Wiskott-Aldrich syndrome (WAS) is an X-linked disease characterized by microthrombocytopenia, eczema and immune deficiency, caused primarily by mutations in the WASP (Wiskott-Aldrich syndrome protein) gene. Female carriers are usually asymptomatic because of the preferential activation of the normal, nonmutated X-chromosome in their hematopoietic cells. We report our observations of a female child with WAS, who displayed symptoms of congenital thrombocytopenia. DNA sequencing analysis of the WASP gene revealed a heterozygous nonsense mutation in exon 10. The expressions of WASP and normal WASP mRNA were defective. We found preferential inactivation of the X-chromosome on which wild-type WASP was located. Single-nucleotide polymorphism microarray testing and the analysis of the polymorphic variable number of tandem repeat regions revealed maternal uniparental isodisomy of chromosome 6 (UPD6). Our results underscore the importance of WASP evaluation in females with congenital thrombocytopenia and suggest that UPD6 might be related to the pathophysiology of nonrandom X-chromosome inactivation.

Massaad MJ, Ramesh N, Geha RS: Wiskott-Aldrich syndrome: a comprehensive review. Ann NY Acad Sci 2013;1285:26-43.
Derry JM, Ochs HD, Francke U: Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell 1994;78:635-644.
Stewart DM, Treiber-Held S, Kurman CC, Facchetti F, Notarangelo LD, Nelson DL: Studies of the expression of the Wiskott-Aldrich syndrome protein. J Clin Invest 1996;97:2627-2634.
Symons M, Derry JM, Karlak B, Jiang S, Lemahieu V, McCormick F, Francke U, Abo A: Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization. Cell 1996;84:723-734.
Huang W, Ochs HD, Dupont B, Vyas YM: The Wiskott-Aldrich syndrome protein regulates nuclear translocation of NFAT2 and NF-kappa B (RelA) independently of its role in filamentous actin polymerization and actin cytoskeletal rearrangement. J Immunol 2005;174:2602-2611.
Cianferoni A, Massaad M, Feske S, de la Fuente MA, Gallego L, Ramesh N, Geha RS: Defective nuclear translocation of nuclear factor of activated T cells and extracellular signal-regulated kinase underlies deficient IL-2 gene expression in Wiskott-Aldrich syndrome. J Allergy Clin Immunol 2005;116:1364-1371.
Wengler G, Gorlin JB, Williamson JM, Rosen FS, Bing DH: Nonrandom inactivation of the X chromosome in early lineage hematopoietic cells in carriers of Wiskott-Aldrich syndrome. Blood 1995;85:2471-2477.
Parolini O, Ressmann G, Haas OA, Pawlowsky J, Gadner H, Knapp W, Holter W: X-linked Wiskott-Aldrich syndrome in a girl. N Engl J Med 1998;338:291-295.
Kawai S, Minegishi M, Ohashi Y, Sasahara Y, Kumaki S, Konno T, Miki H, Derry J, Nonoyama S, Miyawaki T, Horibe K, Tachibana N, Kudoh E, Yoshimura Y, Izumikawa Y, Sako M, Tsuchiya S: Flow cytometric determination of intracytoplasmic Wiskott-Aldrich syndrome protein in peripheral blood lymphocyte subpopulations. J Immunol Methods 2002;260:195-205.
Lanzi G, Moratto D, Vairo D, Masneri S, Delmonte O, Paganini T, Parolini S, Tabellini G, Mazza C, Savoldi G, Montin D, Martino S, Tovo P, Pessach IM, Massaad MJ, Ramesh N, Porta F, Plebani A, Notarangelo LD, Geha RS, Giliani S: A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP. J Exp Med 2012;209:29-34.
Wengler GS, Parolini O, Fiorini M, Mella P, Smith H, Ugazio AG, Notarangelo LD: A PCR-based non-radioactive X-chromosome inactivation assay for genetic counseling in X-linked primary immunodeficiencies. Life Sci 1997;61:1405-1411.
Lyon MF: Gene action in the X-chromosome of the mouse (Mus musculus l.). Nature 1961;190:372-373.
Boonyawat B, Dhanraj S, Al Abbas F, Zlateska B, Grunenbaum E, Roifman CM, Steele L, Meyn S, Blanchette V, Scherer SW, Swierczek S, Prchal J, Zhu Q, Torgerson TR, Ochs HD, Dror Y: Combined de-novo mutation and non-random X-chromosome inactivation causing Wiskott-Aldrich syndrome in a female with thrombocytopenia. J Clin Immunol 2013;33:1150-1155.
Puck JM, Willard HF: X inactivation in females with X-linked disease. N Engl J Med 1998;338:325-328.
Salahshourifar I, Halim AS, Sulaiman WA, Zilfalil BA: Maternal uniparental heterodisomy of chromosome 6 in a boy with an isolated cleft lip and palate. Am J Med Genet A 2010;152A:1818-1821.
Yamazawa K, Ogata T, Ferguson-Smith AC: Uniparental disomy and human disease: an overview. Am J Med Genet C Semin Med Genet 2010;154C:329-334.
Keitges EA, Pasion R, Burnside RD, Mason C, Gonzalez-Ruiz A, Dunn T, Masiello M, Gebbia JA, Fernandez CO, Risheg H: Prenatal diagnosis of two fetuses with deletions of 8p23.1, critical region for congenital diaphragmatic hernia and heart defects. Am J Med Genet A 2013;161A:1755-1758.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.