Wiskott-Aldrich Syndrome (Wiskott-Aldrich-Huntley syndrome, eczema-thrombocytopenia-immunodeficiency syndrome)

Are You Confident of the Diagnosis?

What you should be alert for in the history

Wiskott- Aldrich syndrome (WAS) is characterized by the triad of recurrent pyogenic infections: bleeding due to thrombocytopenia and platelet dysfunction, and recalcitrant eczematous dermatitis.

Characteristic findings on physical examination

Characteristic findings include petechiae and ecchymoses of the skin and oral mucosa early in life and these are often the presenting features. Atopic dermatitis typically develops during the first few months of life, with the face, scalp and flexural areas most severely affected. Exfoliative dermatitis occasionally develops. Secondary bacterial and viral skin infections such as eczema herpeticum and molluscum contagiosum are common (Figure 1).

Figure 1.

Encapsulated bacteria such as Streptococcus pneumonia, Haemophilus influenzae, and Neisseria meningitides are the predominant organisms causing recurrent pyogenic infections. Common infections include otitis media and externa, pneumonia, sinusitis, and meningitis.

With advancing age there is a preponderance towards viral infections. WAS is an IgE mediated condition such as food allergies and urticaria are common.

Expected results of diagnostic studies

• Thrombocytopenia (platelet count less than 80,000/mm³). Low mean platelet volume (less than 5.0 fl)

• Lymphopenia

• Eosinophilia

• Defective monocyte and neutrophil chemotaxis

• Low serum IgM and IgG2

• Elevated serum IgE, IgA, and IgD

• Absent delayed-type hypersensitivity skin testing

Diagnosis confirmation

The differential diagnoses include other primary immunodeficiencies with a propensity towards pyogenic infections and eczema such as ataxia-telangiectasia, chronic granulomatous disease, common variable immunodeficiency, DiGeorge syndrome, Hyper-IgE syndrome, IgA deficiency, IgM deficiency, SCID (severe combined immunodeficiency), and X-inked agammaglobulinemia.

Decreased WASP expression in blood mononuclear cells by flow cytometry-based assays or immunoblot analysis, and mutational analysis confirm the diagnosis.

Who is at Risk for Developing this Disease?

The disease is X-linked recessive, primarily affecting boys. Girls can be affected due to random X-chromosome inactivation (lyonization) or homozygosity from a mild mutation. WAS occurs in 1:250,000 births of European decent and is less common in Asians and Africans.

What is the Cause of the Disease?

WAS is caused by a mutation in the WASP gene. WASP is responsible for actin filament assembly required for microvesicle and pro-platelet formation and is expressed in hematopoietic cells. It is also plays a role in T-cell activation and polarization toward antigen-presenting cells.

Systemic Implications and Complications

Autoimmunity is also more likely with conditions including rheumatoid arthritis, small vessel vasculitis, hemolytic anemia/neutropenia, and inflammatory bowel disease. Hepatosplenomegaly and lymphadenopathy can be appreciated on exam. Lymphomas, predominantly non- Hodgkin’s lymphoma, develop in 25% of patients.

Optimal Therapeutic Approach for this Disease

Appropriate antibiotics and /or antivirals for infections. Suppressive dosing of antivirals like valcyclovir may be necessary if there are recurrent viral infections. However, this should be approached cautiously, because of concern for the patient to become infected with more resistant viruses over time given their immunosuppressive status.

Topical steroids as utilized for atopic dermatitis. Low to mid potency topical steroids such as desonide 0.05% and triamcinolone 0.1% ointments to the affected areas on the face and body respectively in moderation should be effective.

The use of topical calcineurin inhibitors is not contraindicated in WAS. Their use should however be limited to small areas, like the face and body folds, in order to minimize systemic absorption and the potential of further immunosuppression.

The median survival is 15 years with causes of death (outside the setting of transplantation): infection (50%), bleeding (25%), and malignancy (25%).

Hematopoietic stem cell transplantation is the treatment of choice, and increases survival rate (if transplanted before 5 years of age, and from an HLA-matched donor) from less than 50% to 80%.

Splenectomy can help reduce bleeding complications from platelet dysfunction, however this increases the risk of infections with encapsulated organisms.

Patient Management

Genetic counseling for female relatives of patients with WAS is important, as female carriers can be detected by the selective inactivation of the abnormal X chromosome in lymphocytes and platelets. Direct mutational analysis is also available for prenatal diagnosis.

What is the Evidence?

Conley, ME, Saragoussi, D, Nortarangelo, L, Etzioni, A, Casanova, JL. “An international study examining therapeutic options used in treatment of Wiskott-Aldrich Syndrome”. Clin Immunol. vol. 109. 2003. pp. 272-7. (An international study to evaluate current treatment strategies was undertaken. A total of 73 centers from 24 countries participated.)

Ochs, HD, Nortarangelo, LD. “Structure and function of the Wiskott-Aldrich syndrome protein”. Curr Opin Hematol. vol. 12. 2005. pp. 284-91. (A review of studies evaluating the gene WASP, which has multiple domains, each with unique functions that were only recently fully recognized.)

Orange, JS, Stone, KD, Turvey, SE, Krzewski, K. “The Wiskott-Aldrich Syndrome”. Cell Molec Life Sci. vol. 61. 2004. pp. 2361-85. (This article gives a review of the clinical features associated with WAS.)

Bolognia, JL, Jorizzo, JL, Rapini, RP. Dermatology. pp. 821-2. (This text reviews in depth the pathophysiology of the disease, and its clinical features with photos.)

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