SUMMARY

 

1.  Autoimmune lymphoproliferative syndrome (ALPS) is a disease caused by abnormal apoptosis of lymphocytes.  It can be inherited as an autosomal dominant or autosomal recessive disease.

 

2.  The initial onset of symptoms typically occurs during childhood (age 2-5).  Clinical manifestations include lymphoadenopathy, hepatosplenomegaly and autoimmune cytopenias (anemia, thrombocytopenia, neutropenia).  Patients are also at risk for developing lymphoma later in life (10% of ALPS Ia patients). 

 

3.  ALPS is caused by mutations in genes involved in Fas/Fas-L mediated pathway.  ALPS mutations result in impaired apoptosis of activated lymphocytes which proliferate and cause autoimmune inflammation and undergo malignant transformation.  The vast majority of patients have heterozygous mutation in Fas (ALPS-FAS).  The following types of ALPS fave been reported to date:

 

ALPS-FAS (AR): Homozygous mutations in Fas lead to a severe 
        phenotype with lymphoproliferation shortly after birth and death at     
        an early age.  These patients are candidates for stem cell 
        transplantation.  This was previously known as ALPS Type 0

     

 •ALPS-FAS (AD): This is caused by heterozygous mutations in Fas - 
        patients have impaired Fas signal transduction despite the 
        presence of surface protein.  This is the most common type of 
        ALPS.  This was previously known as ALPS Type Ia.    

       

ALPS-sFAS:  Patients fulfill ALPS diagnostic criteria and have somatic 
         mutations in FAS.  

       

ALPS-FASLG (AD):  This is caused by heterozygous mutations in Fas-
         L.  One patient with dominant Fas-L mutation has been 
         described.  This was previously known as ALPS Ib. 

       

ALPS-CASP10 (AD):  This is caused by heterozygous mutations in 
         Caspase 10.  This was previously known as ALPS IIa. 

       

ALPS-U:  These patients have clinical features of ALPS but do 
         not have mutations in any of the known causative genes.   This was 
         previously known as ALPS III

 

4.  The diagnosis of ALPS is suggested by the following:  

 

                      * Chronic nonmalignant lymphoproliferation

* >1% circulating CD4-/CD8- (double negative) T cells

* Defective in vitro Fas-mediated apoptosis 

 

5.  The presence of autoimmune cytopenias and a family history of ALPS can be supportive.  Mutation analysis of known ALPS genes (Fas, Fas-L, caspase 10) can provide a definitive diagnosis. 

 

6.   The treatment of ALPS is mainly focused on the management of autoimmune phenomena.  Autoimmune cytopenias respond to corticosteroids or other immunosuppressive agents.   Rituximab and splenectomy have been used for treatment of severe refractory ITP.  Chronic neutropenia has been treated effectively with G-CSF injections. 

 

7.  Patients with homozygous Fas mutations (ALPS-FAS) have a very short life expectancy - these patients are candidates for hematopoietic stem cell transplantation. 

 

 

 

                                                                                                                                       

OVERVIEW

 

            Autoimmune lymphoproliferative syndrome (ALPS) is a disease caused by abnormal apoptosis of lymphocytes. It can be inherited as an autosomal dominant or autosomal recessive disease. The initial onset of symptoms typically occurs during childhood (age 2-5). Clinical manifestations include lymphadenopathy, hepatosplenomegaly and autoimmune cytopenias (anemia, thrombocytopenia, neutropenia). Autoimmune cytopenia occurs in one-half of patients and can precede the development of lymphadenopathy. Patients are also at risk for developing lymphoma later in life (10% of ALPS Ia patients).

 

          ALPS is caused by mutations in genes involved in Fas/Fas-L mediated pathway. ALPS mutations result in impaired apoptosis of activated lymphocytes which proliferate and cause autoimmune inflammation and undergo malignant transformation. The vast majority of patients have heterozygous mutation in Fas (ALPS-FAS). Fas is highly expressed on activated B and T cells. Activation of Fas by binding to Fas-L mediates formation of the death inducing signaling complex (DISC) - this is formed by interaction of Fas homotrimers with the adapter protein FADD (Fas-associated death domain). There is subsequent recruitment and activation of the proteases caspase 8 and caspase 10 which mediate cell apoptosis.

 

 •ALPS-FAS (AR): Homozygous mutations in Fas lead to a severe 
        phenotype with lymphoproliferation shortly after birth and death at     
        an early age.  These patients are candidates for stem cell 
        transplantation.  This was previously known as ALPS Type 0

       

ALPS-FAS (AD): This is caused by heterozygous mutations in Fas - 
        patients have impaired Fas signal transduction despite the 
        presence of surface protein.  This is the most common type of 
        ALPS.  This was previously known as ALPS Type Ia.    

       

ALPS-sFAS:  Patients fulfill ALPS diagnostic criteria and have somatic 
         mutations in FAS.  

       

ALPS-FASLG (AD):  This is caused by heterozygous mutations in Fas-
         L.  One patient with dominant Fas-L mutation has been 
         described.  This was previously known as ALPS Ib. 

       

ALPS-CASP10 (AD):  This is caused by heterozygous mutations in 
         Caspase 10.  This was previously known as ALPS IIa. 

       

ALPS-U:  These patients have clinical features of ALPS but do 
         not have mutations in any of the known causative genes.   This was 
         previously known as ALPS III

 

                                                                               

 

EVALUATION

 

Evaluation for ALPS should be considered in patients with non-malignant lymphadenopathy, splenomegaly, hepatomegaly, and autoimmune cytopenia.

 

Step 1:  Immune Evaluation 

         

                      * CBC with Differential

* Quantitative immunoglobulins (IgG, IgM, IgA)

* Antibody titers to vaccine antigens

* Flow cytometry for B cell, T cell, and NK cell enumeration CD4-CD8- (double negative) T cell enumeration

* Apoptosis Assay

     

    Patients may have autoimmune anemia, thrombocytopenia, or 
               neutropenia.

     Hypergammaglobulinemia (IgG, IgM, IgA) may be present
     Specific antibody responses to vaccine antigens are typically 
               normal.

     Lymphocytosis may be present due to the underlying defect in 
               lymphocyte apoptosis.

     A CD4-/CD8- (double negative) T cell population greater than  
               1% can be supportive of the diagnosis. 

     Defective lymphocyte apoptosis in vitro is also supportive of the 
               diagnosis.

 

 

Step 2:  Additional Immune Evaluation

           

* Soluble Fas-L and IL-10 levels

* Lymph Node Histopathology

 * T cell activation markers (HLA-DR and Soluble CD25)

 

- Elevated soluble Fas-L and IL-10 levels can be seen in ALPS

- Follicular hyperplasia in lymph nodes and lymphoid hyperplasia of the white pulp can be seen on lymph node biopsy (these findings are not

               specific for ALPS).

- Increased HLA-DR expression and high levels of soluble CD25 (sIL-2 R) can be seen and reflect increased T cell activation.

 

Step 3:  Gene Sequencing

 

* Fas (TNFRSF6) gene sequencing
 * Fas-L (TNFSF6) gene sequencing
 * Caspase 10 gene sequencing

     

Gene sequencing for the above genes is commercially available through Cincinnati Childrens molecular genetics laboratory and Gene Dx.

 

 

                                                                      

MANAGEMENT

         

          The treatment of ALPS is mainly focused on the management of autoimmune phenomena.  Autoimmune cytopenias respond to corticosteroids or other immunosuppressive agents (mycophenoate mofetil, sirolimus, etc.).   Rituximab has been used with success for treatment of severe refractory ITP.  Chronic neutropenia has been treated effectively with granulocyte colony stimulating factor injections. 

 

          Patients with refractory thrombocytopenia/hemolysis or splenic rupture may require splenectomy.  However, patients are at increased risk for developing sepsis from encapsulated bacteria following this procedure.  

                                                                           

          Patients with homozygous Fas mutations (ALPS-FAS) have a very short life expectancy.  These patients are candidates for hematopoietic stem cell transplantation. 

 

 

 

 

RESOURCES

 

 Diagnostic Resources  

 

1.   CINCINNATI CHILDRENS - ALPS Panel, Apoptosis Assay      
      

2.   CINCINNATI CHILDRENS - Cytokines, plasma 
      (includes IL-10) 
      

3.   CINCINNATI CHILDRENS - Soluble IL-2 receptor (CD25) 
      and Lymphocyte Activation Markers (includes HLA-DR)          
    

4.   CINCINNATI CHILDRENS -  
      (Fas, Fas-L, Caspase 10) gene sequencing 
      

5.    GENE DX - ALPS (Fas, Fas-L) gene sequencing 

 

 

 Literature Resources

 

 

1.  Worth 2006 

     ALPS (Review)

 

2.  Del Rey 2006

     Homozygous Fas-L Mutation in an ALPS Patient

 

3.  Sleight 1998

     Correction of ALPS by BMT (Case Report)