characterized by an abnormal immune response to infection with the Epstein-Barr virus (EBV). This is a common virus in the normal population, which causes infectious mononucleosis (“mono or kissing disease”). In normal individuals, EBV causes no long lasting ill effects. In individuals with X-linked lymphoproliferative syndrome, there is a mutation (mistake) in the XLP gene, SH2D1A/DSHP/SAP. This gene helps control the immune response to an EBV infection. As a result, males with XLP who are exposed to the EBV virus can have life-threatening symptoms. Patients with the disorder, in the absence of an acute EBV infection, are also subject to immune system problems, including recurrent infections and an unusual susceptibility to B-cell lymphomas. The diagnosis is confirmed by mutation detection (laboratory tests looking for a mistake in the XLP gene).
One major problem in X-linked lymphoproliferative syndrome (XLP) is that the immune system is unable to properly combat infection by a virus known as Epstein-Barr virus (EBV). In individuals with a normal immune system, infection with Epstein-Barr virus (EBV) causes a temporary illness known as “infectious mononucleosis”. In contrast, in patients with X-linked lymphoproliferative syndrome (XLP), Epstein-Barr virus (EBV) infection can cause a life threatening over-activation of the immune system.A typical response to Epstein-Barr virus (EBV) in individuals with a functioning immune system can include:
• Swollen lymph nodes (glands in the neck, under the arm, or in the groin)
• Sore throat
• High fever
• Lack of energy, tiredness
• Enlargement of the liver and/or spleen
• Muscle aches and pains
Since the immune system of individuals with Epstein-Barr virus (EBV) does not function properly in response to the virus, potentially severe complications can develop such as:
• Hepatitis (inflammation of the liver), which can lead to jaundice
• A condition known as hemophagocytic lymphohistiocytosis, which is characterized by:
• Pancytopenia - Low levels of all types of blood cells, including white blood cells, red blood cells and platelets
• Clotting abnormalities
• Altered levels of certain chemicals or proteins in the blood, such as increased triglycerides, increased ferritin and increased soluble interleukin 2 receptor levels
In addition to their difficulty handling Epstein-Barr virus (EBV) infection, some patients with X-linked lymphoproliferative syndrome (XLP) develop other complications, including:
• Lymphoma - A cancer of the immune cells
• Hypogammaglobulinemia - Low levels of proteins known as “immunoglobulins," or “antibodies," in the blood stream which are necessary to help fight infection
• Aplastic anemia - A form of bone marrow failure - rarely
• Vasculitis - Inflammation of the small blood vessels in various organs of the body such as the lungs, eyes and brain
X-linked lymphoproliferative syndrome (XLP) is caused by alterations, also known as “mutations," at a specific area within an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the necessary instructions that our cells require to perform their different functions within our bodies.
There is a specific gene known as SH2D1A, located on the X chromosome, which is altered in individuals with X-linked lymphoproliferative syndrome (XLP). The SH2D1A gene produces a protein called SAP, which regulates how white blood cells combat infections such as Epstein-Barr virus (EBV) and controls how they produce antibodies and other immunoregulatory molecules. When alterations in the SH2D1A gene are present, usually less SAP protein is produced. Occasionally, a protein is produced, but it is unable to function. Sometimes, individuals diagnosed with X-linked lymphoproliferative syndrome (XLP) may not have an obvious alteration in SH2D1A. This suggests that other genes besides SH2D1A could be responsible for causing certain cases of X-linked lymphoproliferative syndrome (XLP). To date, the only other gene known to cause an illness closely resembling X-linked lymphoproliferative syndrome (XLP) is called BIRC4.
How is X-linked lymphoproliferative (XLP) syndrome inherited?
Except for egg and sperm cells, the other cells in our body have 46 chromosomes containing our genes in the form of DNA. For the most part, each cell has two copies of every chromosome, one inherited from the mother and one from the father. This rule is different when applied to the sex chromosomes, which are also known as “X” and “Y." Females have two X-chromosomes, whereas males have one X-chromosome and one Y-chromosome. Since the SH2D1A gene is located on the X chromosome, females have two copies of the SH2D1A gene, while males have only one copy.
The SH2D1A gene affects females and males differently
Because of this feature, an alteration in the SH2D1A gene will affect female and male individuals differently. If a woman has one X-chromosome with an alteration in SH2D1A and her other X-chromosome has a normal SH2D1A gene, she is said to be a “carrier.” Despite having an alteration in one of her two gene copies, the normal SH2D1A gene will produce enough SAP protein so that she does not develop X-linked lymphoproliferative syndrome (XLP). This normal copy provides a protective effect for a female X-linked lymphoproliferative syndrome (XLP) carrier. This female carrier, however, can pass her X-chromosome with the SH2D1A alteration to a proportion of her future children. Thus, a female carrier can transmit the trait to develop X-linked lymphoproliferative syndrome (XLP).
Since males have a single X-chromosome, they have only one copy of the SH2D1A gene. Therefore, when a male has an alteration in SH2D1A, he will develop clinical signs of X-linked lymphoproliferative syndrome (XLP). This is because he does not have an extra normal copy of SH2D1A on his Y-chromosome to compensate by making normal SAP protein. The Y-chromosome in males does not contain the same genes that are carried on the X-chromosome.
Chances of passing the SH2D1A gene mutation to your children
A female carrier of an SH2D1A gene mutation has a 50 percent (or 1 in 2) chance that she will pass this mutation on to each of her future children. Provided that the male partner of a female carrier does not himself have X-linked lymphoproliferative syndrome (XLP), a female child inheriting the alteration will also be a carrier like her mother and not show symptoms of X-linked lymphoproliferative syndrome (XLP). This is because she will have one X-chromosome with an alteration in the SH2D1A gene (inherited from her mother) and one X-chromosome with a normal copy of the SH2D1A gene (inherited from her father). It is also possible that a female child could inherit the normal copy of SH2D1A from both her carrier mother and her father. This child would not be a carrier of X-linked lymphoproliferative syndrome (XLP) and therefore, she could not pass the SH2D1A alteration to her future children.
A male child will always receive an X-chromosome from his mother and a Y-chromosome from his father. Thus, if the child born to a female X-linked lymphoproliferative syndrome (XLP) carrier is a male, there is a 50 percent chance that he will inherit the X chromosome carrying the SH2D1A alteration. If this were the case, the child would have X-linked lymphoproliferative syndrome (XLP). Similarly there is a 50 percent chance that he will inherit the X-chromosome with the normal SH2D1A gene copy. In this case, the male child would not have X-linked lymphoproliferative syndrome (XLP).
If a man with X-linked lymphoproliferative syndrome (and hence an SH2D1A alteration) has children with a female partner who does not carry an alteration in SH2D1A, he will either pass on a Y-chromosome to his sons (who will therefore be unaffected by the syndrome) or he will pass the X-chromosome with the SH2D1A alteration to his daughters (who will be X-linked lymphoproliferative syndrome carriers). This type of inheritance of XLP follows an “X-linked” or “sex-linked” recessive pattern.
It is recommended that boys with known or suspected XLP receive regular intravenous (IV) IgG replacement therapy every three to four weeks until definitive treatment can be provided even though earlier attempts to prevent EBV infection with the use of IVIG and/or acyclovir prophylaxis have not been completely effective.
Hematopoietic cell transplantation (HCT) is the only curative therapy and should be strongly considered in children with confirmed XLP as early in life as possible.
If a child has severe symptoms in response to infection with Epstein-Barr virus (EBV), a physician may consider a diagnosis of X-linked lymphoproliferative syndrome (XLP). The diagnosis might also be considered if there is a family history where relatives were affected by illnesses found in X-linked lymphoproliferative syndrome (XLP), such as fatal Epstein-Barr virus (EBV) infection, lymphoma or hypogammaglobulinemia. There are several ways that X-linked lymphoproliferative syndrome (XLP) can be diagnosed. For example, a blood test can be completed to evaluate for the presence or absence of functional SAP protein within immune cells. In addition, one can complete genetic testing to examine whether there is an alteration in the SH2D1A gene. However, even if an alteration in this gene is not found, a child can still have a diagnosis of X-linked lymphoproliferative syndrome (XLP) based on the clinical symptoms and other laboratory test results.
How do you test for X-linked lymphoproliferative (XLP) syndrome?
In order to confirm that an individual has X-linked lymphoproliferative syndrome (XLP), most commonly a genetic test must be completed:
• A blood sample is obtained from a male who has clinical symptoms of X-linked lymphoproliferative syndrome (XLP) or from a female who wants to see if she is a carrier of an SH2D1A alteration.
• DNA is isolated from the sample and either one copy (in a male) or two copies (in a female) of the SH2D1A gene are evaluated by a method known as direct DNA sequencing. Sequencing is a process by which a person’s genetic code is compared to a “normal” reference code. In the case of X-linked lymphoproliferative syndrome (XLP), the patient’s one copy (for a male) or two copies (for a female) of the SH2D1A gene are evaluated and compared to the normal reference sequence for this gene.
• If an alteration is identified, one can next examine whether the alteration has been previously reported in other individuals with X-linked lymphoproliferative syndrome (XLP). This information could strengthen the conclusion that the SH2D1A alteration was linked to the diagnosis of X-linked lymphoproliferative syndrome (XLP) or XLP carrier state in the individual being tested. SH2D1A genetic test results can provide important information for other family members. Knowing the specific alteration that is present in an individual with X-linked lymphoproliferative syndrome (XLP)allows for other family members to undergo testing to determine whether or not they also carry this alteration in the SH2D1A gene.
There are several reproductive options for an individual with an alteration in SH2D1A who does not want to pass this alteration on to his or her future children.
Prenatal genetic diagnosis
The usual procedure is to first determine the sex of the developing baby by performing chromosome analysis through the isolation of DNA from its cells. This can be done though one of two procedures --chorionic villus sampling (CVS) or amniocentesis -- which are offered at a different time during the pregnancy. If one of these tests reveals that the baby is a boy, DNA from his fetal cells can be analyzed for presence or absence of the SH2D1A mutation
What are the cancer risks for children and adults with X-linked lymphoproliferative (XLP) syndrome?
It is estimated that 30 percent of X-linked lymphoproliferative syndrome (XLP) patients develop lymphoma, an aggressive but usually curable cancer of a type of immune cell known as lymphocyte. Most of the time, lymphomas develop in X-linked lymphoproliferative syndrome (XLP) patients who have previously been infected with Epstein-Barr virus (EBV). However, in some cases, boys or young men with X-linked lymphoproliferative syndrome (XLP) can develop lymphoma without ever having had Epstein-Barr virus (EBV) infection. The average age of lymphoma onset in X-linked lymphoproliferative syndrome (XLP) is estimated to be 6 years, but tumors can present at any age and any anywhere in the body.
What is the recommended cancer screening protocol for children?
It is not yet clear whether surveillance testing for lymphoma is useful in X-linked lymphoproliferative syndrome (XLP) patients since it is difficult to predict when and where lymphoma will occur in the body. Instead, boys and men with X-linked lymphoproliferative syndrome (XLP) should be seen on a regular basis by their physicians and remain aware of the signs and symptoms of lymphoma, such as development of one or more firm and/or enlarged lymph nodes, fatigue, fever, weight loss, night sweats and shortness of breath. If any of these symptoms should occur and cannot otherwise be easily explained, an X-linked lymphoproliferative syndrome (XLP) patient should undergo prompt evaluation.
Regardless of clinical phenotype, the only curative treatment is allogeneic hematopoietic cell transplantation (HCT), which should be considered in all patients as early as possible. Treatment of hemophagocytic lymphohistiocytosis (HLH) is similar to that of other life-threatening genetic hemophagocytic disorders and includes immunosuppressive agents such as steroids, etoposide, and cyclosporin. Rituximab may also be used when HLH is associated with EBV. Hypogammaglobulinemia is treated with IVIG replacement therapy. Lymphoma is treated with standard chemotherapy appropriate to the tumor. Surveillance: monitoring of immune function for evidence of EBV infection at least every six months and more frequently if symptoms warrant Testing of relatives at risk: Molecular genetic testing of at-risk sibs and other relatives for the family-specific mutation facilitates early diagnosis and treatment.
In the past, the following terms were used to describe XLP:
• Epstein-Barr virus infection, familial fatal
• EBV susceptibility (EBVS)
• Purtilo syndrome
• Duncan disease