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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.
- 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.
- 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, 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.
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.