Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive genetic condition arising from variants in the WAS gene. WAS encodes a protein crucial for actin cytoskeleton reorganisation, and dysfunction leads to microthrombocytopenia and early presentation with eczema and recurrent infections. Additional features include increased risk of autoimmunity and malignancy.

WAS typically presents with a classic triad:

1. microthrombocytopenia: low platelet count with characteristically small platelet size (this may be an incidental finding or present with bleeding diathesis);
2. atopic dermatitis, which presents early in infancy and is typically severe; and
3. recurrent infections, which occurs due to combined immunodeficiency.

Other features that may occur during the disease course include:

• autoimmune manifestations, such as cytopaenia;
• bleeding complications, such as epistaxis and gastrointestinal bleeding;
• failure to thrive;
• increased predisposition to lymphoma and leukaemia; and
• laboratory tests showing hypogammaglobulinaemia with reduced antibody responses and progressive lymphopaenia.

Missense variants in WAS may also cause X-linked thrombocytopenia and (more rarely) X-linked neutropaenia, without the full clinical spectrum of WAS.

WAS results from hemizygous pathogenic variants in the WAS gene located on the X chromosome (Xp11.23). The gene encodes the Wiskott-Aldrich syndrome protein (WASp), which is crucial for actin cytoskeletal reorganisation. This process is required for T-cell activation and immunological synapse formation with other immune cells. It is also required for platelet formation and neutrophil migration.

Protein-truncating variants in WAS that cause complete loss of WASp expression typically cause the full WAS spectrum, while some missense variants produce dysfunctional WASp, which results in X-linked thrombocytopaenia (XLT).

XLT missense variants typically occur in the WH1 and GTPase domains, with R86H and R86C the most common variants described. These typically retain between 20%–50% WASp expression, meaning that disease caused by these variants may have milder features.

Some heterozygous female carriers manifest with reduced platelet counts, though females presenting with microthrombocytopaenia should have X-inactivation studies to exclude the full clinical phenotype.

X-linked neutropaenia is associated with deleterious, gain-of-function missense variants in WAS. The most common WAS variants associated with X-linked neutropaenia are L270P and S272P. These occur secondary to constitutive activation of WASp, which results in ineffective neutrophil production with absence of microthrombocytopaenia.

WAS should be considered in male patients with early-onset symptoms or asymptomatic patients with microthrombocytopenia.

According to the European Society for Immunodeficiency, WAS can be diagnosed in a male patient with thrombocytopenia (less than 100,000 platelets/mm3, measured at least twice) and small platelets (platelet volume <7.5fl) with at least one of the following:

• eczema;
• recurrent bacterial or viral infections;
• autoimmune diseases (including vasculitis);
• malignancy;
• reduced WASp expression in a fresh blood sample;
• atypical antibody response to polysaccharide antigens and/or low isohemagglutinins; and/or
• positive maternal family history of XLT/WAS.

WAS may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services. Please refer to the local pathway for your region for this condition.

For information about testing, see ‘Male child with recurrent infections, eczema and a low platelet count‘.

WAS is caused by pathogenic genetic variants in the WAS gene, which lies on the X chromosome. It is inherited in an X-linked recessive pattern. It is a very rare disease that typically affects boys, with an estimated prevalence of 1 per 100,000.

• X-linked recessive conditions are usually only present in males.
• Males with X-linked conditions cannot pass the variant on to their sons, but they always pass their affected X chromosome to their daughters. If the condition is recessive, their daughters will be carriers for the condition.
• Female carriers of X-linked recessive conditions have a second, working copy of the gene and are therefore usually unaffected, or affected only mildly.
• Sons of female carriers of X-linked recessive conditions have a 1-in-2 (50%) chance of being affected by the condition, and their daughters have a 1-in-2 (50%) chance of being carriers.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. Typically, mothers are asymptomatic carriers. De novo variants commonly arise, and patients may also have a family history of male relatives with thrombocytopaenia only.

Reproductive options are available and genetic counselling, ideally prior to conception, is recommended. Options are likely to include testing in early pregnancy or preimplantation genetic testing.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

WAS is a severe, life-threatening condition, often requiring prompt specialist intervention.

Patients should initially receive supportive care, which can involve:

• no live vaccinations given;
• platelet transfusions as required;
• immunoglobulin replacement therapy;
• prophylactic antibiotics;
• aggressive treatment of infections, including with antivirals and antifungals if appropriate;
• emollients and topical steroids for eczema; and
• immunosuppressive agents, which may be required for autoimmune manifestations.

The primary curative treatment is haematopoietic stem cell transplantation (HSCT). This involves replacing stem cells from the patient’s bone marrow with that of a compatible donor. Patients who receive allogeneic HSCT soon after birth tend to have the best outcomes with fewer complications. Five-year survival rates are >90% if HSCT is commenced when the patient is less than three months old. However, this survival rate declines with increasing age of transplantation and in the presence of active infections at the time of transplant. Patients require long-term monitoring following HSCT to assess immune reconstitution and monitor for potential complications.

Multiple phase 1/2 trials have demonstrated gene therapy for WAS to be a safe, effective treatment in children with severe WAS and no suitable allogenic HSCT donor. The procedure involves patient stem cells being corrected in-vitro using retroviral gene transfer, and subsequently being re-infused back to the patient.

WAS may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• European Society for Immunodeficiencies: Diagnosis criteria
• OMIM: 301000 Wiskott-Aldrich syndrome

References:

• Rivers E, Worth A, Thrasher AJ and others. ‘How I manage patients with Wiskott Aldrich syndrome‘. British Journal of Haematology 2019: volume 185, issue 4, pages 647–655. DOI: 10.1111/bjh.15831
• Vieira RC, Pinho LG and Westerberg LS. ‘Understanding immunoactinopathies: A decade of research on WAS gene defects‘. Pediatric Allergy and Immunology 2023: volume 34, issue 4, page e13951. DOI: 10.1111/pai.13951

For patients

• Immune Deficiency Foundation
• Immunodeficiency UK