Wiskott-Aldrich Syndrome (WAS) is a rare, inherited disorder classified as a primary immunodeficiency. WAS impacts the production and structure of various immune cells and platelets. The disorder is classified as X-linked, meaning its genetic basis is carried on the X chromosome. This results in WAS primarily affecting males from early infancy.
The Characteristic Symptoms
Wiskott-Aldrich Syndrome is characterized by three main issues. The first is thrombocytopenia, a persistently low number of platelets in the blood. These platelets are often abnormally small. This deficit leads to significant issues with blood clotting, causing easy bruising, tiny red spots called petechiae, and an increased risk of serious internal bleeding.
The second issue is immunodeficiency, which compromises the body’s ability to fight off pathogens. Patients frequently suffer from recurrent and severe infections, including common respiratory illnesses and ear infections. The immune system dysfunction involves both B-cell and T-cell abnormalities, resulting in poor antibody responses.
The third element is eczema, characterized by dry, intensely itchy, and inflamed skin. This skin condition often begins in infancy and can be difficult to manage.
The Genetic Cause
Wiskott-Aldrich Syndrome is caused by a mutation in the WAS gene, located on the X chromosome. This gene provides instructions for making the Wiskott-Aldrich Syndrome protein (WASp). WASp is highly expressed in blood-forming cells and regulates the actin cytoskeleton, the internal scaffolding system that allows cells to move and interact.
In immune cells, WASp is instrumental in processes like cell migration and target recognition. When the WAS gene is mutated, the resulting WASp is non-functional, absent, or reduced. This deficiency impairs the ability of T-cells to mount an effective response and prevents platelets from forming the structure needed for proper clotting.
Since the WAS gene is on the X chromosome, the disorder follows an X-linked recessive inheritance pattern. Males, who have only one X chromosome, develop the syndrome if they carry the faulty gene. Females usually have two X chromosomes, so a healthy copy often compensates, making them carriers who do not exhibit symptoms.
Identifying and Monitoring the Syndrome
Suspicion for Wiskott-Aldrich Syndrome is often raised early in life when a complete blood count (CBC) shows persistent, low platelet counts. The finding of microthrombocytopenia, where platelets are reduced in number and visibly smaller, prompts further laboratory investigations.
Flow cytometry is used to measure the amount of WASp present within a patient’s lymphocytes. The absence or significant reduction of WASp expression confirms the diagnosis. Definitive confirmation involves genetic sequencing to identify the specific mutation within the WAS gene.
Once diagnosed, patients require ongoing monitoring to manage the disorder’s progressive nature. This includes routine checks of platelet counts and immune function, assessing T-cell and B-cell numbers and antibody production. Regular screening is also necessary to detect secondary complications, such as autoimmune conditions or the emergence of certain types of malignancies.
Current Treatment Options
Management is divided into curative intervention and ongoing supportive care. The only curative treatment is Hematopoietic Stem Cell Transplantation (HSCT). HSCT replaces the patient’s defective blood-forming cells with healthy stem cells from a suitable donor, permanently correcting the underlying immune and platelet defects.
The procedure carries risks, including graft-versus-host disease and life-threatening infections while the new immune system develops. The decision to use HSCT requires a well-matched donor, such as a matched sibling, and consideration of the patient’s overall health. Outcomes are better when the transplant is performed early in life with a fully matched donor.
Supportive Care
For patients awaiting a transplant or those for whom HSCT is not an option, supportive therapies manage symptoms and prevent complications. Standard supportive care includes:
- Immunoglobulin Replacement Therapy (IVIG) to compensate for poor antibody production.
- Prophylactic antibiotics, antivirals, or antifungals to prevent recurrent severe infections.
- Vigilant management of bleeding risk, including avoiding medications that impair platelet function.
- Platelet transfusions, reserved for episodes of serious or life-threatening bleeding.
- Management of chronic eczema using topical steroids and anti-inflammatory medications.
Gene Therapy
Looking toward the future, gene therapy represents a promising treatment approach for WAS. This technique involves collecting the patient’s own hematopoietic stem cells and genetically modifying them in the laboratory to correct the WAS gene defect. The corrected cells are then reinfused back into the patient. This approach eliminates the risks associated with using a donor’s cells, potentially making a curative option available to a wider range of patients.