Wiskott-Aldrich Syndrome

Synonym: Wiskott-Aldrich-Huntley syndrome

This is an X-linked recessive condition with immunodeficiency as an underlying problem. It is characterised by:¹

• Recurrent bacterial infections of the sinuses and lungs
• Eczema that resembles an atopic dermatitis
• A bleeding tendency due to thrombocytopenia and platelet dysfunction

Less than one third of affected individuals have the full triad at presentation but almost 90% present with features of thrombocytopenia.¹ Around 5% present only with infection and 20% only haematological problems.² There may also be autoimmune disease and malignancy.

• The underlying mutation is in the gene for the Wiskott-Aldrich syndrome protein (WASP) on the X-chromosome at Xp11.22-23.³
• WASP is needed for normal antibody function, T-cell responses and platelet production.¹

• Incidence is 1 in 250,000 live male births.¹
• Being X-linked and potentially lethal, it would be expected to almost invariably affect males and more than 90% of affected patients are male. However, affected females have been reported.¹
• Affected females usually have no family history and some have been shown to have nonrandom inactivation of the X chromosome bearing the functional WAS allele.¹

Presentation can be any time from birth to 25 years but most cases present in the first 2 years of life.

• Bleeding problems:
  • Petechiae and ecchymoses can occur.These may be around the oral mucosa.
  • Bloody diarrhoea is quite common.
  • There may be bleeding from the umbilical stump or after circumcision.
  • In less than 2% there is intracranial haemorrhage. This may happen at birth, possibly from the trauma of delivery.
• Infections:
  • These usually begin after maternal IgG declines in the first 3 months of life.
  • Pneumonia, meningitis and sinusitis are often due to Streptococcus pneumoniae, Haemophilus influenzae type b (HIB), and Staphylococcus aureus.
  • Opportunistic, fungal and viral infections can occur.
  • Otitis media is also very common.
• Eczema:
  • Tends to develop during the first year of life and it is clinically similar to atopic eczema.
  • However, it presents earlier than usual and may be worse during infection.
  • There may be other atopic conditions such as allergic rhinitis.
• Autoimmune disease:
  • This 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, 40 individuals (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%).⁴
• Malignancy:
  • This 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 most common malignancy is non-Hodgkin's lymphoma.

• Bruton agammaglobulinaemia
• Neonatal alloimmune thrombocytopenia
• Atopic eczema
• Di George's syndrome
• Histiocytosis
• X-linked severe combined immunodeficiency

• Low platelet count (≤70 x 10⁹/L)¹
• Low mean platelet volume (< 5fL)¹
• Low IgG and IgM levels with elevated IgA and IgE (values need to be interpreted for age).
• Testing may show impairment of cell mediated immunity.
• Autoantibodies may be detected if autoimmune disease is present, especially in autoimmune haemolytic anaemia and immune thrombocytopenia and neutropenia.
• Consider the diagnosis in boys with thrombocytopenia. Detection of the Wiskott-Aldrich syndrome protein (WASP) can facilitate the diagnosis.⁵
• Bacteriology is required to help treat infection.
• Chest X-ray may be indicated depending on infective symptoms.
• Renal and liver function should be monitored.
• Tissue typing of the patient and close family members may be indicated if stem cell transplantation is considered.
• Carrier females may have low platelets.⁶

General

• All immunisations 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 should be treated, including treating eczema with moisturising creams and topical steroid preparations as indicated.
• If there is exposure to chickenpox, immunoglobulin or antivirals such as aciclovir are indicated. Varicella vaccine may be protective.
• In severe thrombocytopenia, splenectomy may be indicated but this also increases the risk of infection. Prophylactic antibiotics and immunisation (pneumococcal, HiB and meningococcal) are needed.¹
• Autoimmune diseases are managed in the normal way.

Potential cure

• Stem cell transplant can offer the chance of cure. It may be successful in over 90% of cases.^7,1
• In the future, gene therapy may also be an option.⁸

• Recurrent infections as outlined above.
• Bleeding can be difficult to control and intracranial bleeding may occur.
• Chronic renal disease may be associated with autoimmune disease.
• Haematological malignancy, especially non-Hodgkin's lymphoma.
• Graft-versus-host disease and other complications from stem cell transplantation.

• The prognosis has improved enormously over the years due to improved control of infection, transfusion services and stem cell transplantation.
• If stem cell transplantation is not carried out, individuals usually survive until their second or third decade and die from bleeding, malignancy or infection.¹
• Successful stem cell transplantation can mean reversal to normal immune function and the potential for a normal life span.¹
• A recent multi-centre study looked at long-term outcome following stem-cell transplantation in Wiskott-Aldrich syndrome. Amongst 96 patients, three patients died 2.1 to 21 years following transplantation. Overall 7-year event-free survival rate was 75%.⁹

• This can detect mutations in the WASP gene in those with a family history of Wiskott-Aldrich syndrome.
• It may allow planning for Caesarean section to reduce the risk of intracranial bleeding due to birth trauma.
• It may also allow planning for early stem cell transplantation as this can improve prognosis.

• Wiskott-Aldrich syndrome was first described by Wiskott in Germany in 1937¹⁰ and later by Aldrich in the USA in 1954.¹¹
• Wiskott worked in Munich and called the disorder 'Werlhof's disease,' the eponymous name for thrombocytopenia purpura. He described 3 affected German patients in 1937.¹⁰
• In 1954 Aldrich et al described patients of Dutch extraction with the condition.¹¹
• In 1964 Van den Bosch and Drukker⁶ described several families in Holland.
• Descriptions of the condition go back to the 19th century.¹²