Wiskott-Aldrich syndrome

Synonym: Wiskott-Aldrich-Huntley syndrome

This is an X-linked recessive condition with immunodeficiency as an underlying problem. An autosomal dominant form has also been described.¹ It is characterised by:²

• Recurrent bacterial infections of the sinuses and lungs.

• Eczema that resembles an atopic dermatitis.

• A bleeding tendency due to thrombocytopenia and platelet dysfunction.

Wiskott-Aldrich syndrome (WAS) was first described by Wiskott in Germany in 1937³ and later by Aldrich in the USA in 1954.⁴ However, descriptions of the condition go back to the 19th century.⁵

Pathophysiology

• The underlying mutation is in the gene for the Wiskott-Aldrich syndrome protein (WASP) on the X-chromosome at Xp11.22-23.⁶

• WASP is needed for normal antibody function, T-cell responses and platelet production.

Epidemiology

• The incidence of the classic syndrome is estimated to be between one and ten in one million individuals, although it is likely to be higher.⁷

• Being X-linked and potentially lethal, it would be expected almost invariably to affect males and more than 90% of affected patients are male. However, affected females have been reported.

• Affected females usually have no family history and some have been shown to have nonrandom inactivation of the X chromosome bearing the functional Wiskott-Aldrich syndrome (WAS) allele.

Presentation⁶

Presentation can be any time from birth to 25 years but most cases present in the first 2 years of life. Less than one third of affected individuals have the full triad at presentation but almost 90% present with features of thrombocytopenia. Around 5% present only with infection and 20% only with haematological problems.⁸

• 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 fewer 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:
  

  • This 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%).⁹

• 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.

Differential diagnosis²

• Bruton's agammaglobulinaemia.

• Neonatal alloimmune thrombocytopenia.

• Atopic eczema.

• Di George's syndrome.

• Histiocytosis.

• X-linked severe combined immunodeficiency.

Investigations

• Low platelet count (≤70 x 10⁹/L).²

• Low mean platelet volume (<5fL).

• 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.¹⁰

• 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 platelet counts.¹¹

Management

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.²

• 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.²¹²

• In the future, gene therapy may also be an option.¹³

Complications

• 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.

Prognosis

• 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.²

• Successful stem cell transplantation can mean reversal to normal immune function and the potential for a normal life span.²

• A recent multicentre study looked at long-term outcome following stem cell transplantation in Wiskott-Aldrich syndrome (WAS). Amongst 96 patients, three patients died 2.1 to 21 years following transplantation. Overall 7-year event-free survival rate was 75%.¹⁴

Prenatal diagnosis

• This can detect mutations in the Wiskott-Aldrich syndrome protein (WASP) gene in those with a family history of Wiskott-Aldrich syndrome (WAS).

• 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.