Wiskott-Aldrich syndrome is an immunodeficiency disorder that involves a combined B-cell and T-cell defect and is characterized by recurrent infection, eczema, and thrombocytopenia. Diagnosis involves assessment of immunoglobulin levels, platelet count and volume, and white blood cell function. Treatment is prophylactic antibiotics and immune globulins and hematopoietic stem cell transplantation.
(See also Overview of Immunodeficiency Disorders and Approach to the Patient With an Immunodeficiency Disorder.)
Wiskott-Aldrich syndrome is a primary immunodeficiency disorder that involves combined humoral and cellular immunity deficiencies.
Inheritance is X-linked recessive. Wiskott-Aldrich syndrome is caused by mutations in the gene that encodes the Wiskott-Aldrich syndrome protein (WASP), a cytoplasmic protein necessary for normal B-cell and T-cell signaling. Thrombocytopenia likely occurs due to various reasons, including increased platelet clearance, ineffective thrombocytopoiesis, and/or decreased platelet survival (1).
Because B-cell and T-cell functions are impaired, infections with pyogenic bacteria and opportunistic organisms, particularly viruses and Pneumocystis jirovecii, develop. Infections with varicella zoster virus and herpes simplex virus are common.
General reference
1. Shcherbina A, Rosen FS, Remold-O'Donnell E: Pathological events in platelets of Wiskott-Aldrich syndrome patients. Br J Haematol 106(4):875–883, 1999. doi:10.1046/j.1365-2141.1999.01637.x
Symptoms and Signs of Wiskott-Aldrich Syndrome
The first manifestations are often hemorrhagic (usually bloody diarrhea, melena, purpura, epistaxis, hematuria), followed by recurrent respiratory infections, eczema, and thrombocytopenia.
Cancers, especially B-cell lymphomas (EBV+) and acute lymphocytic leukemia, develop in approximately 10% of patients > 10 years.
Diagnosis of Wiskott-Aldrich Syndrome
Immunoglobulin levels
Platelet count and volume assessment
White blood cell function tests (eg, neutrophil chemotaxis, T-cell function)
Diagnosis of Wiskott-Aldrich syndrome is based on the following:
Decreased T-cell count and function
Elevated IgE and IgA levels
Low IgM levels
Low or normal IgG levels
Decreased natural killer cell cytotoxicity
Impaired neutrophil chemotaxis
Thrombocytopenia
Antibodies to polysaccharide antigens (eg, blood group antigens A and B) may be selectively deficient; quantitative immunoglobulin response to polysaccharide vaccines (eg, pneumococcal vaccine) is usually measured. Platelets are small and defective, and splenic destruction of platelets is increased, causing thrombocytopenia. Mutation analysis may be used to confirm the diagnosis if there is clinical and laboratory evidence of Wiskott-Aldrich syndrome.
Genetic testing is recommended for first-degree relatives.
Because risk of lymphoma and leukemia is increased, a complete blood count with differential is usually done every 6 months. Acute changes in symptoms related to B-cell dysfunction require more in-depth evaluations.
Treatment of Wiskott-Aldrich Syndrome
For symptomatic thrombocytopenia, platelet transfusion and rarely splenectomy
Hematopoietic stem cell transplantation
Gene therapy
Treatment of Wiskott-Aldrich syndrome is prophylactic antibiotics and immune globulin1). If thrombocytopenia is severe, splenectomy can be done, but it is usually avoided because it increases risk of septicemia.
Hematopoietic stem cell transplantation is well-established as a cure for Wiskott-Aldrich syndrome, but gene therapy is under study. A small study of lentiviral hematopoietic stem/progenitor cell gene therapy in 8 patients with Wiskott-Aldrich syndrome who were followed for up to 7.6 years demonstrated resolution of severe infections and eczema and a decrease in autoimmune and bleeding disorders in all of the patients (2, 3).
Without aggressive intervention with transplantation or gene therapy, most patients die by age 15 years; however, some patients survive into adulthood.
Treatment references
1. Moriyama M, Nishikawa T, Nakamura T, et al: [Improvement in platelet count and bleeding symptom during treatment with eltrombopag in a patient with X-linked thrombocytopenia.] Rinsho Ketsueki 62(4):257–261, 2021. doi:10.11406/rinketsu.62.257
2. Magnani A, Semeraro M, Adam F, et al: Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott-Aldrich syndrome [published correction appears in Nat Med 2022 Oct;28(10):2217]. Nat Med 28(1):71–80, 2022. doi:10.1038/s41591-021-01641-x
3. Mudde A, Booth C: Gene therapy for inborn error of immunity - current status and future perspectives. Curr Opin Allergy Clin Immunol 23(1):51–62, 2023. doi:10.1097/ACI.0000000000000876
