Dermatologic Manifestations of Wiskott-Aldrich Syndrome

Updated: Aug 13, 2019
Author: Akimichi Morita, MD, PhD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder originally described as a clinical triad of thrombocytopenia,[1] eczema (atopiclike dermatitis), and recurrent pyogenic infections. Only 27% of patients have the classic triad, 20% of patients have hematologic manifestations alone, and 5% have infectious features before diagnosis. Recurrent infections result from immunodeficiency of both humoral immune responses and T-cell–mediated immune responses. The responsible gene (WASP) was identified in 1994,[2, 3] and, since then, about 300 mutations have been reported.[4]

Other Medscape Reference articles on Wiskott-Aldrich syndrome include Wiskott-Aldrich Syndrome and Pediatric Wiskott-Aldrich Syndrome.

Pathophysiology

Wiskott-Aldrich syndrome's hemorrhagic condition is due to both quantitative platelet defects and qualitative platelet defects. Thrombocytopenia is persistent. Platelets are small and fail to aggregate. Recurrent pyogenic infections are secondary to immunodeficiency of both humoral immune responses and T-cell–mediated immune responses. Eczema appears to be related to the abnormal function of the T cells.

Etiology

Sialylated glycoprotein (CD43), a component of the T-cell activation pathway that binds intercellular adhesion molecule-1 (ICAM-1), is not stably expressed by lymphocytes and platelets; it was suspected to be the primary cause.[5]

Several mutations in the WASP gene, which consists of 12 exons and encodes 502 amino acids, have been identified in patients with Wiskott-Aldrich syndrome. WASP is an important transcription factor of lymphocyte and platelet function. It has been also shown that activating mutations of WASP are responsible for X-linked thrombocytopenia or myelodysplasia.

The Wiskott-Aldrich syndrome protein (WASp) is a key regulator of actin polymerization in hematopoietic cells. Mutations in WASp cause a severe immunodeficiency characterized by defective initiation of primary immune response and autoimmunity.[6] WASp expression in dendritic cells regulates both the ability to traffic to secondary lymphoid organs and to activate naive T cells in lymph nodes.[7, 8]

Eczema appears to be related to the abnormal function of the T cells.

Epidemiology

Frequency

The prevalence of Wiskott-Aldrich syndrome is approximately 4 cases per 1 million births.[9]

Race

Most Wiskott-Aldrich syndrome patients are white. Blacks and Asians are rarely affected.

Sex

Most Wiskott-Aldrich syndrome patients are male. One case was reported in a girl.[10]

Age

Thrombocytopenia and platelet dysfunction can be found from birth, with dermatitis following in a few months.

Prognosis

Death usually occurs during infancy. Death usually occurs during the first decade, although survival to 18 years has been recorded. The cause of death in Wiskott-Aldrich syndrome is infection in 55-60% of patients, bleeding in 24-27% of patients, and lymphoreticular malignancy in about 5-10% of patients. Ten percent of Wiskott-Aldrich syndrome patients die from lymphoreticular malignancy, usually as adolescents or young adults.

 

Presentation

History

Thrombocytopenia and platelet dysfunction are often present from birth in Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome patients usually develop bleeding and bloody diarrhea during the first weeks or months of life. Hematuria, epistaxis, and cutaneous petechiae may appear.

The characteristic triad of thrombocytopenia, eczema, and recurrent infections generally becomes apparent during the first year of life.

Eczema usually appears during the first month and fulfills the Rajka and Hanifin diagnostic criteria for atopic dermatitis.

Recurrent bacterial infections begin in infancy as placentally transmitted maternal antibody levels diminish. Patients are susceptible to a wide variety of bacterial infections, including septicemia, pneumonia, meningitis, pansinusitis, conjunctivitis, furunculosis, otitis externa, and otitis media.

Physical Examination

Eczema commonly develops in the scalp, on the face, in the flexures, and in the diaper area, although patients commonly have widespread involvement with progressive lichenification. The lesion is essentially indistinguishable from atopic dermatitis apart from the frequent presence of purpura and/or petechiae and excessive bleeding from excoriations. Serosanguineous crust may appear. (See images below.)

Eczematous lesions in Wiskott-Aldrich syndrome. Th Eczematous lesions in Wiskott-Aldrich syndrome. The lesion is essentially indistinguishable from that of atopic dermatitis except for the presence of purpura and petechiae.
A bloody crust can be seen on the red papules. A bloody crust can be seen on the red papules.

Immunoglobulin E (IgE)–mediated allergic diseases (eg, urticaria, food allergies, asthma) may appear.

Mucocutaneous petechiae may appear.

Spontaneous bleeding from the oral cavity and hematuria are common in Wiskott-Aldrich syndrome.

Secondary bacterial infection of eczematous lesions is common.

Hepatosplenomegaly is common in Wiskott-Aldrich syndrome.

Lymphadenopathy, transient arthritis, nephropathy, and nodular vasculitis are occasionally present in Wiskott-Aldrich syndrome.

Complications

With advancing age, T-cell function is progressively impaired, and patients are increasingly susceptible to infections caused by herpes and other viruses and Pneumocystis carinii.

Autoimmune phenomena may develop. Arthritis, renal disease, dermatomyositis, and autoimmune hemolytic anemia have been reported.

Lymphoreticular malignancy develops in 18-20% of patients, particularly in those with autoimmune manifestations. Non-Hodgkin lymphoma is the most common malignancy.[11, 12, 13, 14]

Intracranial hemorrhage is a constant threat.

 

DDx

 

Workup

Laboratory Studies

In Wiskott-Aldrich syndrome (WAS), thrombocytopenia is persistent in the range of 1,000-80,000 platelets/µL. The platelets are small and fail to aggregate normally. Their survival is shortened. No antiplatelet antibodies can be detected.

Blood analysis shows Coombs-positive hemolytic anemia, leukocytopenia, lymphopenia, and eosinophilia.

Total serum gammaglobulin levels are usually in the reference range. The immunoglobulin M level is low, but immunoglobulin A, IgE, and immunoglobulin D levels are usually elevated. The immunoglobulin G level is in the reference range in almost all cases. This distinctive immunoglobulin pattern may not be present until the patient is several years of age.

The number of T cells and responses to mitogens in vitro may be normal in early life but often decreases in older age.

Natural killer cell–mediated cytotoxicity is deficient.

CD43 expression on the surface of lymphocytes is low. This finding can be detected by flow cytometry or western blot analysis.

The expression of WAS protein from peripheral blood mononuclear cells by flow cytometry or Western blot analysis help in making the diagnosis prior to mutational analysis. The level of WAS protein correlates with the phenotype of affected patient and the clinical course.[15]

After the above screening methods, the mutational analysis of the WASP gene is important to make a definitive diagnosis.

Other Tests

Delayed hypersensitivity skin testing results, such as Candida and purified protein derivative of tuberculin, are reduced.

Histologic Findings

A lesional skin specimen from a Wiskott-Aldrich syndrome patient shows findings similar to those of atopic dermatitis.

 

Treatment

Medical Care

Transfusions of platelets and plasma decrease the risk of fatal hemorrhage in Wiskott-Aldrich syndrome patients. Agents such as eltrombopag that mimic thrombopoietin are promising.[16, 17]

Appropriate antibiotics should be used to treat bacterial infections. The antibiotics should be chosen based on the bacteria obtained and detected from the infected site.

Intravenous infusions of immune globulin decrease the risks of infection.

Infusion of transfer factor results in decreased frequency of infection and improvement of eczema.[18]

Bone marrow transplantation with HLA-identical marrow should be considered if patients have recurrent problems. Full engraftment results in normal platelet numbers and functions, immunologic status, and clearance of the eczema.[19]

Topical steroids may improve the eczema.

Gene therapy is promising for Wiskott-Aldrich syndrome.[20, 21, 22, 23, 24, 25, 26]

Surgical Care

Splenectomy should be considered for Wiskott-Aldrich syndrome patients with thrombocytopenia who have no HLA-matched bone marrow transplantation donor.[19, 27, 28]

Consultations

Possible consultations include a pediatrician and/or oncologist.

Diet

In patients with food allergies, diet control must be considered.

Long-Term Monitoring

Obtaining a blood analysis on at least a monthly basis is necessary in Wiskott-Aldrich syndrome patients. Malignancy evaluations should be conducted, especially in elderly Wiskott-Aldrich syndrome patients.

 

Medication

Medication Summary

Agents for Wiskott-Aldrich syndrome medical therapy are selected based on clinical presentation and response. When treating infections, if possible, identify the suspected pathogen before selecting antibiotics. Antibiotics are indicated to treat bacterial infections and for prophylaxis in patients who have had a splenectomy. Immunoglobulins and systemic corticosteroids are indicated to treat thrombocytopenia. Use topical steroids to treat eczema. Topical steroids are effective for the eczematous lesion.

Immunoglobulins

Class Summary

These agents provide functional immunoglobulins in patients whose ability to respond to bacterial antigens is abnormal, and they may inhibit platelet sequestration by the reticuloendothelial system.

Immune globulin (Gamimune N, Gammagard S/D, Sandoglobulin)

Immune globulin is used to treat thrombocytopenia; it may be indicated if the serum IgG level is low or the patient cannot produce functional antibody responses (eg, to polysaccharide antigens). Little data support routine use for immune defects in WAS in the absence of low serum IgG levels.

Corticosteroids

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Hydrocortisone topical (Dermacort, CortaGel, Cortaid, Westcort)

Topical hydrocortisone is an adrenocorticosteroid derivative suitable for application to skin or external mucous membranes. It has mineralocorticoid and glucocorticoid effects, resulting in anti-inflammatory activity. It is used to treat eczema.

Prednisone (Deltasone)

Prednisone is an immunosuppressant for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

 

Questions & Answers

Overview

What is Wiskott-Aldrich syndrome (WAS)?

What is the pathophysiology of Wiskott-Aldrich syndrome (WAS)?

What causes Wiskott-Aldrich syndrome (WAS)?

What is the prevalence of Wiskott-Aldrich syndrome (WAS)?

What are the racial predilections of Wiskott-Aldrich syndrome (WAS)?

What are the sexual predilections of Wiskott-Aldrich syndrome (WAS)?

Which age groups have the highest prevalence of Wiskott-Aldrich syndrome (WAS)?

What is the prognosis of Wiskott-Aldrich syndrome (WAS)?

Presentation

Which clinical history findings are characteristic of Wiskott-Aldrich syndrome (WAS)?

Which physical findings are characteristic of Wiskott-Aldrich syndrome (WAS)?

What are the possible complications of Wiskott-Aldrich syndrome (WAS)?

DDX

What are the differential diagnoses for Dermatologic Manifestations of Wiskott-Aldrich Syndrome?

Workup

What is the role of lab tests in the workup of Wiskott-Aldrich syndrome (WAS)?

What is the role of skin testing in the workup of Wiskott-Aldrich syndrome (WAS)?

Which histologic findings are characteristic of Wiskott-Aldrich syndrome (WAS)?

Treatment

How is Wiskott-Aldrich syndrome (WAS) treated?

What is the role of surgery in the treatment of Wiskott-Aldrich syndrome (WAS)?

Which specialist consultations are beneficial to patients with Wiskott-Aldrich syndrome (WAS)?

Which dietary modifications are used in the treatment of Wiskott-Aldrich syndrome (WAS)?

What is included in the long-term monitoring of Wiskott-Aldrich syndrome (WAS)?

Medications

What is the role of medications in the treatment of Wiskott-Aldrich syndrome (WAS)?

Which medications in the drug class Corticosteroids are used in the treatment of Dermatologic Manifestations of Wiskott-Aldrich Syndrome?

Which medications in the drug class Immunoglobulins are used in the treatment of Dermatologic Manifestations of Wiskott-Aldrich Syndrome?