Wiskott-Aldrich syndrome is a rare X-linked recessive immune deficiency characterized by thrombocytopenia (low platelet count), small platelet size, eczema, and recurrent infections. It occurs early in childhood, usually before age 3. The condition is caused by mutations in the WASP gene and results in deficiencies in platelet formation and function as well as immune dysfunction. Management involves treating and preventing infections; splenectomy may help in severe cases, while bone marrow transplantation is the only cure.
Wiskott-Aldrich syndrome is a rare X-linked recessive immune deficiency characterized by thrombocytopenia (low platelet count), small platelet size, eczema, and recurrent infections. It occurs early in childhood, usually before age 3. The condition is caused by mutations in the WASP gene and results in deficiencies in platelet formation and function as well as immune dysfunction. Management involves treating and preventing infections; splenectomy may help in severe cases, while bone marrow transplantation is the only cure.
Wiskott-Aldrich syndrome is a rare X-linked recessive immune deficiency characterized by thrombocytopenia (low platelet count), small platelet size, eczema, and recurrent infections. It occurs early in childhood, usually before age 3. The condition is caused by mutations in the WASP gene and results in deficiencies in platelet formation and function as well as immune dysfunction. Management involves treating and preventing infections; splenectomy may help in severe cases, while bone marrow transplantation is the only cure.
1 Creation Date: December 1996 Updates: April 2001 May 2003 Scientific Editor: Professor Alain Fischer 1 Hpital Necker enfants malades, INSERM U 429, 149 Rue de Svres, 75743 Paris Cedex 15, France. sbasile@necker.fr Abstract Keywords Name of the disease and synonyms Diagnostic criteria/definition Differential diagnosis Incidence Clinical description Methods of biological diagnosis Management/treatments Etiology Genetic counseling/prenatal diagnosis References Abstract The Wiskott-Aldrich syndrome (WAS) is a rare hereditary immune deficiency with recessive inheritance linked to the X chromosome (Xp11.22-p11.23). This syndrome is characterized by the association of thrombocytopenia with small-sized platelets, eczema and repeated infections. The deficiency occurs early in childhood, during the first decade and usually before the age of 3 years. Several clinical signs can orientate this diagnosis. The subject is a young boy with hemorrhagic signs (purpura, petechiae, ecchymoses, epistaxis, bloody diarrhoea or others), recurrent infections (bronchial, pulmonary, ENT (ear, nose, throat), eczema and, sometimes, signs of autoimmunity. Children with WAS should be followed in paediatric centres specialized in immunology and haematology. Management consists of treating and preventing infections. When the thrombocytopenia is very severe, splenectomy may be beneficial . Only a bone-marrow transplantation can cure this pathology. Keywords Immune deficiency, X linked inheritance, thrombocytoperia, small sized platelets, eczema, repeated infections, bone-marrow transplantation.
Name of the disease and synonyms Wiskott-Aldrich syndrome Diagnostic criteria/definition The Wiskott-Aldrich syndrome (WAS) (OMIM 301000) is a rare hereditary immune deficiency with recessive inheritance linked to the X chromosome. This syndrome is characterized by the association of thrombocytopenia with small- sized platelets, eczema and repeated infections. Differential diagnosis WAS differs from isolated thrombocytopenia linked to the X chromosome and other idiopathic thrombocytopenias that do not have an immune deficiency. Isolated thrombocytopenia linked to the X chromosome presents the same hematological characteristics as WAS but the thrombocytopenia in the former is the sole symptom, with no particular susceptibility to infections. This isolated thrombocytopenia is most often benign. It is due, as in WAS, to anomalies in the WASP gene (11, 12). Between X-linked thrombocytopenia and WAS, a
de Saint Basile G.; Wiskott-Aldrich syndrome. Orphanet encyclopedia, May 2003. http://www.orpha.net/data/patho/GB/uk-wiskott.pdf 1
continuum of disease severity can be seen (13). No clear relationship exists between disease severity and the type of mutation responsible, even though the mutations that allow residual expression of the protein WASP tend to cause less severe forms of the disease (14). Activated WASP associates with actin and plays a role in the reorganization of the cellular cytoskeleton (15). Incidence The incidence is 1/20,000 births/year. Clinical description This deficiency occurs early in childhood, during the first decade and usually before the age of 3 years. Several clinical signs can orient this diagnosis. The subject is a young boy with hemorrhagic signs (purpura, petechiae, ecchymoses, epistaxis, bloody diarrhea or others), recurrent infections (bronchial, pulmonary, ENT (ear, nose, throat), eczema and, sometimes, signs of autoimmunity (2). Methods of biological diagnosis A complete blood count shows severe thrombocytopenia, often fewer than 50,000 platelets. Analysis of platelet size shows them to be small (4-5 microns). When performed, the bone-marrow biopsy does not reveal the presence of a central mechanism. Management/treatments Children with WAS should be followed in pediatric centers specialized in immunology and hematology. Management consists of treating and preventing infections. When the thrombocytopenia is very severe, splenectomy may be beneficial (3). Only a bone-marrow transplantation can cure this pathology (4). Its success depends on the availability of an HLA- identical donor. Good management of infections can considerably lower the risk of the disease evolving towards the development of lymphoma or tumors (5). Etiology WAS is a disease with X-linked recessive inheritance whose gene has been localized to chromosome Xp11.22-p11.23 and is linked to polymorphic markers (6-7). The gene responsible has been characterized (8). The anomalies of this gene found in patients vary widely and differ from one family to another (9,11-15). Genetic counseling/prenatal diagnosis When the mutation in the family at risk has already been identified, analysis of the gene responsible for WAS enables early prenatal diagnosis on a trophoblast biopsy at 11 weeks of amenorrhea. In the familial forms (more than 1 member affected), it is also possible to use the polymorphic markers linked to the locus of the disease to evaluate the risk of a woman being a carrier or to perform an early prenatal diagnosis. Women carriers of WAS have a specific pattern of chromosome X inactivation in all their hematopoietic cell lines (10). References 1. Ochs, H.D.; Slichter, S.J .; Harker, LA.; Von Behrens, W.E.; Clark, R.A.; Wedgwood, R.J . The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets. Blood 55: 243-252, 1980. 2. Spitler, L.E.; Wray, B.B.; Mogerman, S.; Miller, J .J III O'Reilly, R.J .; Lagios, M. Nephropathy in the Wiskott-Aldrich syndrome. Pediatrics 66: 391-398, 1980. 3. Nathan, D.G. Splenectomy in the Wiskott- Aldrich syndrome. (Editorial) New Engl. J . Med. 302: 916-917, 1980. 4. Parkman, R.; Rappeport, J .; Geha, R.; Belli, J .; Cassady, R.; Levey, R.; Nathan, D.G.; Rosen, F.S. Complete correction of the Wiskott-Aldrich syndrome by allogeneic bone marrow transplantation. New Engl. J . Med. 298: 921-927, 1978. 5. ten Bensel, R.W.; Stadlan, E.M.; Krivit, W. The development of malignancy in the course of the Aldrich syndrome. J . Pediatr. 68: 761-767, 1966. 6. Peacocke, M.; Siminovitch, K.A. Linkage of the Wiskott-Aldrich syndrome with polymorphic DNA sequences from the human X chromosome. Proc. Natl. Acad. Sci. USA. 84: 3430-3433, 1987. 7. de Saint Basile, G.; Arveiler, B.; Fraser, N.F.; Boyd, Y.; Graig, I.W.; Griscelli, G.; Fischer, A. Close linkage of hypervariable marker DXS255 to disease locus of Wiskott-Aldrich syndrome. Lancet II: 1319-1321, 1989. 8. Derry, J .M.J .; Ochs, H.D.; Francke, U. Isolation of a novel gene mutated in Wiskott- Aldrich syndrome. Cell 78: 635-644, 1994. 9. Gerwin N, Friedrich C, Perez-Atayde A, Rosen FS, Gutierrez-Ramos J C. Multiple antigens are altered on T and B lymphocytes from peripheral blood and spleen of patients with Wiskott-Aldrich syndrome. Clin Exp Immunol. 1996 Nov; 106(2): 208-17 10. Fearon, E.R.; Kohn, D.B.; Winkelstein, J .A.; Vogelstein, B.; Blaese, R.M. Carrier detection in the Wiskott-Aldrich syndrome. Blood 72: 1735- 1739, 1988. 11. Derry, J . M. J .; Kerns, J . A.; Weinberg, K. I.; Ochs, H. D.; Volpini, V.; Estivill, X.; Walker, A. P.; Francke, U. WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. Hum. Mol. Genet. 4: 1127- 1135, 1995. 12. de Saint-Basile, G.; Lagelouse, R.D.; Lambert, N.; Schwarz, K.; Le Mareck, B.; Odent, S.; Schlegel, N.; Fischer, A. Isolated X-linked
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14. Lemahieu V, Gastier J M, Francke U.Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes.Hum Mutat. 14 : 54-66, 1999. thrombocytopenia in two unrelated families is associated with point mutations in the Wiskott- Aldrich syndrome protein gene. J . Pediat.129: 56-62, 1996. 13. Zhu, Q.; Zhang, M.; Blaese, R.M.; Derry, J .M.J .; J unker, A.; Francke, U.; Chen, S.-H.; Ochs, H. D.The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene. Blood 86: 3797-3804, 1995. 15. Kim AS, Kakalis LT, Abdul-Manan N, Liu GA, Rosen MK. Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein. Nature. 404 : 151-8, 2000.
de Saint Basile G.; Wiskott-Aldrich syndrome. Orphanet encyclopedia, May 2003. http://www.orpha.net/data/patho/GB/uk-wiskott.pdf 3