What is Wiskott-Aldrich syndrome (WAS)?

Wiskott-Aldrich syndrome (WAS) is a complex X-linked primary immunodeficiency disorder characterized by rashes, recurrent infections and abnormally low blood platelet levels. Bleeding problems are typically the result of dysfunctional blood platelets that interfere with the body's normal clotting abilities. Many patients also have autoimmune problems with blood cells, severe allergies and some develop cancers such as lymphoma.

Mutations in the WAS gene disable its ability to produce WAS protein, which plays a crucial role in the different types of immune cells. Without WAS protein, immune cells are disabled and incapable of providing immune defenses. Patients with Wiskott-Aldrich syndrome are more susceptible to premature death from infection, bleeding or cancers.

WAS typically only affects males, while female are more commonly asymptomatic carriers of the genetic mutation and pass it onto their children. In rare cases, mild forms of WAS may not produce the usual symptoms, often delaying diagnosis and treatment. Some patients will experience only low platelet counts, this is sometimes called X-linked thrombocytopenia or “XLT”.

Symptoms of Wiskott-Aldrich syndrome

Most children with Wiskott-Aldrich syndrome begin to display symptoms of the disorder within the first year of life. Classic symptoms of WAS include:

• An increased tendency to bleed, caused by a significantly reduced number of platelets, typically affecting the face, brain and bowel
• Recurrent viral, bacterial and fungal infections
• Eczema and red patches on the skin ranging from mild to severe
• Severe food allergies

In addition, many children with WAS have an increased risk of developing:

• Recurrent bacterial and viral infections such as ear infections, cytomegalovirus, herpes simplex and Epstein-Barr
• Skin changes, including frequent bruising (purpura) on and under the skin, small red dots on the skin (petechiae), cellulitis and abscesses
• Severe autoimmune diseases, such as inflammatory bowel disease, rheumatoid arthritis, hemolytic anemia and vasculitis, as well as damage to the kidneys and liver
• Some types of cancer, such as lymphoma or leukemia

While most symptoms of Wiskott-Aldrich syndrome appear in infancy, in more mild forms of the disease, symptoms may not be evident until later in childhood.

Causes of Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome is a genetic disorder caused by a mutation on an X-chromosome, one of the two chromosomes that determine a person's gender. It can be passed from mother to son – but not all sons are affected.

Women have XX sex chromosomes and if they are "carriers" of WAS, may pass either a faulty or normal X-gene to each child they have. Males have XY sex chromosome and pass along one to each child they have. Therefore, if a mother is a carrier of the WAS gene, with each pregnancy she has a:

• 25 percent chance of having an affected male child
• 25 percent chance of having a female child who is a carrier of the defective gene and may pass it along to her child
• 50 percent chance of having a child not affected by the disorder

Because of the genetic inheritance pattern, Wiskott-Aldrich almost always affects males, but rarely female patients have been described.

Testing and diagnosis for Wiskott-Aldrich syndrome

Diagnosis of WAS may be suspected based on signs and symptoms of the disorder, or a known family history of the disease. In most cases, symptoms of WAS appear by age 1.

At Children's Hospital of Philadelphia (CHOP), evaluation begins with a thorough medical history and physical examination of your child. Clinical experts will use a variety of diagnostic tests to diagnose Wiskott-Aldrich syndrome and possible complications, including:

• Specialized blood tests, to check your child's platelet count and determine platelet size. This can help determine if your child's blood is clotting properly and if it contains measurable amounts of WAS protein.
• Other blood testing of the immune system, to check immune cell counts and immune protein levels, also known as immunoglobulins. This can help determine if the immune system is developing properly to fight off infections and avoid autoimmune disease.
• Genetic testing, of the child's DNA – and that of their parents – to help determine if the WAS gene is present. This information can help diagnose the child and help parents who may be carriers of the faulty gene to determine future family planning.
• Additional tests – such as X-rays, skin or urine tests – may be performed, depending on the child's symptoms, to help guide treatment.

We'll also perform baseline blood tests while the child is feeling healthy so we can compare results when your child is ill. Regular blood tests are vitally important for children with Wiskott-Aldrich syndrome because they can often identify problems before symptoms arise; then infections and inflammation can be addressed quickly.

Treatment for Wiskott-Aldrich syndrome

Currently, the only definitive therapy for Wiskott-Aldrich syndrome that is available outside of a clinical research study is hematopoietic stem cell transplantation, sometimes also called bone marrow transplant, which carries its own risks and is not appropriate for all patients.

Allogeneic hematopoietic stem cell transplant can be used to remove diseased cells from the child and replace them with healthy blood cells from another matched donor. In some cases, a relative can be used as a donor, in other cases a match may be found through the National Marrow Donor Program's Be the Match Registry. Treating a child with WAS with stem cells depends on a multitude of factors including donor availability, the child's overall prognosis and a family's preference.

Researchers are also investigating the use of other therapies to help children with Wiskott-Aldrich syndrome. The most promising of which is gene therapy.

In gene therapy, a normal copy of the WAS gene is delivered into cells taken from the affected child’s bone marrow using a virus as the vehicle to transport the normal gene. Once these bone marrow cells have taken up the virus, they are then infused back into the patient. This then prompts blood cells coming from the bone marrow to make normal WAS protein for the body.   

By modifying the patient's own cells, there is no risk of graft-versus-host disease, a common challenge after bone marrow transplantation. The most concerning risk of gene therapy is that the virus used to insert a copy of DNA into the patient’s chromosomes may cause abnormal production of a protein that can cause cancer.

Gene therapy has been successfully used to treat a small number of patients with WAS, however, a small percentage of patients developed cancer as a result. Studies are currently underway to test new gene therapy viruses and develop non-viral gene therapy methods.

Some patients are treated with medical therapy before transplant or if transplant is not a treatment option. Additional supportive therapies that may be used to help patients with WAS include:

• Immunoglobulin infusions to prevent infections, this therapy can be given either intravenously or subcutaneously.
• Antibiotic prophylaxis, or low doses of antibiotics taken every day or a few days every week are used to prevent infections that the immune cells of a patient who has WAS will have difficulty avoiding.
• Platelet transfusions may be used to prevent or treat bleeding episodes.
• Systemic steroids or high-dose immunoglobulin replacement therapy may be used to treat autoimmune complications.

Long-term outcomes for Wiskott-Aldrich syndrome

A generation ago, Wiskott-Aldrich syndrome was considered a fatal disorder and life expectancy was only 2-3 years. Today, thanks to experienced clinicians, new transplant protocols, improved immunoglobulin supplements and antibiotics, as well as other supportive care interventions, patients' lives have dramatically improved not just in quantity, but also in quality.

Hematopoietic stem cell transplant continues to be the only definitive therapy for Wiskott-Aldrich syndrome. But that may not be the case for much longer. Recent gene therapy successes hold promise to become the treatment of choice in the future for children with WAS.