Diagnosis and clinical management of Wiskott–Aldrich syndrome: current and emerging techniques

ABSTRACT

Introduction

Wiskott–Aldrich syndrome (WAS) serves as the prototype of how variants in a gene, which encodes a protein central to actin cytoskeletal homeostasis can manifest clinically in a variety of ways including infection, atopy, autoimmunity, inflammation, bleeding, neutropenia, non-malignant lymphoproliferation, and malignancy. Despite the discovery of the WAS gene almost 30 years ago, our understanding of the pathophysiological mechanisms underlying WAS continues to unfold.

Areas covered

This review will provide an overview of the approach to the diagnosis of WAS as well as the management of its associated complications. Advances in the use of allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy as well as the associated challenges unique to WAS will be discussed.

Expert opinion

Basic research, combined with clinical research focusing on longitudinal analysis of WAS patients, will help clarify determinants that influence WAS pathogenesis as well as clinical complications and outcomes. Advances in curative approaches including the use of alternative donor HSCT for WAS continue to evolve. Gene therapy employing safer and more effective protocols ensuring full correction of WAS will provide life-saving benefit to WAS patients who are unable to undergo HSCT.

KEYWORDS:

• Actin
• combined immunodeficiency
• gene therapy
• hematopoietic stem cell transplantation
• inborn errors of immunity
• primary immunodeficiency

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article highlights

• Wiskott–Aldrich syndrome (WAS) is a severe X-linked immunodeficiency caused by variants in the gene encoding WASP, a regulator of actin assembly in hematopoietic cells.

• Complications of WAS include bacterial, viral, and opportunistic infections, atopy, autoimmunity, inflammation, bleeding, as well as non-malignant lymphoproliferation, and malignancy.

• X-linked thrombocytopenia (XLT) is a milder version of WAS in which variants preserve residual WASP expression; however, typical WAS associated complications may occur albeit less frequently.

• The physical exam of patients with WAS (eczema, ecchymosis, petechiae, bloody diarrhea) as well as laboratory testing (thrombocytopenia, microthrombocytes, abnormal immune function) may disclose features that are suggestive of the diagnosis.

• The routine use of flow cytometric analysis of WASP expression as a screening tool in all cases of suspected WAS is recommended followed by genetic sequencing to allow for confirmation.

• Hematopoietic stem cell transplantation (HSCT) is the recommended curative approach for patients with WAS. HSCT outcomes for patients (<5 years of age) with WAS are excellent with an overall survival (OS) >90% regardless of donor type.

• Gene therapy has demonstrated safety and efficacy in patients with WAS; however, some issues related to incomplete correction such as thrombocytopenia may still persist.

Additional information

Funding

This paper was not funded.