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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. It is characterised by:
- 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 1937 and later by Aldrich in the USA in 1954. However, descriptions of the condition go back to the 19th century.
- The underlying mutation is in the gene for the Wiskott-Aldrich syndrome protein (WASP) on the X-chromosome at Xp11.22-23.
- WASP is needed for normal antibody function, T-cell responses and platelet production.
- 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.
- 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.
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.
- 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.
- 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.
- 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%).
- 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's agammaglobulinaemia.
- Neonatal alloimmune thrombocytopenia.
- Atopic eczema.
- Di George's syndrome.
- X-linked severe combined immunodeficiency.
- Low platelet count (≤70 x 109/L).
- 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.
- 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.
- All immunisations should be given as usual. Hib is especially important.
- Encourage normal work and school but avoid contact sports.
- 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.
- Autoimmune diseases are managed in the normal way.
- Stem cell transplant can offer the chance of cure. It may be successful in over 90% of cases.[2, 12]
- In the future, gene therapy may also be an option.
- 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.
- Successful stem cell transplantation can mean reversal to normal immune function and the potential for a normal life span.
- 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%.
- 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.
Further reading and references
Wiskott Aldrich Syndrome Autosomal Dominant, Online Mendelian Inheritance in Man (OMIM)
Schwartz RA et al, Pediatric Wiskott-Aldrich Syndrome, Medscape, Sep 2010
Wiskott, A; Familiarer, angeborener Morbus Werlhofii? Mschr. Kinderheilk. 68: 212-216, 1937
Aldrich RA, Steinberg AG, Campbell DC; Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea. Pediatrics. 1954 Feb13(2):133-9.
Perry GS 3rd, Spector BD, Schuman LM, et al; The Wiskott-Aldrich syndrome in the United States and Canada (1892-1979). J Pediatr. 1980 Jul97(1):72-8.
Wiskott Aldrich Syndrome X-linked recessive #301000, Online Mendelian Inheritance in Man (OMIM)
Thrasher AJ; New insights into the biology of Wiskott-Aldrich syndrome (WAS). Hematology Am Soc Hematol Educ Program. 2009:132-8.
Sullivan KE, Mullen CA, Blaese RM, et al; A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr. 1994 Dec125(6 Pt 1):876-85.
Dupuis-Girod S, Medioni J, Haddad E, et al; Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics. 2003 May111(5 Pt 1):e622-7.
Qasim W, Gilmour KC, Heath S, et al; Protein assays for diagnosis of Wiskott-Aldrich syndrome and X-linked thrombocytopenia. Br J Haematol. 2001 Jun113(4):861-5.
Van Den Bosch J, Drukker J; The Aldrich Syndrome - A clinical and genetic study of several Dutch families. Maandschr Kindergeneeskd. 1964 Jul32:359-73.
Tsuji Y, Imai K, Kajiwara M, et al; Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. Bone Marrow Transplant. 2006 Mar37(5):469-77.
Chinen J, Puck JM; Successes and risks of gene therapy in primary immunodeficiencies. J Allergy Clin Immunol. 2004 Apr113(4):595-603
Ozsahin H, Cavazzana-Calvo M, Notarangelo LD, et al; Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation. Blood. 2008 Jan 1111(1):439-45. Epub 2007 Sep 27.