Wiskott–Aldrich Syndrome

Overview

Wiskott–Aldrich syndrome (WAS) is a rare, X-linked primary immunodeficiency disorder characterized by a classic triad of eczema, thrombocytopenia (low platelet count), and recurrent infections. First described by Alfred Wiskott in 1937 and further detailed by Robert Aldrich in 1954, the condition primarily affects males and manifests in infancy or early childhood. Due to its impact on the immune system and blood cells, individuals with WAS are at increased risk of bleeding, autoimmunity, and certain cancers such as lymphoma.

WAS is caused by mutations in the WAS gene, which disrupts normal functioning of immune cells and platelets. The severity of the disease can vary depending on the type of mutation, ranging from classic Wiskott–Aldrich syndrome to milder forms such as X-linked thrombocytopenia (XLT). Early diagnosis and treatment are critical for improving outcomes and quality of life.

Causes

Wiskott–Aldrich syndrome is caused by mutations in the WAS gene located on the X chromosome (Xp11.23). This gene encodes the Wiskott–Aldrich syndrome protein (WASP), which plays a crucial role in the cytoskeletal structure and signaling of white blood cells and platelets. WASP is essential for the movement, shape, and communication of immune cells such as T cells, B cells, and natural killer (NK) cells.

Because the condition is X-linked recessive, it primarily affects males. Females are typically carriers and usually do not exhibit symptoms, although in rare cases they may show mild immune or hematological abnormalities due to skewed X-inactivation.

Symptoms

The symptoms of Wiskott–Aldrich syndrome typically begin in infancy and become more pronounced over time. The severity and combination of symptoms can vary depending on the specific genetic mutation.

Hematological Symptoms

• Thrombocytopenia: Low platelet count, often associated with small-sized platelets

• Easy bruising and petechiae: Small red or purple spots on the skin due to bleeding

• Prolonged bleeding: From minor cuts, surgical procedures, or even spontaneously

• Gastrointestinal bleeding: Sometimes presenting with blood in the stool

Immunological Symptoms

• Recurrent infections: Especially of the ears, sinuses, lungs, and skin

• Poor response to vaccinations

• Chronic viral infections: Including herpesviruses and cytomegalovirus (CMV)

Dermatological Symptoms

• Severe eczema: Persistent and difficult-to-treat skin inflammation resembling atopic dermatitis

Autoimmune and Malignant Complications

• Autoimmune diseases: Such as autoimmune hemolytic anemia, vasculitis, and arthritis

• Malignancies: Increased risk of lymphoma and leukemia, particularly in adolescence and adulthood

Diagnosis

Diagnosis of Wiskott–Aldrich syndrome involves a combination of clinical evaluation, laboratory testing, and genetic analysis. Due to the overlap with other immunodeficiencies and hematological disorders, a high index of suspicion is required in infants presenting with eczema, bleeding, and recurrent infections.

Diagnostic Tests

• Complete blood count (CBC): Shows low platelet count and small platelets (mean platelet volume is decreased)

• Immunoglobulin levels: Typically show low IgM, elevated IgA and IgE, and normal to high IgG

• Flow cytometry: To assess WASP protein expression in white blood cells

• Genetic testing: Confirms diagnosis by identifying mutations in the WAS gene

• Family history: Evaluation of maternal carrier status and affected male relatives

Treatment

Management of Wiskott–Aldrich syndrome is complex and requires a multidisciplinary approach. The goals of treatment are to control bleeding, prevent infections, manage eczema, and reduce the risk of complications such as autoimmune diseases and cancer.

Supportive and Medical Treatments

• Platelet transfusions: For active bleeding or before surgical procedures

• Antibiotic prophylaxis: To prevent bacterial infections

• Immunoglobulin replacement therapy: Intravenous (IVIG) or subcutaneous (SCIG) to boost immune defenses

• Topical corticosteroids and skin care: For eczema management

• Immunosuppressive therapy: For autoimmune complications

Definitive Treatment

• Hematopoietic stem cell transplantation (HSCT): The only curative treatment for Wiskott–Aldrich syndrome. Ideally performed early in life, HSCT can correct both the immunodeficiency and the platelet defect.

• Gene therapy: An emerging and promising approach under clinical investigation. It involves correcting the defective WAS gene in the patient's own stem cells.

Prognosis

The prognosis for individuals with Wiskott–Aldrich syndrome has improved significantly with advances in supportive care and stem cell transplantation. Without treatment, the condition can lead to life-threatening infections, bleeding complications, and malignancies. With early diagnosis and HSCT, long-term survival and quality of life can be significantly enhanced.

Prognostic Factors

• Severity of mutation: Determines disease expression and treatment urgency

• Timing of HSCT: Early transplantation before the onset of severe infections or complications leads to better outcomes

• Access to multidisciplinary care: Including immunology, hematology, dermatology, and genetics

With early intervention and appropriate management, many individuals with Wiskott–Aldrich syndrome can live healthier and longer lives. Ongoing research, including gene therapy trials, continues to improve the outlook for future generations affected by this rare but serious condition.