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Dermatology > PEDIATRIC DISEASES
Wiskott-Aldrich Syndrome
Article Last Updated: Feb 14, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Akimichi Morita, MD, Chairman, Professor, Department of Dermatology, Nagoya City University Medical School, Japan
Editors: Jacek C Szepietowski, MD, PhD, Professor and Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Poland; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
WAS, X-linked disorders, thrombocytopenia, eczema, recurrent pyogenic infections
Background
Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder originally described as a clinical triad of thrombocytopenia, 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.
Pathophysiology
The 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.
Frequency
United States
The prevalence is approximately 4 cases per 1 million births.
Mortality/Morbidity
Death in childhood is common. Death usually occurs during the first decade, although survival to 18 years has been recorded.
Race
Most patients are white. Blacks and Asians are rarely affected.
Sex
Most patients are male. One case was reported in a girl.
Age
Thrombocytopenia and platelet dysfunction can be found from birth, with dermatitis following in a few months.
History
- Thrombocytopenia and platelet dysfunction are often present from birth.
- 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
- 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.
- 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.
- Secondary bacterial infection of eczematous lesions is common.
- Hepatosplenomegaly is common.
- Lymphadenopathy, transient arthritis, nephropathy, and nodular vasculitis are occasionally present.
Causes
- 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.
- Several mutations in the WASP gene, which consists of 12 exons and encodes 502 amino acids, have been identified in patients with WAS. 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.
- Eczema appears to be related to the abnormal function of the T cells.
Atopic Dermatitis
DiGeorge Syndrome
Langerhans Cell Histiocytosis
Seborrheic Dermatitis
Other Problems to be Considered
Leiner disease
Lab Studies
- 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.
- 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 shows findings similar to those of atopic dermatitis.
Medical Care
- Transfusions of platelets and plasma decrease the risk of fatal hemorrhage.
- 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.
- 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.
- Topical steroids may improve the eczema.
- Gene therapy is promising.
Surgical Care
Splenectomy should be considered for patients with thrombocytopenia who have no HLA-matched bone marrow transplantation donor.
Consultations
Diet
In patients with food allergies, diet control must be considered.
Agents 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.
Drug Category: Immunoglobulins
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.
| Drug Name | Immune globulin (Gamimune N, Gammagard S/D, Sandoglobulin) |
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| Description | Used to treat thrombocytopenia; also may be indicated if serum IgG level is low or 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. |
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| Adult Dose | 400 mg/kg/d IV for 2-5 d or 1 g/kg/d IV for 1-2 d; may need to repeat q10-21d |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity; IgA deficiency |
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| Interactions | Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine) |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Check serum IgA before IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion); increases risk of renal tubular necrosis in elderly patients and in those with diabetes, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia |
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Drug Category: Corticosteroids
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.
| Drug Name | Hydrocortisone (Dermacort, CortaGel, Cortaid, Westcort) |
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| Description | Adrenocorticosteroid derivative suitable for application to skin or external mucous membranes. Has mineralocorticoid and glucocorticoid effects, resulting in anti-inflammatory activity. Used to treat eczema. |
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| Adult Dose | Apply sparingly to affected areas bid/qid |
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| Pediatric Dose | Apply as in adults |
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| Contraindications | Documented hypersensitivity; viral, fungal, and bacterial skin infections |
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| Interactions | None reported |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Prolonged use, applying over large surface areas, applying potent steroids, and use of occlusive dressings may increase systemic absorption of corticosteroids and may cause Cushing syndrome, reversible HPA-axis suppression, hyperglycemia, and glycosuria |
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| Drug Name | Prednisone (Deltasone) |
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| Description | Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocyte and antibody production. |
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| Adult Dose | 1-2 mg/kg/d PO qd or divided bid/qid; taper over 2-3 wk as symptoms resolve |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity; viral, fungal, tubercular skin, or connective tissue infections; peptic ulcer disease; hepatic dysfunction; GI tract disease |
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| Interactions | Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| Precautions | Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use |
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Further Outpatient Care
- Obtaining a blood analysis on at least a monthly basis is necessary.
- Malignancy evaluations should be conducted, especially in elderly patients.
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.
- Intracranial hemorrhage is a constant threat.
Prognosis
- Death usually occurs during infancy.
- The cause of death 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 patients die from lymphoreticular malignancy, usually as adolescents or young adults.
Patient Education
Medical/Legal Pitfalls
- Failure to diagnose is a pitfall.
- The skin lesion may be misdiagnosed as atopic dermatitis.
Special Concerns
- Almost all cases occur in the pediatric population. If patients survive, lymphoreticular malignancy may develop.
| Media file 1:
Eczematous lesions in Wiskott-Aldrich syndrome. The lesion is essentially indistinguishable from that of atopic dermatitis except for the presence of purpura and petechiae. |
 |  View Full Size Image | |
Media type: Photo
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Wiskott-Aldrich Syndrome excerpt Article Last Updated: Feb 14, 2007
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