Wiskott-Aldrich Syndrome

Synonym: Wiskott-Aldrich-Huntley syndrome.

It was first described by Wiskott in Germany in 1937¹ and Aldrich in the USA in 1954.²

It is an X-linked recessive condition with immunodeficiency as an underlying problem and characterised by:

• Recurrent bacterial infections of the sinuses and lungs
• Eczema that appears atopic in nature
• A bleeding tendency due to thrombocytopenia and platelet dysfunction.

Less than a third have the full triad but almost 90% present with features of thrombocytopenia. Around 5% have only infection and 20% only haematological problems.³ There may also be autoimmune disease and malignancy.

The underlying mutation is on the X-chromosome at Xp11.22-23.⁴ An apparently autosomal dominant form has been described but in 3 generations of a single family.⁵

The incidence is about 1 in 250,000 male births or 1 in 500,000 live births overall.

Being X-linked and potentially lethal, it would be expected to be almost invariably in males and more than 90% of affected patients are male, but females have been reported in the literature. Females usually have no family history and so are presumable spontaneous mutations. In some cases, females have been shown to have nonrandom inactivation of the X chromosome bearing the functional WAS allele.

Presentation can range from birth to age 25 years but most cases present in the first 2 years of life.

• Baby boys may present at birth with petechiae and ecchymoses. They may be around the oral mucosa and bloody diarrhoea is quite common. There may be bleeding from the umbilical stump or after circumcision. In less than 2% there is intracranial haemorrhage, possibly from the trauma of delivery.
• Infections usually begin in early infancy after maternal IgG declines in the first 3 months of life and they become more frequent. Pneumonia, meningitis and sinusitis are often due to Streptococcus pneumoniae, Haemophilus influenzae type b (HIB), and Staphylococcus aureus. Otitis media is also very common.
• Eczema develops during the first year of life and it is clinically similar to atopic eczema. It presents earlier than usual and may be worse during infection.
• Autoimmune disease can occur at any age and is most often autoimmune haemolytic anaemia. Renal failure can result from glomerulonephritis. In a series of 55 patients from France,⁶ 40 (72%) had at least 1 autoimmune or inflammatory complication. 20 cases (36%) had autoimmune haemolytic anaemia, always starting before 5 years old. Other problems were neutropenia (25%), arthritis (29%), skin vasculitis (22%), cerebral vasculitis (7%), inflammatory bowel disease (9%), and renal disease (3%).
• Malignancy may occur in children but is more common in adults. Around a quarter of those over 20 years develop lymphoma. Leukaemia may also occur but the commonest malignancy is non-Hodgkin's lymphoma.

• Agammaglobulinaemia.
• Atopic eczema.
• Di George's Syndrome affects cell mediated immunity and may have features of hypocalcaemia due to parathyroid deficiency.
• Histiocytosis X.
• Severe combined immunodeficiency.

• The platelet count is low at 70,000/ml or less and if platelet volume is measured, it is less than 5fl.
• Immunoglobulin analysis will show low IgG and IgM with elevated IgA and IgE but in young infants this may not be apparent and values need to be interpreted for age.
• There may be impairment of tests for cell mediated immunity and CMI often deteriorates with time.
• Autoantibodies may be detected in autoimmune disease especially haemolytic anaemia, thrombocytopenia and neutropenia.
• In boys with thrombocytopenia, the diagnosis may be considered and detection of the Wiskott-Aldrich syndrome protein (WASP) will facilitate the diagnosis.⁷
• Bacteriology is required to help treat infection.
• Chest x-ray may be indicated.
• Tissue typing of the patient and close family members may be indicated if stem cell transplantation is considered.
• Carrier females may have low platelets.⁸

Lifestyle

• All immunisation should be given as usual. HiB is especially important.
• Encourage normal work and school but avoid contact sports.

Medical management

• Infections will need appropriate antibiotics. Infusion of immunoglobulin may also be required.
• Bleeding may require transfusion of packed red cells and platelets. Blood should be low in white cells to reduce the risk of isoimmunisation as a stem cell transplant may be required in the future.
• Skin disease is treated as in immunocompetent patients including treating eczema with moisturising creams and topical steroid preparations as indicated.
• If there is exposure to chickenpox, antivirals such as aciclovir are indicated.
• In severe thrombocytopenia, splenectomy may be indicated but this also increases the risk of infection and pneumococcal vaccine is mandatory.

Potential cure

• Stem cell reconstitution in the form of bone marrow transplantation (BMT) may be used. Stem cell transplantation is now successful in over 90% of cases.⁹
• In the future, gene therapy may be an option¹⁰ but it is not yet available.

• Recurrent infections as outlined above.
• Bleeding can be difficult to control and intracranial bleeding may occur.
• Haematological malignancy, especially non-Hodgkin's lymphoma.

The prognosis has improved enormously over the years due to improved control of infection and bone marrow transplantation. The median age of death has risen from 8 months in 1935 to 6 years in the 1960s¹¹ to 11 in 1994 to around 15 now. Successful BMT will improve this outlook much further.

Of those who do not receive BMT:

• A quarter will die from bleeding
• A quarter will die from malignancy
• Half will die of infection.

The first patient to receive a BMT did so in 1968 and he is still alive and clinically and immunologically normal.

Wiskott worked in Munich and called the disorder 'Werlhof's disease,' the eponymous name for thrombocytopenia purpura. He described 3 German patients in 1937.¹ In 1954 Aldrich et al described patients of Dutch extraction.² In 1964 Van den Bosch and Drukker⁸ described several families in Holland. In 3 of 5 female carriers, the platelet count was below the lower limit of normal. Descriptions of the disease go back to the 19th century.¹¹