Wiskott–Aldrich Syndrome: Pathophysiology, Diagnosis, and Emerging Therapies

Wiskott–Aldrich syndrome

Wiskott–Aldrich syndrome (WAS) is a rare, inherited primary immunodeficiency disorder characterized by combined defects in the immune system and blood clotting mechanisms. The disease is classically defined by the triad of eczema, thrombocytopenia with small platelets, and recurrent infections, though its clinical spectrum ranges from mild to severe. WAS predominantly affects males and typically presents in infancy or early childhood.

Classification

Wiskott–Aldrich syndrome belongs to the group of combined immunodeficiency disorders, in which both cellular and humoral immunity are impaired. It is part of a broader disease spectrum caused by mutations in the same gene, which includes:

• Classic Wiskott–Aldrich syndrome – severe form with bleeding, infections, eczema, autoimmunity, and malignancy risk
• X-linked thrombocytopenia (XLT) – milder phenotype with primarily platelet abnormalities
• X-linked neutropenia – rare and severe variant with recurrent bacterial infections

Signs and symptoms

Hematological manifestations

• Thrombocytopenia is a hallmark feature and often the earliest sign
• Platelets are abnormally small (microthrombocytes), which is diagnostically distinctive
• Clinical consequences include:
• Petechiae and purpura
• Easy bruising
• Prolonged bleeding after minor trauma
• Gastrointestinal bleeding
• Intracranial hemorrhage in severe cases

Dermatological manifestations

• Eczema often appears within the first months of life
• May be severe, persistent, and difficult to control
• Frequently complicated by secondary bacterial or viral skin infections

Immunological manifestations

• Recurrent infections involving:
• Respiratory tract (otitis media, pneumonia, sinusitis)
• Skin and soft tissues
• Gastrointestinal tract
• Common pathogens include encapsulated bacteria, viruses, and opportunistic organisms

Autoimmune and inflammatory complications

• Occur in a significant proportion of patients
• Examples include:
• Autoimmune hemolytic anemia
• Immune thrombocytopenia
• Vasculitis
• Inflammatory bowel disease–like colitis

Malignancy risk

• Increased lifetime risk of cancer, especially:
• Non-Hodgkin lymphoma
• Leukemia
• Malignancies often develop during adolescence or early adulthood in untreated individuals

Genetics and inheritance

Wiskott–Aldrich syndrome is caused by mutations in the WAS gene, located on the Xp11.23 region of the X chromosome. The disorder follows an X-linked recessive inheritance pattern:

• Affected males inherit the mutated gene from a carrier mother
• Female carriers are usually asymptomatic but may show mild thrombocytopenia or eczema due to skewed X-chromosome inactivation

More than 300 distinct mutations of the WAS gene have been identified, including missense, nonsense, frameshift, and splice-site variants. The type of mutation often correlates with disease severity.

Molecular biology and pathophysiology

The WAS gene encodes the Wiskott–Aldrich syndrome protein (WASp), a key regulator of actin cytoskeleton remodeling in hematopoietic cells.

Role of WASp

WASp is essential for:

• Immune synapse formation
• Signal transduction after antigen recognition
• Cell migration and adhesion
• Phagocytosis and cytotoxic activity

Cellular effects

Deficiency or dysfunction of WASp leads to:

• T lymphocyte defects – impaired activation and proliferation
• B lymphocyte abnormalities – defective antibody production and class switching
• Natural killer (NK) cell dysfunction – reduced cytotoxicity
• Dendritic cell impairment – defective antigen presentation
• Megakaryocyte dysfunction – abnormal platelet formation and reduced platelet survival

These combined defects explain the immunodeficiency, bleeding tendency, autoimmunity, and malignancy risk associated with the syndrome.

Diagnosis

Clinical evaluation

Diagnosis is suspected in male infants presenting with:

• Persistent thrombocytopenia
• Eczema
• Recurrent or severe infections

Laboratory findings

• Complete blood count showing:
• Low platelet count
• Reduced mean platelet volume (MPV)
• Immunological abnormalities:
• Low or normal IgG
• Reduced IgM
• Elevated IgA and IgE
• Abnormal T-cell function

Specialized testing

• Flow cytometry to assess WASp expression in lymphocytes
• Genetic testing to confirm mutations in the WAS gene

Prenatal and carrier testing are available in families with a known mutation.

Differential diagnosis

Conditions that may resemble Wiskott–Aldrich syndrome include:

• Immune thrombocytopenic purpura (ITP)
• Severe atopic dermatitis
• Other primary immunodeficiency disorders
• Congenital thrombocytopenia syndromes

The presence of small platelets is a key distinguishing feature.

Management and treatment

Supportive management

• Prophylactic antibiotics to prevent infections
• Immunoglobulin replacement therapy
• Aggressive treatment of eczema
• Platelet transfusions for severe bleeding
• Avoidance of live vaccines in immunodeficient patients

Curative therapies

• Hematopoietic stem cell transplantation (HSCT)
• Currently the standard curative treatment
• Best outcomes when performed early in life using a matched donor
• Gene therapy
• Emerging treatment using viral vectors to correct the WAS gene
• Shows promising results in restoring immune function

Prognosis

Before the advent of modern therapies, life expectancy was significantly reduced. With early diagnosis, improved supportive care, and timely HSCT:

• Survival rates have increased dramatically
• Immune function can be largely restored
• Risk of infections and bleeding is significantly reduced

Long-term outcomes depend on disease severity, donor availability, and presence of complications prior to definitive treatment.

Epidemiology

• Estimated incidence: 1–10 cases per million live male births worldwide
• Occurs in all ethnic and geographic populations
• Considered an ultra-rare disease in many regions

History

The disorder was first described in 1937 by pediatrician Alfred Wiskott, who observed affected brothers with thrombocytopenia and infections. In 1954, Robert Aldrich recognized its inherited nature and X-linked transmission, leading to the modern understanding of the disease.

Ongoing research

Current research focuses on:

• Improved gene therapy vectors
• Long-term outcomes of HSCT and gene therapy
• Understanding autoimmune mechanisms
• Development of targeted immunomodulatory treatments

Market trends

Treatment landscape

The Wiskott–Aldrich syndrome treatment market has historically been limited to supportive therapies (such as immunoglobulin infusions and platelet transfusions) and HSCT. Recent advancements are reshaping this landscape:

• In December 2025, the U.S. Food and Drug Administration (FDA) approved Waskyra (etuvetidigene autotemcel)—the first gene therapy for WAS, developed by the Italian nonprofit Fondazione Telethon. This ex vivo gene therapy uses patients’ genetically corrected hematopoietic stem cells to address the underlying genetic defect and reduce the frequency of severe infections and bleeding events. Approval follows positive regulatory opinion from European authorities earlier in 2025, marking significant progress in curative treatment options. Telethon+1
• Other gene therapies, including OTL-103, have been in clinical development, reflecting ongoing efforts by biotech companies to expand therapeutic choices. Wikipedia

Key trends

• Expansion of gene therapy approvals and access: Regulatory momentum for gene-based treatments is enabling market entry of therapies that can potentially cure or transform disease outcomes. Telethon
• Awareness and diagnostics: Increased awareness among clinicians and patients is improving early diagnosis and uptake of advanced care.

Overall, while WAS remains a rare condition, recent scientific and regulatory developments are driving significant evolution in treatment options and market dynamics, with gene therapy emerging as a cornerstone of future therapeutic strategies.