SUMMARY

 

1.  X-linked lymphoproliferative syndrome (XLP) is a genetic disorder characterized by severe immune dysregulation.  The key disease features include the following: 

 

-Fulminant EBV (50-60%)  - This is the most common presenting feature and is associated with fever, lymphadenopathy, hepatosplenomegaly, pancytopenia, and hepatitis.  This is a form of hemophagocytic lymphohistiocytosis (HLH) that is thought to occur from impaired cell cytotoxicity - failure to eliminate proliferating EBV-infected B cells leads to prolonged antigen presentation and subsequent hyperproliferation and tissue infiltration of macrophages and cytotoxic lymphocytes.  Patients are well clinically until EBV infection occurs but the majority will die within 1 month of this infection (most commonly from liver failure secondary to hepatic necrosis).  

 

-Immunodeficiency (30%) - Immunodeficiency typically occurs after EBV infection if patients survive.  This may be due to the extensive necrosis in lymphoid organs and bone marrow that occurs.  However, some patients may have immune abnormalities in the absence of EBV infection.  Patients can have decreased IgG, IgM, and IgA (some patients may have elevated IgA and IgM).  Specific antibody responses to vaccine antigens may be reduced.  T cell numbers may be normal but there may be an inversion of the CD4:CD8 ratio.  T cell and NK cell function may be normal or low.  Some patients with XLP may be erroneously diagnosed with CVID.  

 

-Lymphoma (30%) - One-third of patients develop B cell lymphomas, possibly due to impaired immune surveillance by T cells.  Lymphomas are often extranodal with 75% occurring in the ileocecal region (other locations include liver, CNS and kidneys).   
          
 -Less common clinical features include the following:
          -Lymphocytic vasculitis (3%)
          -Aplastic anemia (3%)
          -Lymphomatoid granulomatosis (3%)
          -Chronic hemorrhagic colitis (17% of XIAP deficiency patients)

 

2.  Two molecular causes of XLP have been identified to date but the genetic basis for other forms of XLP remains to be characterized:

 

-SAP Deficiency (XLP-1):  This is caused by mutations in the SH2D1A gene which encodes for the SLAM-associated protein (SAP).  This accounts for 60% of patients with XLP.  The interaction of SAP with SLAM family receptors (including SLAM, 2B4, CD84, CD229, NTBA, and CS1) mediates the activation and interaction of T cells, B cells, and NK cells  this influences cell cytotoxicity, cytokine production, and antibody production. 

 

-XIAP Deficiency (XLP-2):  This is caused by mutations in the gene encoding X-linked inhibitor of apoptosis (XIAP).  Lymphocytes from XIAP-deficient patients display increased susceptibility to apoptotic stimuli excessive lymphocyte apoptosis may lead to defective control of EBV infection in this disease.  

 

3.  The diagnosis of XLP should be considered in any male patient with severe infectious mononucleosis progressing to HLH or a family history of severe EBV infection in males. 

 

4.  A rapid screen for SAP and XIAP protein expression by flow cytometry is available.  Definitive diagnosis requires gene sequencing.  

 

5.  The management of XLP focuses on the treatment of disease manifestations.  Fulminant EBV infection should be treated with an appropriate HLH protocol.  Patients who develop antibody deficiency benefit from IVIG replacement therapy.  Lymphomas require chemotherapy or radiotherapy. 

 

6.  The prognosis is quite poor with 70% of patients dying before the first 10 years of life.  The only curative therapy for XLP is a hematopoietic stem cell transplantation.  Younger age and lack of infections at the time of transplant are associated with better outcomes.  

 

 

 

 

OVERVIEW

 

    X-linked lymphoproliferative syndrome (XLP) is a genetic disorder characterized by severe immune dysregulation.  The key disease features include the following: 

 

-Fulminant EBV (50-60%) - This is the most common presenting feature and is associated with fever, lymphadenopathy, hepatosplenomegaly, pancytopenia, and hepatitis.  This is a form of hemophagocytic lymphohistiocytosis (HLH) that is thought to occur from impaired cell cytotoxicity - failure to eliminate proliferating EBV-infected B cells leads to prolonged antigen presentation and subsequent hyperproliferation and tissue infiltration of macrophages and cytotoxic lymphocytes.  Patients are well clinically until EBV infection occurs but the majority will die within 1 month of this infection (most commonly from liver failure secondary to hepatic necrosis).  

 

-Immunodeficiency (30%) - Immunodeficiency typically occurs after EBV infection if patients survive.  This may be due to the extensive necrosis in lymphoid organs and bone marrow that occurs.  However, some patients may have immune abnormalities in the absence of EBV infection.  Patients can have decreased IgG, IgM, and IgA (some patients may have elevated IgA and IgM).  Specific antibody responses to vaccine antigens may be reduced.  T cell numbers may be normal but there may be an inversion of the CD4:CD8 ratio.  T cell and NK cell function may be normal or low.  Some patients with XLP may be erroneously diagnosed with CVID.  

          The overall risk of misdiagnosing XLP patients with CVID appears to be fairly low:  in one study, 60 males 
          with a diagnosis of CVID were evaluated for XLP  only one patient was found to have XLP (the patients 
          family history was consistent with an X-linked inheritance pattern).
  
-Lymphoma (30%) - One-third of patients develop B cell lymphomas, possibly due to impaired immune surveillance by T cells.  Lymphomas are often extranodal with 75% occurring in the ileocecal region (other locations include liver, CNS and kidneys).   

 

Less common clinical features include the following:
 

-Lymphocytic vasculitis (3%)
-Aplastic anemia (3%)
-Lymphomatoid granulomatosis (3%)
-Chronic hemorrhagic colitis (17% of patients with XIAP deficiency)

       

 

 

PATHOGENESIS

 

Two molecular causes of XLP have been identified to date but the genetic basis of other forms of XLP remains to be characterized:

 

-SAP Deficiency (XLP-1):  This is caused by mutations in the SH2D1A gene which encodes for the SLAM-associated protein (SAP).  This accounts for 60% of patients with XLP.  The interaction of SAP with SLAM family receptors (including SLAM, 2B4, CD84, CD229, NTBA, and CS1) mediates the activation and interaction of T cells, B cells, and NK cells  this influences cell cytotoxicity, cytokine production, and antibody production.  In T cells, SAP-SLAM interaction is involved in cell activation.  In NK cells, SAP normally blocks interactions between the activating receptor 2B4 and inhibitory molecules  when SAP is absent, NK cell activation is inhibited.    

 

-XIAP Deficiency (XLP-2):  This is caused by mutations in the gene encoding X-linked inhibitor of apoptosis (XIAP).  Lymphocytes from XIAP-deficient patients display increased susceptibility to apoptotic stimuli  excessive lymphocyte apoptosis may lead to defective control of EBV infection in this disease.   

 

 

 

 

EVALUATION

 

The diagnosis of XLP should be considered in any male patient with severe infectious mononucleosis progressing to HLH or a family history of severe EBV infection in males.  It should be on the differential diagnosis for male patients with CVID.  

 

 

Step 1:  HLH Laboratory Studies (during acute EBV infection)

 

-EBV PCR
-CBC with Differential
-Liver Function Tests
-PT, PTT
-Triglyceride and Fibrinogen levels
-Ferritin Levels
-Soluble IL-2 Receptor
-Bone Marrow or Lymph Node biopsy

 

-EBV DNA can typically be detected by PCR during acute infection
-Cytopenia in at least two cell lines is a diagnostic criteria for HLH (Hb < 9 mg/l, Platelets <100,000/ul, Neutrophils <1,000/ul)
-Liver dysfunction including markedly elevated liver transaminases and hyperbilirubinemia are common
-Coagulation abnormalities occur due to profound liver dysfunction
-Hypertriglyceridemia and hypofibrinogenemia may be present
-Elevated Ferritin > 500 ng/ml may be present
-Soluble IL-2 Receptor (sCD25) levels may be elevated.  
-Tissue demonstration of hemophagocytosis may require multiple biopsy attempts (in 20% of HLH cases, demonstration of hemophagocytosis on a first bone marrow attempt is not possible).  

 

 

Step 2: Immune Evaluation  patients typically develop immune abnormalities following EBV infection but some patients may have abnormalities even in the absence of infection. 

 

-Quantitative immunoglobulins (IgG, IgM, IgA) 
-Antibody titers to vaccine antigens   
-Flow cytometry for B cell, T cell, and NK cell enumeration
-Switched memory B cell  (CD27+IgD-IgM-) enumeration
-T cell proliferation to mitogens
-NK Functional Assay

 

-Patients may have low IgG, IgM, and IgA.  Elevated IgM and IgA have been described in some patients.  
-Specific antibody responses to vaccines may be decreased.  
-Total T cell numbers are typically normal but an inverted CD4:CD8 ratio may be present 
-Reduced numbers of switched memory B cells may be present
-T cell and NK cell function may be decreased 

 

 

Step 3:  XLP Screening Studies

 

-SAP Flow Cytometry
-XIAP Flow Cytometry

 

-SAP and XIAP detection by flow cytometry can provide rapid diagnosis of XLP.

 

 

Step 4:  Genetic confirmation

 

-XLP-1:  SH2D1A (SAP) gene sequencing
-XLP-2:  XIAP gene sequencing

 

-The diagnosis can be confirmed by detection of mutations in the SH2D1A or XIAP gene.  Sequencing for both genes is now commercially available. 

 

 

 

 

MANAGEMENT

 

   The management of XLP focuses on the treatment of disease manifestations.  Fulminant EBV infection should be treated with an appropriate HLH protocol.  Patients who develop antibody deficiency benefit from IVIG replacement therapy.  Lymphomas require treatment with standard chemotherapy protocols but relapses may be common. 
 
     The prognosis is quite poor with 70% of patients dying before the first 10 years of life.  The only curative therapy for XLP is a hematopoietic stem cell transplantation.  Younger age and lack of infections at the time of transplant are associated with better outcomes.  

 

 

 

 

                                                                           

RESOURCES

 

Diagnostic Resources     

 

1. CINCINNATI CHILDRENS - SAP and XIAP flow cytometry 

2. CINCINNATI CHILDRENS - SH2D1A (SAP) and BIRC4 (XIAP) gene sequencing           

3. CORRELAGEN - SH2D1A (SAP) gene sequencing 

4.  SEATTLE CHILDRENS - SAP and XIAP flow cytometry
                                              SAP and XIAP gene sequencing

 

 

 

Literature Resources

 

1.  Rezaei 2010 
     X-linked Lymphoproliferative Syndrome (review)     
    

2.  Marsh 2010 
     Using flow cytometry to screen for SAP and XIAP deficiency in XLP
     

3.  Lankester 2005 
     HSCT for XLP (2 cases and review of literature)
     

4.  Soresina 2002 
     XLP mimicking CVID (2 cases)
     

5.  Eastwood 2004 
     Prevalence of XLP in 60 male patients diagnosed with CVID (only 1 patient)