Wiskott-Aldrich syndrome

Author: Doctor Genevive de Saint-Basile

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
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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

de Saint Basile G.; Wiskott-Aldrich syndrome. Orphanet encyclopedia, May 2003.
http://www.orpha.net/data/patho/GB/uk-wiskott.pdf
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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
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