What Is X-Linked Lymphoproliferative Disease?

X-linked lymphoproliferative disease (XLP) is a rare genetic disorder that causes the immune system to overreact to infections. It mostly affects boys because of how the genes are inherited. Another name for this condition is Duncan’s syndrome.

There are two types of X-linked lymphoproliferative diseases: XLP1 and XLP2/XIAP Deficiency. An estimated one out of every one million boys has XLP1. XLP2 is even more rare, affecting about one in five million boys.

X-Linked Lymphoproliferative Disease Causes

XLP1 is caused by a change in the SH2D1 gene (also known as BIRC4 gene). XLP2/XIAP Deficiency is caused by changes in the XIAP gene.

These conditions are “X-linked recessive.” This means that the changed gene is on the X chromosome. Since boys have one X chromosome and one Y chromosome, a genetic change on their X chromosome can cause X-linked lymphoproliferative disease.

Girls have two X chromosomes. In order to have XLP, they would need to have changes on both X chromosomes. This is rare, so most girls with the genetic change are carriers. They do not have the disease themselves, but they can pass it on to their male children.

X-Linked Lymphoproliferative Disease Signs, Symptoms and Other Problems

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. Symptoms can be mild or severe.

One big risk factor for children with X-linked lymphoproliferative disease is that their immune system cannot fight the Epstein-Barr virus (EBV). EBV is a common virus that can cause infectious mononucleosis (mono) and other illnesses.

In children with a working immune system, EBV infection symptoms can include extreme fatigue, fever and sore throat. However, children with X-linked lymphoproliferative disease can develop potentially severe complications in response to EBV. These include:

  • Hepatitis, in which the liver is inflamed
  • Hemophagocytic lymphohistiocytosis (HLH), a severe immune response that can be life-threatening. This is more common in children with XLP2/XIAP Deficiency. 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)
    • Digestive problems, such as problems absorbing nutrients

Other signs and symptoms of X-linked lymphoproliferative disease include:

  • Hypogammaglobulinemia (lower than normal levels of proteins called antibodies), which increases the risk of infection and can lead to recurrent infections
  • Recurrent fevers, an enlarged spleen and low blood counts
  • Aplastic anemia (bone marrow failure)
  • Vasculitis (small blood vessel inflammation)

In addition, children with XLP1 can develop a blood cancer called lymphoma as a result of the condition. Children with XLP2/XIAP Deficiency are at risk of developing inflammatory bowel disease. Symptoms include belly pain, loose stools and bleeding in the gastrointestinal tract.

Frequency of complications associated with XLP1:

  Percent of Patients
HLH 45-58%
Low Antibody Levels 31-67%
Lymphoma 21-30%

Table 1. Manifestations of SAP deficiency (XLP1). Based on Seemayer et al. 1995; Schmid et al. 2011; Kanegane et al. 2012; Booth et al. 2011.

Frequency of complications associated with XLP2/ XIAP Deficiency:

  Percent of Patients
HLH 67-90%
Incomplete HLH (Splenomegaly, with or without low blood counts, fever) 33-87%
Low Antibody Levels 22-33%
Inflammatory Bowel Disease 17-22%

Table 2. Manifestations of XIAP deficiency (XLP2). Based on Pachlopnik Schmid et al 2011, Yang et al 2012, Marsh et al 2010.

X-Linked Lymphoproliferative Disease Diagnosis

If your child has a severe response to the Epstein-Barr virus, your doctor may consider testing them for X-linked lymphoproliferative disease. This involves doing genetic tests and protein tests, usually with a blood sample. These tests can help confirm the diagnosis. It can also help the doctor figure out what kind of XLP your child has.

The doctor may suggest that other members of the family have genetic testing for XLP. This may begin with the patient’s mother to see if she is a carrier. Siblings of the patient would be tested next. Aunts, uncles and cousins may be tested, too. Your child’s doctor or genetic counselor can tell you more about genetic testing options.

X-Linked Lymphoproliferative Disease Treatment

The only cure for XLP1 and XLP2/XIAP Deficiency at this time is allogeneic hematopoietic stem cell transplantation (bone marrow transplant with blood-forming stem cells).

If your child has X-linked lymphoproliferative disease, the care team will develop a comprehensive treatment plan. The plan will focus on finding problems (such as HLH and lymphoma) and providing effective therapy.

For example:

  • Treatment for HLH can involve using steroids, chemotherapy or other medicines that help suppress the immune system.
  • In children who develop inflammatory bowel disease, immune suppression therapy can be helpful.
  • Doctors can treat low antibody levels with immunoglobulin replacement therapy.

Children with XLP1 and XLP2/XIAP Deficiency should avoid live virus vaccines because of their abnormal immune system. These include measles, mumps and rubella (MMR); rotavirus; and chickenpox/varicella.