The Wiskott-Aldrich syndrome

doi:10.1016/j.jaci.2006.02.005

Journal of Allergy and Clinical Immunology

Volume 117, Issue 4, April 2006, Pages 725-738

https://doi.org/10.1016/j.jaci.2006.02.005 Get rights and content

The Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder with variable clinical phenotypes that correlate with the type of mutations in the WAS protein (WASP) gene. WASP, a key regulator of actin polymerization in hematopoietic cells, has 5 well-defined domains that are involved in signaling, cell locomotion, and immune synapse formation. WASP facilitates the nuclear translocation of nuclear factor κB and was shown to play an important role in lymphoid development and in the maturation and function of myeloid monocytic cells. Mutations of WASP are located throughout the gene and either inhibit or dysregulate normal WASP function. Analysis of a large patient population demonstrates a phenotype-genotype correlation: classic WAS occurs when WASP is absent, X-linked thrombocytopenia when mutated WASP is expressed, and X-linked neutropenia when missense mutations occur in the Cdc42-binding site. The progress made in dissecting the function of WASP has provided new diagnostic possibilities and has propelled our therapeutic strategies from conservative symptomatic treatment to curative hematopoietic stem cell transplantation and toward gene therapy.

Section snippets

Clinical and pathologic manifestations

The incidence of the classic WAS phenotype has been estimated to be between 1 and 10 in 1 million individuals.8, 9 With broader awareness of the different clinical phenotypes, along with the availability of reliable diagnostic tools, the incidence might be much higher. Clinical manifestations suggesting WAS-XLT are often present at birth and consist of petechiae, bruising, and bloody diarrhea.¹ Excessive hemorrhage after circumcision is an early diagnostic sign. Eczema is a frequent

Molecular basis

By studying DNA from large WAS families with multiple affected members, the WASP gene was mapped to the region Xp11.22-Xp11.3.⁴¹ On the basis of these mapping data, Derry et al⁴ isolated the WASP gene by means of positional cloning and demonstrated mutations in lymphoblastoid cell lines derived from patients with WAS-XLT. The WASP gene (Fig 1) encodes a 502-amino-acid intracellular protein (WASP) expressed exclusively in hematopoietic cells.

Mutation analysis

The cloning and sequencing of the gene responsible for WAS-XLT has not only provided new insight into the function of WASP but has lead to the discovery of powerful tools to confirm molecularly the diagnosis in symptomatic male subjects, identify carrier female subjects, and diagnose WAS-XLT in at-risk fetuses. These new techniques include methods of screening lymphocytes for the presence or absence of WASP by means of flow cytometry (Fig 3) or Western blot analysis and sequencing cDNA, genomic

Establishing the diagnosis of WAS-XLT

Because of the wide spectrum of clinical findings, the diagnosis of WAS-XLT should be considered in any male patient presenting with petechiae, bruises, and congenital or early-onset thrombocytopenia associated with small platelet size. The presence of transient, mild, or severe eczema supports the diagnosis of WAS-XLT. It is important to note that infections and immunologic abnormalities might be absent, mild, or severe, and autoimmune disease develops more often in patients with WAS than in

Conventional treatment

Management of patients with WAS continues to present major challenges, particularly in attenuated phenotypes, where the natural history of disease progression is less predictable. Early diagnosis is most important for effective prophylaxis and treatment. If an infection is suspected, careful evaluation for bacterial, viral, or fungal causes followed by appropriate antimicrobial therapy is of crucial importance. Infants with WASP mutations and lymphopenia are candidates for Pneumocystis carinii

Conclusion

WAS is a perfect example of the effect of molecular genetics on the understanding of complex diseases. WASP plays important roles in actin polymerization, development of hematopoietic cells, IS formation, cell signaling, and lymphocyte apoptosis. Mutations of WASP result in phenotypically unique diseases entities, depending on the effect of the mutation of WASP expression. Understanding the molecular basics has important implications for the diagnosis, treatment, and genetic counseling of

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