Clinical spectrum, pathophysiology and treatment of the Wiskott–Aldrich syndrome

Albert, Michael H^a; Notarangelo, Luigi D^b; Ochs, Hans D^c

^aDepartment of Pediatric Hematology/Oncology, Dr von Haunersches Kinderspital der Ludwig-Maximilians-Universität, Munich, Germany

^bThe Manton Center for Orphan Disease Research and the Division of Immunology, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA

^cDepartment of Pediatrics, University of Washington, and Seattle Children's Research Institute, Center for Immunity and Immunotherapy, Seattle, Washington, USA

Correspondence to Dr med. Hans D. Ochs, MD, Professor of Pediatrics, Jeffrey Modell Chair of Pediatric Immunology Research, Seattle Children's Hospital Research Institute, Research Center for Immunity and Immunotherapy, 1900 Ninth Avenue, 7th Floor, Seattle, WA 98101, USA Tel: +1 206 987 7318; fax: +1 206 987 7310; e-mail:[email protected],[email protected]

Current Opinion in Hematology18(1):p 42-48, January 2011. |DOI:10.1097/MOH.0b013e32834114bc

Abstract

Purpose of review

The Wiskott–Aldrich syndrome (WAS), caused by mutations in theWAS gene, is a complex and diverse disorder with X-linked inheritance. This review focuses on recent developments in the understanding of its basic pathophysiology, diverse clinical phenotypes and optimal patient management including novel therapies.

Recent findings

The protein encoded by theWAS gene is a multifunctional signaling element expressed in immune and hematopoietic cells that plays a critical role in cytoskeletal reorganization, immune synapse formation and intracellular signaling. The type of specific mutation, its location within the gene and its effect on protein expression play a major role in determining an individual patient's clinical phenotype. Recent clinical observations and molecular studies have created a sophisticated picture of the disease spectrum. The improved outcome of stem cell transplantation from related and unrelated matched donors and promising early results from the first clinical gene therapy trial have added new therapeutic options for these patients.

Summary

Classic WAS, X-linked thrombocytopenia and X-linked neutropenia are caused byWAS gene mutations, each having a distinct pattern of clinical symptoms and disease severity. New developments in the understanding of these syndromes and novel therapeutic options will have a major impact on the treatment of individuals withWAS mutations.