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Wiskott-Aldrich Syndrome (WAS)

Written2012-01Adrian Thrasher, Winnie Ip
Molecular Immunology Unit, Centre for Immunodeficiency, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK (AT); Clinical Fellow in Immunology, Great Ormond Street Hospital, Great Ormond Street, London, WC1N 3JH, London, UK (WI)

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Identity

Other namesEczema-thrombocytopenia-immunodeficiency syndrome
Atlas_Id 10027
Genes implicated inWAS  WIPF1  
Note The clinical spectrum of disease also includes chronic or intermittent X-linked thrombocytopaenia (XLT), a milder clinical variant; and X-linked neutropaenia (XLN) due to an arrest of myelopoiesis.
Inheritance X-linked recessive; overall incidence is estimated to be 4,0 per million live male births, with no known ethnic or geographical predominance.

Clinics

Note WAS is characterized by low numbers of small platelets, easy bruising and prolonged bleeding, eczema and recurrent infections. It can be complicated by autoimmunity and haematopoietic cell malignancies.
Phenotype and clinics Clinical manifestations suggesting WAS/XLT are often present at birth and consist of petechiae, bruising, and bloody diarrhoea. Excessive haemorrhage after circumcision is an early diagnostic clue.
Infections, including purulent otitis media, pneumonia and skin infections, are common during the first 6 months of life. Infections are most often caused by bacteria and viruses such as CMV, rarely by Pneumocystis carinii. Patients with XLT have fewer problems with eczema and infections and are often misdiagnosed as having idiopathic thrombocytopaenia (ITP).
Thrombocytopaenia associated with small platelet volume is a consistent finding in both classical WAS and XLT and is a key diagnostic indicator. In most patients the mean platelet volume is half that of normal control subjects. Life-threatening bleeding, including severe oral bleeding, gastrointestinal bleeding, and intracranial haemorrhage, has been reported in up to 30% of patients.
Compromised humoral and cellular adaptive immunity is a hallmark of classical WAS. Common findings include mild to moderate lymphopaenia, defective T cell proliferation in response to TCR stimulation, low levels of IgM and high levels of IgA and IgE. Antigen-specific T and B cell responses, particularly to polysaccharides, are also impaired in patients with WAS. Patients with XLT by definition have minimal immunological disturbances.
Autoimmune diseases are frequent, the most common being haemolytic anaemia, thrombocytopaenia, neutropaenia followed by vasculitis, renal disease, Henoch-Schonlein-like purpura, and inflammatory bowel disease. Incidence of autoimmune disease is less in XLT but has been reported to occur.
Prominent features of XLN include chronic neutropaenia and monocytopaenia, although some cases have values that fall within the low-normal range. Low-normal IgA levels, low to low-normal platelet counts (normal mean platelet volume) and reduced natural killer (NK)-cell counts have been reported.
Neoplastic risk Malignancies are more frequent in adolescents and young adults with the classic WAS phenotype. Most frequent malignancies reported are B cell lymphoma (often Epstein-Barr virus-positive) and leukaemia. Some younger patients may also present with marrow dysplasia. In XLN there is experimental evidence of genomic instability that may predispose patients to myeloid malignancy.
Treatment Classic WAS has a poor prognosis, but early treatment with haematopoietic stem cell transplant is curative in most patients. More recently, gene-modified stem cell therapy using retroviral or lentiviral vectors has become available as an alternative.
XLT and XLN, with a better prognosis, may be treated more conservatively with antibiotic prophylaxis. In XLN G-CSF should be used with caution as long term G-CSF usage may predispose to CSF3R mutations, and this is highly predictive for malignant transformation.
Intravenous immunoglobulin (IVIG) therapy is indicated in patients with a significant antibody deficiency.
Autoimmune manifestations may require immunosuppressant. Autoimmune cytopaenia often responds to a monoclonal antibody targeting the CD20 antigen (rituximab).
Prognosis Reported median survival in patients with WAS is age 20 years. Death results from infections, bleeding complications, autoimmune diseases, and malignancies.
WAS-associated malignancies have a poor prognosis.

Genes involved and Proteins

Gene NameWAS (Wiskott-Aldrich syndrome)
Location Xp11.23
DNA/RNA
Description 12 exons spanning 9 kb of genomic DNA.
Protein
 
  
Description 502 amino acids; 54 kDa; consists of an N-terminal Ena-VASP homology domain 1 (EVH1), a basic domain, a GTPase binding domain (GBD), polyproline domain and the C-terminal domain comprising of a cluster of verprolin homology (V), central (C) and acidic regions (A) (the VCA domain).
Expression WAS protein (WASp) is constitutively expressed in all haematopoietic stem-cell-derived lineages, except in mature red blood cells.
Localisation WASp is located in the cytoplasmic compartment with highest density along the cell membrane.
Function WASp acts as an adaptor to bring together downstream mediators that facilitate Arp2/3-mediated actin polymerization. A lack of WASp results in cytoskeletal defects that compromise multiple aspects of normal cellular activity including proliferation, phagocytosis, immune synapse formation, adhesion and directed migration.
Mutations
 
Germinal More than 295 unique mutations have been identified.
158 unique WASP gene mutations had been identified in a cohort of 270 unrelated WAS/XLT families. The most common are missense mutations, followed by splice-site mutations, short deletions, and nonsense mutations. Insertions, complex mutations, and large deletions are less frequent. Most deletions and insertions involve fewer than 10 nucleotides and result in frame shifting and early termination of transcription.
Amino acid substitutions are typically located in exons 1-4. Splice-site mutations occur predominantly in the downstream half of the WASP gene (introns 6-12).
Mutations affecting invariant splice sites may result in multiple splicing products, which often include small amounts of normal WASP cDNA.
Six mutational hotspots, defined as occurring in > 2,5% of the population, have been identified. Three of these hotspots represent point mutations within the coding regions, whereas the other 3 involve splice sites.
Patients who have missense or splice-site mutations may have residual protein expression and have a less severe clinical phenotype.
X-linked neutropaenia result from missense mutations in the Cdc42-binding site.

Bibliography

Clinical spectrum, pathophysiology and treatment of the Wiskott-Aldrich syndrome.
Albert MH, Notarangelo LD, Ochs HD.
Curr Opin Hematol. 2010 Nov 11. [Epub ahead of print]
PMID 21076297
 
A large kindred with X-linked neutropenia with an I294T mutation of the Wiskott-Aldrich syndrome gene.
Beel K, Cotter MM, Blatny J, Bond J, Lucas G, Green F, Vanduppen V, Leung DW, Rooney S, Smith OP, Rosen MK, Vandenberghe P.
Br J Haematol. 2009 Jan;144(1):120-6. Epub 2008 Nov 1.
PMID 19006568
 
The Wiskott-Aldrich syndrome: The actin cytoskeleton and immune cell function.
Blundell MP, Worth A, Bouma G, Thrasher AJ.
Dis Markers. 2010;29(3-4):157-75. (REVIEW)
PMID 21178275
 
Wiskott-Aldrich Syndrome: Immunodeficiency resulting from defective cell migration and impaired immunostimulatory activation.
Bouma G, Burns SO, Thrasher AJ.
Immunobiology. 2009;214(9-10):778-90. Epub 2009 Jul 22. (REVIEW)
PMID 19628299
 
Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation.
Jin Y, Mazza C, Christie JR, Giliani S, Fiorini M, Mella P, Gandellini F, Stewart DM, Zhu Q, Nelson DL, Notarangelo LD, Ochs HD.
Blood. 2004 Dec 15;104(13):4010-9. Epub 2004 Jul 29.
PMID 15284122
 
Wiskott-Aldrich syndrome: diagnosis, clinical and laboratory manifestations, and treatment.
Ochs HD, Filipovich AH, Veys P, Cowan MJ, Kapoor N.
Biol Blood Marrow Transplant. 2009 Jan;15(1 Suppl):84-90. (REVIEW)
PMID 19147084
 
Wiskott Aldrich Syndrome.
Ochs HD, Rosen FS.
Ochs HD, Smith CIE, Puck JM (eds.) Primary Immunodeficiency Diseases a molecular and genetic approach. Oxford University Press. 1999; pp. 292-302.
 
The Wiskott-Aldrich syndrome.
Ochs HD, Thrasher AJ.
J Allergy Clin Immunol. 2006 Apr;117(4):725-38; quiz 739. (REVIEW)
PMID 16630926
 
WASP: a key immunological multitasker.
Thrasher AJ, Burns SO.
Nat Rev Immunol. 2010 Mar;10(3):182-92. (REVIEW)
PMID 20182458
 
New insights into the biology of Wiskott-Aldrich syndrome (WAS).
Thrasher AJ.
Hematology Am Soc Hematol Educ Program. 2009:132-8. (REVIEW)
PMID 20008191
 

Citation

This paper should be referenced as such :
Thrasher, A ; Ip, W
Wiskott-Aldrich Syndrome (WAS)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(6):432-435.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Tumors/WiskottAldrichID10027.html


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