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Disease Information

Inherited Immunodeficiencies: X-linked Lymphoproliferative Syndrome (XLP)

Alternate Names: XLP

Definition

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 test looking for a mistake in the XLP gene).

Incidence

X-linked lymphoproliferative syndrome occurs with a frequency of less than 1/million.

Influencing Factors

Pattern of inheritance
The gene for X-linked lymphoproliferative syndrome is found on the X chromosome. Because females have two X chromosomes, if they have a mutation on one X chromosome, they have a spare X that can help compensate for the mutation. Males have only one X chromosome and one Y chromosome. Since they do not have a spare X chromosome, they show signs of a mutation inherited on the X chromosome. Although a female who carries the mutation for X-linked lymphoproliferative syndrome on one of her X chromosomes shows no signs of immunodeficiency, her sons and daughters have a 50 percent chance of inheriting the X chromosome with the mutation (and a 50 percent chance of inheriting the normal X chromosome). The sons who inherit the mutant X chromosome will have XLP and the daughters who inherit the mutant X chromosome will be carriers like their mother. Carriers of XLP can be identified by mutation detection (a laboratory test). 

All of the daughters of a man with X-linked lymphoproliferative syndrome will be carriers of XLP; but the sons, who have inherited his unaffected Y chromosome, will be normal.  About 50 percent of patients with X-linked lymphoproliferative syndrome will have a brother, cousin or uncle with XLP.  In most remaining families, the affected individual represents the first sign of a new mutation (mistake) in the XLP gene in his family. We do not know what causes new mutations in most families.

Typically the disorder affects males, but there have been some females who appear to have the same physical problems as males with X-linked lymphoproliferative syndrome, without the genetic mutation (mistake).

Clinical Features and Symptoms

The diagnosis of X-linked lymphoproliferative syndrome is suspected in males who have a severe, abnormal immune system response to infection with EBV. Patients can experience swollen lymph nodes (palpable glands in the neck, groin), sore throat, fever, and severe hepatitis. After infection with EBV, some patients develop aplastic anemia (low levels of all type of blood cells), and hypogammaglobulinemia  (low levels of antibodies in the bloodstream). Severe symptoms occur because the immune system cannot effectively handle the EBV as in normal individuals.

Survival Rates

Patients with X-linked lymphoproliferative syndrome can vary in their responses to infection with EBV. Younger males with acute infection are more likely to have fatal outcomes. Older males who develop the infection may develop hypogammaglobulinemia which results in poor antibody function, or severe anemia and require therapies for these problems.

Treatment Strategies

Currently, the only curative option is bone marrow transplant. The best donor is a brother or sister who is a match. If a matched brother or sister is not available, a matched unrelated donor may be used.

Patients with altered antibody responses may be placed on chronic daily antibiotics, antiviral medicines and monthly infusions of IVIG.

Current Research

• Understanding the role of the XLP gene in the normal immune system
• How to treat patients with X-linked lymphoproliferative syndrome during an acute infection with EBV
• Improving bone marrow transplant to cure X-linked lymphoproliferative syndrome

 

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