SUMMARY
1. Wiskott-Aldrich syndrome (WAS) is an X-linked disease characterized by thrombocytopenia with small platelets, eczema, cellular and humoral immunodeficiency, autoimmune disease, and malignancy. WAS is caused by mutations in the Wiskott-Aldrich Syndrome Protein (WASP).
2. The classic Wiskott-Aldrich syndrome phenotype is characterized by the following clinical features:
-Immunodeficiency - Patients with WAS develop a combined immunodeficiency. Decreased IgM, normal IgG, and elevated IgA and IgE levels have been reported. Patients have diminished antibody responses to polysaccharide antigens and isohemagglutinins. T cell lymphopenia and decreased mitogen proliferation may be present. Defects in innate immunity have also been described including decreased NK cell cytotoxicity. The types of infections seen in patients reflect the combined nature of the immunodeficiency. Patients experience recurrent bacterial sinopulmonary and invasive (meningitis, sepsis) infections with encapsulated bacteria. Viral infections (HSV, Molluscum) and opportunistic infections (Pneumocystis jiroveci pneumonia, Candida) can also occur.
-Thrombocytopenia - Low platelet counts are present at birth and patients commonly present with bloody diarrhea, bruising, petechiae, purpura, and bleeding from the circumcision site. The mean platelet volume is decreased (3.8-5.0 fl) compared to normal individuals (7.1-10.5 fl).
-Eczema - Mild to severe eczema develops in a majority of patients with WAS. The eczema is often complicated by superinfection with bacterial and viral (HSV, Molluscum) pathogens.
-Autoimmune disease - Autoimmune disease has been reported in 40% of WAS patients. The most common manifestations include hemolytic anemia, ITP, vasculitis, nephritis, and inflammatory bowel disease. Less common autoimmune manifestations include arthritis, neutropenia, dermatomyositis, and uveitis. Increased autoimmunity in WAS may in part be explained by impaired regulatory T cell function.
-Malignancy - Malignancies develop in 13% of patients and occur during adolescence or adulthood. EBV-positive B cell lymphoma is the most common type of cancer.
3. It has now become clear that mutations in WASP can result in a wide spectrum of disease severity. Four distinct clinical phenotypes resulting from WASP mutations have been described. The amount of WASP protein expression largely determines whether patients develop WAS vs. XLT. In some cases, genotype does not correlate with the clinical phenotype.
-Wiskott-Aldrich Syndrome (WAS) - This is the classic severe form of the disease characterized by combined immunodeficiency, eczema, and thrombocytopenia. This phenotype is associated with the complete absence of WASP protein expression due to nonsense and frameshift mutations.
-X-Linked Thrombocytopenia (XLT) - This is a milder form of disease characterized by thrombocytopenia and mild or no immunodeficiency. Patients typically have reduced but not absent protein expression resulting from missense (exons 1-3) mutations and inframe deletions or insertions.
Intermittent X-Linked Thrombocytopenia (IXLT) - In this mild form of disease, patients have intermittent thrombocytopenia but no immunodeficiency, autoimmune disease or malignancies. This is caused by missense mutations in the WASP gene. Protein expression is typically normal.
-X-Linked Neutropenia - Mutations in the Cdc42-binding site of the WASP protein can result in a form of congenital neutropenia. These patients do not have thrombocytopenia, eczema, or humoral/T cell immunodeficiency. WASP protein expression is normal.
4. WASP protein is expressed in hematopoietic cells and functions to enhance actin polymerization and branching allowing cells to rearrange their actin cytoskeleton. Cytoskeletal rearrangement is vital for a number of key functions in immune cells such as endocytosis, exocytosis, chemotaxis, and formation of the immunologic synapse.
5. Screening for Wiskott-Aldrich syndrome can be accomplished by performing flow cytometry for WASP protein expression. As described above, WASP protein levels may be normal in XLT. Sequencing of the WASP gene provides a definitive diagnosis.
6. WAS patients with antibody deficiency benefit from IVIG replacement therapy. Patients may also benefit from prophylactic antibiotic therapy (ex. Amoxicillin 20mg/kg divided BID - maximum 500mg BID). Patients with a severe immunodeficiency may require trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis jiroveci pneumonia.
7. Thrombocytopenia resulting in bleeding may require platelet transfusions, IVIG, or steroid therapy. Splenectomy typically results in an increase in platelet number and platelet size and appears to significantly improve survival in patients (median survival 25 yrs vs. 5 years for non-splenectomized group) who do not undergo hematopoietic stem cell transplantation (HSCT).
8. WAS patients with severe disease who have an HLA-matched sibling donor are good candidates for HSCT (ideally before the age of 5). This therapy can cure both the immunological and hematological abnormalities. Five year survival following fully matched sibling transplantion is 90%. Results for matched unrelated donor (MUD) transplants in WAS before the age of 5yo are almost equivalent to matched sibling transplants. Survival following haploidentical transplants is significantly lower.
9. The major causes of death for patients include infections, bleeding, or malignancy. Autoimmune disease (particularly hemolytic anemia and ITP) are associated with poor prognosis. Patients with WAS typically live until the second decade of life without a transplant while the majority of XLT patients reach adulthood.
OVERVIEW
Wiskott-Aldrich syndrome (WAS) is an X-linked disease characterized by thrombocytopenia with small platelets, eczema, cellular and humoral immunodeficiency, autoimmune disease, and malignancy. WAS is caused by mutations in the Wiskott-Aldrich Syndrome Protein (WASP).
The classic Wiskott-Aldrich syndrome phenotype is characterized by the following clinical features:
-Immunodeficiency - Patients with WAS develop a combined immunodeficiency. Decreased IgM, normal IgG, and elevated IgA and IgE levels have been reported. Patients have diminished antibody responses to polysaccharide antigens and isohemagglutinins. T cell lymphopenia and decreased mitogen proliferation may be present. Defects in innate immunity have also been described including decreased NK cell cytotoxicity. The types of infections seen in patients reflect the combined nature of the immunodeficiency. Patients experience recurrent bacterial sinopulmonary and invasive (meningitis, sepsis) infections with encapsulated bacteria. Viral infections (HSV, Molluscum) and opportunistic infections (Pneumocystis jiroveci pneumonia, Candida) can also occur.
-Thrombocytopenia - Low platelet counts are present at birth and patients commonly present with bloody diarrhea, bruising, petechiae, purpura, and bleeding from the circumcision site. The mean platelet volume is decreased (3.8-5.0 fl) compared to normal individuals (7.1-10.5 fl).
-Eczema - Mild to severe eczema develops in a majority of patients with WAS. The eczema is often complicated by superinfection by bacterial and viral (HSV, Molluscum) pathogens.
-Autoimmune disease - Autoimmune disease has been reported in 40% of WAS patients. The most common manifestations include hemolytic anemia, ITP, vasculitis, nephritis, and inflammatory bowel disease. Less common autoimmune manifestations include arthritis, neutropenia, dermatomyositis, and uveitis. Increased autoimmunity in WAS may in part be explained by impaired regulatory T cell function.
-Malignancy - Malignancies develop in 13% of patients and occur during adolescence or adulthood. EBV-positive B cell lymphoma is the most common type of cancer.
It has become clear that mutations in WASP can result in a spectrum of disease severity. Four distinct clinical phenotypes resulting from WASP mutations have been described. The amount of protein expression largely determines whether patients develop WAS vs. XLT. In some cases, genotype does not correlate with the clinical phenotype due to spontaneous genetic reversions.
-Wiskott-Aldrich Syndrome (WAS) - This is the classic severe form of the disease characterized by immunodeficiency, eczema, and thrombocytopenia. This phenotype is associated with the complete absence of WASP protein expression due to nonsense and frameshift mutations.
-X-Linked Thrombocytopenia (XLT) - This is a milder form of disease characterized by thrombocytopenia and mild or no immunodeficiency. Patients typically have reduced but not absent protein expression resulting from missense (exons 1-3) mutations and inframe deletions or insertions.
Intermittent X-Linked Thrombocytopenia (IXLT) - In this mild form of disease, patients have intermittent thrombocytopenia but no immunodeficiency, autoimmune disease or malignancies. This is caused by missense mutations in the WASP gene. Protein expression is normal.
-X-Linked Neutropenia - Mutations in the Cdc42-binding site of the WASP protein can result in a form of congenital neutropenia. These patients do not have thrombocytopenia, eczema, or humoral/T cell immunodeficiency. WASP protein expression is normal.
The major causes of death for patients include infections, bleeding, or malignancy. Autoimmune disease (particularly hemolytic anemia and ITP) are associated with poor prognosis. Patients with WAS typically only live until the second decade of life without a transplant while the majority of XLT patients reach adulthood.
PATHOGENESIS
WASP is an intracellular protein expressed exclusively in hematopoietic cells. It functions to enhance actin polymerization and branching allowing cells to rearrange their actin cytoskeleton. Cytoskeletal rearrangement is vital for a number of key functions in immune cells such as endocytosis, exocytosis, chemotaxis, and formation of the immunologic synapse.
WASP-interacting protein (WIP) constitutively interacts with the EVH1 domain of WASP to inhibit its function. TCR-mediated activation results in phophorylation or WIP and allows for activation of WASP by Rho-family GTPases (Rho, Rac, Cdc42). Following activation WASP assumes an open configuration; actin related protein 2/3 (Arp 2/3) then binds the VCA domain of WASP leading to actin polymerization and permitting the reorganization of the cytoskeleton.
It is believed that mutations in WASP interfere with proper cell signaling and growth of hematopoietic cells, resulting in thrombocytopenia and immunodeficiency. The exact mechanisms of how WASP mutations lead to the clinical phenotype have not been elucidated.
EVALUATION
Wikott-Aldrich syndrome should be suspected in males with early onset thrombocytopenia, eczema, and sinopulmonary infections. X-linked thrombocytopenia should be suspected in males with thrombocytopenia who have a family history suggestive of X-linked inheritance pattern.
Step 1: Immune Evaluation
-CBC with Differential
-Quantitative immunoglobulins (IgG, IgM, IgA, IgE)
-Antibody titers to vaccine antigens
-Isohemaglutinin Titers
-Flow cytometry for B cell, T cell, and NK cell enumeration
-T cell proliferation to mitogens and specific antigens (candida and tetanus)
-NK cell functional assay
-Thrombocytopenia with small platelet size (MPV 3.8-5.0 fl) is present from birth
-Low IgM, normal IgG, and elevated IgA/IgE have been reported.
-Antibody responses to protein and polysaccharide antigens can be decreased.
-Isohemaglutinin titers are decreased
-T cell lymphopenia may be present
-Decreased mitogen proliferation is present in one-half of patients
-Decreased NK cell cytotoxic function may be present
Step 2: WAS Screening Studies
-WASP protein analysis
-A rapid intracellular flow cytometry assay to assess for the presence or absence of WASP protein is commercially available (Cincinnati Childrens). Some patients (particularly with XLT) can have normal protein levels.
Step 3: Genetic confirmation
-WAS gene sequencing
-Sequencing of the WAS gene provides a definitive diagnosis. This test is commercially available through Correlagen Diagnostics or Cincinnati Childrens Hospital. Genetic confirmation of WAS can be achieved by sanger sequencing, whole exome sequencing or whole genome sequencing.
MANAGEMENT
WAS patients with antibody deficiency benefit from IVIG replacement therapy. Patients may also benefit from prophylactic antibiotic therapy (ex. Amoxicillin 20mg/kg divided BID maximum 500mg BID). PJP prophylaxis with trimethoprim-sulfamethoxazole should be considered for patients with significant T cell lymphopenia or decreased T cell proliferation to mitogens.
Thrombocytopenia resulting in bleeding may require platelet transfusions, IVIG, or steroid therapy. Splenectomy typically results in an increase in platelet number and platelet size. It appears to significantly improve survival in patients (median survival 25 yrs vs. 5 years for non-splenectomized group) who do not undergo hematopoietic stem cell transplantation (HSCT).
WAS patients with severe disease who have an HLA-matched sibling donor are good candidates for HSCT (ideally before the age of 5). This therapy can cure both the immunological and hematological abnormalities seen in patients. Five year survival following fully matched transplantion is 90%. Matched unrelated donor transplants in WAS children less than five years of age have been almost as successful as matched sibling transplants. The patient survival following haploidentical transplants are significantly lower (approximately 50%).
RESOURCES
Diagnostic Resources
1. WASP Flow Cytometry (Cincinnati)
2. WAS Gene Sequencing (Correlagen or Cincinnati)
Literature Resources
1. Sullivan 1994
Wiskott Aldrich Syndrome Multi-institutional Survey
2. Ochs 2006
Wiskott Aldrich Syndrome Review
3. Dupuis-Girod 2003
Autoimmunity in Wiskott-Aldrich - Hemolytic anemia and ITP predict poor prognosis
4. Adriani 2007
Impaired regulatory T cell function in Wiskott-Aldrich
5. Stewart 2007
The phenomenon of spontaneous genetic reversions in WAS
6. Mullen 1993
Splenectomy in the management of Wiskott-Aldrich Syndrome (39 cases)
7. Filipovich 2001
Impact of donor type and outcome of BMT for Wiskott-Aldrich
8. Kobayashi 2006
Stem cell transplantation for WAS - 57 patients in Japan
9. Pai 2006
Stem cell transplantation for WAS - matched unrelated donors