What is X-linked lymphoproliferative (XLP) syndrome?

X-linked lymphoproliferative syndrome (XLP), or Duncan’s 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, which work together to protect our bodies from the detrimental effects of pathogens, including bacteria, viruses and fungi. Most of the time, the immune system does a great job of keeping people healthy and preventing infections. However, in individuals with X-linked lymphoproliferative syndrome, the immune system does not always respond as it should to specific challenges.

Risks for children

Susceptibility to Epstein-Barr virus (EBV)

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.” In patients with X-linked lymphoproliferative syndrome, Epstein-Barr virus can cause a life threatening over-activation of the immune system.

For children with a functioning 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, tiredness
• Enlargement of the liver and/or spleen
• Muscle aches and pains

For children with X-linked lymphoproliferative (XLP) syndrome — whose immune system does not function properly in response to Epstein-Barr — 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

Other complications

Some patients with X-linked lymphoproliferative syndrome develop other complications, including:

• Lymphoma — a cancer of the immune cells
• Hypogammaglobulinemia — low levels of proteins known as “immunoglobulins," or “antibodies," in the bloodstream 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

Causes

X-linked lymphoproliferative syndrome is caused by alterations, also known as “mutations," at specific areas 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.

X-linked lymphoproliferative syndrome develops as the result of a mutation in one of two different genes, SH2D1A or XIAP (also known as BIRC4), both of which are located on the X chromosome. When XLP is due to mutations in the SH2D1A gene, it is sometimes referred to as "XLP1." When XLP is due to mutations in the XIAP gene, it is sometimes referred to as "XLP2."

The SH2D1A gene produces a protein called SAP, which regulates how white blood cells combat infections such as Epstein-Barr virus 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, an abnormal protein is produced, but it is unable to function properly.

The XIAP gene produces a protein known as X-linked inhibitor of apoptosis (XIAP), which functions to prevent cell death. When alterations in the XIAP gene are present, usually less XIAP protein is produced, which is believed to result in decreased numbers of specific types of white blood cells. It is not yet understood how this causes the features of X-linked lymphoproliferative syndrome.

Other forms of hereditary lymphoproliferative syndrome (XLP)

In addition to X-linked lymphoproliferative syndrome, there are two similar conditions associated with abnormal lymphoproliferation, immunodeficiency and/or increased susceptibility to Epstein-Barr virus infection.

• Lymphoproliferative syndrome due to mutations in the ITK gene: Mutations in the ITK gene cause symptoms similar to those seen in X-linked lymphoproliferative syndrome, including impaired liver function, hypogammaglobulinemia, anemia, swollen lymph nodes, enlarged liver and spleen, and lymphoma. Unlike XLP1 or XLP2, which only affect boys and are caused by mutations in genes residing on the X chromosome, ITK deficiency is caused by mutations affecting both copies of the ITK gene, which is located on chromosome 5.
• X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) due to mutations in the MAGT1 gene: Patients with mutations in MAGT1 often develop recurrent infections (including Epstein Barr virus), defects involving cells of the immune system, and lymphoma. Like XLP1 and XLP2, XMEN is inherited in an "X-linked" pattern.

Because these syndromes share several features with X-linked lymphoproliferative syndrome, additional genetic testing to investigate for alterations in the ITK and/or MAGT1 genes may be recommended depending on the patient's personal and family history.

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 genes are located on the X chromosome, females have two copies of each of these genes, while males have only one copy.

The SH2D1A and XIAP genes affect females and males differently

Because of this feature, an alteration in the SH2D1A or XIAP gene will affect female and male individuals differently. If a woman has one X chromosome with an alteration in SH2D1A or XIAP and her other X chromosome has a normal SH2D1A or XIAP gene, she is said to be a “carrier” of the gene mutation. Despite having a mutation in one of her two gene copies, the normal SH2D1A or XIAP gene will produce enough protein so she does not develop X-linked lymphoproliferative syndrome. This normal copy provides a protective effect for a female X-linked lymphoproliferative syndrome carrier. This female carrier, however, can pass her X chromosome with the SH2D1A or XIAP alteration to a proportion of her future children. Thus, a female carrier can transmit the trait to develop X-linked lymphoproliferative syndrome.

Since males have a single X-chromosome, they have only one copy of the SH2D1A and XIAP genes. Therefore, when a male has an alteration in SH2D1A or XIAP, he will develop clinical signs of X-linked lymphoproliferative syndrome. This is because he does not have an extra normal copy of SH2D1A or XIAP on his Y chromosome to compensate by making normal SAP or XIAP protein.  The Y chromosome in males does not contain the same genes that are carried on the X chromosome.

Chances of passing the SH2D1A or XIAP gene mutation to your children

A female carrier of an SH2D1A or XIAP gene mutation has a 50 percent chance that she will pass this mutation onto 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. This is because she will have one X chromosome with an alteration in the SH2D1A or XIAP gene (inherited from her mother) and one X chromosome with a normal copy of the SH2D1A and XIAP genes (inherited from her father).

It is also possible that a female child could inherit the normal copy of SH2D1A and XIAP from both her carrier mother and her father. This child would not be a carrier of X-linked lymphoproliferative syndrome and therefore, she could not pass the SH2D1A or XIAP 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 carrier is a male, there is a 50 percent chance that he will inherit the X chromosome carrying the SH2D1A or XIAP alteration. If this were the case, the child would have X-linked lymphoproliferative syndrome. Similarly there is a 50 percent chance that he will inherit the X chromosome with the normal SH2D1A or XIAP gene copy. In this case, the male child would not have X-linked lymphoproliferative syndrome.

If a man with X-linked lymphoproliferative syndrome (and hence an SH2D1A or XIAP mutation) has children with a female partner who does not carry an alteration in SH2D1A or XIAP, 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 or XIAPalteration 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.

Diagnosis

If a child has severe symptoms in response to infection with Epstein-Barr virus, a physician may consider a diagnosis of X-linked lymphoproliferative syndrome. The diagnosis might also be considered if there is a family history where relatives were affected by illnesses found in X-linked lymphoproliferative syndrome, such as fatal Epstein-Barr virus infection, lymphoma or hypogammaglobulinemia.

There are several ways that X-linked lymphoproliferative syndrome can be diagnosed:

• A blood test can evaluate for the presence or absence of functional SAP or XIAP protein within immune cells.
• Genetic testing can be used to learn whether there is an alteration in the SH2D1A or XIAP gene.

Even if an alteration in one of the associated genes is not found, a child can still have a diagnosis of X-linked lymphoproliferative syndrome based on the clinical symptoms and other laboratory test results.

Testing for XLP

In most cases, a genetic test is used to confirm that an individual has X-linked lymphoproliferative syndrome.

• 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 or XIAP alteration.
• DNA is isolated from the sample and either one copy (in a male) or two copies (in a female) of the SH2D1A and/or XIAP 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, the patient’s one copy (for a male) or two copies (for a female) of the SH2D1A and/or XIAP 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. This information could strengthen the conclusion that the SH2D1A or XIAP alteration was linked to the diagnosis of X-linked lymphoproliferative syndrome or XLP carrier state in the individual being tested.SH2D1A and XIAP 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 allows for other family members to undergo testing to determine whether or not they also carry this mutation in the SH2D1A or XIAP gene. 

Reproductive options

There are several reproductive options for an individual with an alteration in SH2D1A or XIAP who does not want to pass this alteration onto 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 or XIAP gene mutation.

Preimplantation genetic diagnosis (PGD)

This reproductive technology is available to individuals who are known to have a genetic alteration that causes a condition such as X-linked lymphoproliferative syndrome. PGD is performed in combination with in vitro fertilization (IVF) and offers a way to test patient's embryos for genetic disorders before transferring them into the uterus. The procedure is particularly useful for patients with a serious inherited disorder such as X-linked lymphoproliferative syndrome, who wish to avoid passing the disorder to their children. For best results, the SH2D1A or XIAP mutation carried by the mother must be identified before either prenatal testing or PGD can be performed.

Cancer risks

It is estimated that 30 percent of patients with XLP1 develop lymphoma, an aggressive but usually curable cancer of a type of immune cell known as lymphocyte. Most of the time, lymphomas develop in XLP1 patients who have previously been infected with Epstein-Barr virus. However, in some cases, boys or young men with XLP1 can develop lymphoma without ever having had Epstein-Barr virus infection. The average age of lymphoma onset in XLP1 is estimated to be 6 years, but tumors can present at any age and anywhere in the body. To date, no patients with XLP2 have developed lymphoma.

Cancer screening protocol for children with XLP

It is not yet clear whether surveillance testing for lymphoma is useful in X-linked lymphoproliferative syndrome (XLP1) patients since it is difficult to predict when and where lymphoma will occur in the body. Instead, boys and men with XLP1 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 XLP1 patient should undergo prompt evaluation.