X-Linked Lymphoproliferative Disease (XLP)

X-Linked Lymphoproliferative Disease (XLP)

What Is XLP? 

X-linked lymphoproliferative disease (XLP) is a genetic condition where the immune system doesn’t work like it should.

XLP mainly affects males.

There are two types of XLP: XLP1 (sometimes called Duncan’s syndrome) and XLP2. 

What Causes XLP?

XLP can be caused by variations in the genetic makeup of a person. Genes are part of our genetic makeup. They provide the instructions our cells need to do their roles within our bodies. XLP can be caused by changes or mutations in one of these genes: SH2D1A or XIAP / BIRC4. When these genes have a defect, the immune system doesn’t work the right way. This can cause the manifestations of XLP to develop.   

How is XLP inherited?  
XLP1 and XLP2 are both X-linked diseases. This means the genes which cause them are on the X chromosome.  Boys have one X chromosome and one Y chromosome.  Girls have two X chromosomes.  When a boy has an X chromosome that has a mutated, or “bad,” copy of the SH2D1A or XIAP / BIRC4 gene, he develops XLP.   

Mothers or sisters of patients with XLP may also have an X chromosome that has a bad copy of the SH2D1A or XIAP / BIRC4 gene.  Since females have two X chromosomes, most females will never have any symptoms of the disease. This is because there is a normal copy of the gene on their other X chromosome. Very rarely, female carriers may also develop symptoms of XLP1. 

In most cases, patients inherit the X chromosome with the bad copy of the gene from their mother.  In some cases, the mutation spontaneously occurs in the child.   

I am an XLP carrier. What are the chances my children are affected?  
Women who have a bad copy of an XLP gene on one of their X chromosomes are called carriers. For these women, each pregnancy has a 50 percent chance of getting the X chromosome with the bad copy of the gene. Each male child of an XLP carrier has a 50 percent chance of being affected by XLP. Each female child has a 50 percent chance of being a carrier. They will likely never be sick, but their future male children may be affected.

What Are the Symptoms of XLP?

The symptoms of XLP and the ages of onset vary greatly in patients. This even varies in patients in the same family. Some symptoms of XLP1 and XLP2 include:  

  • HLH: Patients with XLP1 and XLP2 can develop hemophagocytic lymphohistiocytosis (HLH).  Symptoms of HLH include persistent fevers, rash, enlarged liver and/or spleen, enlarged lymph nodes, anemia, low platelets, low white blood cells, bleeding or easy bruising, jaundice, hepatitis, liver failure, respiratory problems, seizures, and altered mental function.   
  • Low antibody levels: Patients with XLP1 and XLP2 can both develop low antibody levels (hypogammaglobulinemia).  Low antibody levels can lead to recurrent infections (such as ear infections, sinus infections, pneumonia, blood stream infections and other illness). 
  • Lymphoma: Only patients with XLP1 develop lymphoma. Patients with lymphoma may develop fatigue, fevers, easy bruising, a pale look, body aches, weight loss and swollen lymph nodes in the neck, armpit, groin or abdomen. 
  • Recurrent fevers, splenomegaly and low blood counts: Patients with XLP2 are likely to develop recurring fevers, low blood counts and enlarged spleens, but without the full picture of HLH.
  • Inflammatory bowel disease: Patients with XLP2 are also at risk of developing inflammatory bowel disease (which is often diagnosed as Crohn’s disease).  Symptoms may include belly pain, loose stools or gastrointestinal bleeding.   

What are the differences between XLP1 and XLP2?  

XLP1

  • Caused by mutations in SH2D1A
  • Results in either absence or poor function of the protein SAP
  • Often called SAP deficiency after the protein defect it causes
  • Associated with HLH, lymphoma and hypogammaglobulinemia, and other more rare manifestations

XLP2

  • Caused by mutations in XIAP / BIRC4
  • Results in either absence or poor function of the protein XIAP
  • Often called XIAP deficiency, after the protein defect it causes
  • Associated with HLH, hypogammaglobulinemia, recurrent fevers, recurrent low blood counts, splenomegaly, and inflammatory bowel disease
  • Not associated with lymphoma

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:

   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. 

How Is XLP Diagnosed?

Both XLP1 and XLP2 are most often diagnosed by genetic testing and/or protein testing. Testing is most often done with blood samples.  

My son was diagnosed with XLP. Do my other children need to be tested?  
Your doctor may suggest testing the patient’s mother first to see if she is a carrier.  Then they will evaluate other children in the family. Or your doctor may test other children right away. Testing may even need to be done in aunts, uncles and cousins within the family. Your doctor or genetic counselor can tell you more about testing. 

How Is XLP Treated?

Patients need treatment for hemophagocytic lymphohistiocytosis (HLH) when it occurs.  Treatment can involve steroids, chemotherapy or other immune suppressive medicines.   

Patients with XLP1 who develop lymphoma need treatment with current standard-of-care lymphoma treatment. Low antibody levels are often treated with immunoglobulin replacement (IVIG or subcutaneous antibody replacement).  Immune suppression is often needed for patients with inflammatory bowel disease.  The only cure for XLP1 and XLP2 at this time is bone marrow transplant. 

Patients with XLP1 and XLP2 should avoid all live virus vaccines (MMR, rotavirus and chicken pox / varicella) because of their weakened immune system.

Last Updated 11/2018

Who treats this.

Cincinnati Children's specialists in the Immune Deficiency and Histiocytosis Program have extensive experience in diagnosing and managing rare immune deficiencies.