eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Wiskott-Aldrich Syndrome

Robyn Siperstein, MD, Staff Physician, Department of Dermatology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School
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
Contributor Information and Disclosures

Updated: Aug 10, 2006

Introduction

Background

Wiskott-Aldrich syndrome (WAS) was first described by Wiskott in 1937 and further characterized by Aldrich in 1954. It is an X-linked recessive immunodeficiency disorder characterized by the triad of recurrent bacterial sinopulmonary infections, eczema (atopiclike dermatitis), and a bleeding diathesis caused by thrombocytopenia and platelet dysfunction. However, only 27% of patients with the syndrome have the classic triad. Almost 90% of patients have manifestations of thrombocytopenia at presentation. Other symptoms may include autoimmune phenomena and malignancies.

The gene for the WAS protein (WASP) is localized to Xp11.22-23 and consists of 12 exons that encode a 502–amino acid (53 kD) protein. About 300 mutations have been found throughout the gene and can include base pair substitutions, insertions, and deletions. WASP is a cytosolic protein expressed on all hematopoietic cell lineages and is essential for normal antibody function, T-cell responses, and platelet production. Further evidence for WASP importance is the nonrandom inactivation of the X chromosome in T cells, B cells, and myeloid cells of obligate carriers. WAS can occur in females when the X chromosome containing the functional allele is inactivated, although this is rare.

Pathophysiology

WASP is a key regulator of actin polymerization in hematopoietic cells. As a cytoskeletal regulator, it is necessary for induction of normal immunity.

In mice, WASP was found to be essential for NF-ATp activation, and for nuclear translocation of p-Erk, Elk1 phosphorylation, and c-fos gene expression in T cells. These defects in mutated forms of WASP are the likely etiology of defective IL-2 expression and T-cell proliferation in WAS.

WASP has several well-defined domains (pleckstrin, cofilin, verprolin, SH3) that are involved in signaling, cell locomotion, and immune synapse formation. In vitro studies with T cells, platelets, phagocytes, and dendritic cells of patients with WAS shows defects in the formation of microvilli, filopodia, phagocytic vacuoles, and podosomes respectively; these structures depend upon cytoskeletal reorganization of actin filaments.

Clot formation is interrupted by impaired formation of fibrin strands. WASP binds to calcium and integrin binding protein (CIB) on platelets. The complex of mutated WASP and CIB reduces alpha2-beta3–mediated cell adhesion and causes defective platelet aggregation, resulting in bleeding.

Frequency

United States

The estimated incidence of WAS in the United States is 1 in 250,000 live male births.

International

The frequency in the European population has been reported to be similar to that of the United States (1 in 250,000 live male births).

Mortality/Morbidity

Morbidity and mortality have gradually improved with better antibiotics, advances in blood banking, better supportive care, and the ability to successfully provide immune reconstitution by stem cell transplantation. Younger patients are more likely to die from bleeding, children are more likely to die from infection, and children and young adults die most often from malignancies. The average lifespan for patients who do not receive immune reconstitution is the second to third decade of life, although patients have survived into the fifth decade of life. Following major histocompatibility complex (MHC)–matched stem cell transplantation, the patient who escapes graft versus host disease (GVHD) usually has completely normal immune function and, therefore, has an excellent prognosis for normal survival.

Race

WAS has been reported in individuals of European, African, and Asian ancestry; however, Blacks and Asians are less likely to be affected.

Sex

More than 90% of affected patients are male, but females have been reported in the literature. Females typically have no family history. In some cases, females have been shown to have nonrandom inactivation of the X chromosome bearing the functional WAS allele.

Age

Age at presentation ranges from birth to 25 years. In one review, the average age of presentation was 21 months.

• Male infants present at birth with petechiae and ecchymoses.
• Infections usually begin in early infancy after maternal IgG is lost during the first 3 months of life. The frequency of infections usually increase with age. Patients are especially susceptible to encapsulated organisms.
• Eczema develops during the first year of life and resembles classic atopic dermatitis.
• Malignancies may occur in children but are more frequent in affected adults. Lymphomas occur in 26% of patients aged 20 years and older.

Clinical

History

The characteristic triad of bleeding, eczema, and recurrent infections generally become evident during the first year of life.

• The first clinical signs are petechiae and ecchymoses of the skin and oral mucosa and bloody diarrhea. Patients may have prolonged bleeding after circumcision or from the umbilical stump. CNS bleeding occurs in fewer than 2% of patients, but it may occur at birth, as well as later from minor trauma.
• With the loss of maternally transported IgG, infants begin to have infections, most commonly otitis media, at 4-8 months. Pneumonia, sepsis, and meningitis are caused by polysaccharide-coated bacteria, predominantly Streptococcus pneumoniae, Haemophilus influenzae type b (HIB), and Staphylococcus aureus. Less commonly, gram-negative bacteria such as Klebsiella pneumoniae and Escherichia coli are etiologic agents for sepsis or meningitis. Viral infections may be unusually severe. Herpes simplex often causes mucocutaneous infections, and varicella-zoster virus may be life-threatening. Opportunistic infections such as Pneumocystis carinii have been reported, but these are rare. Fungal infections are usually restricted to mucocutaneous candidiasis.
• Eczema ranges from mild to severe, and patients usually present earlier than immunocompetent infants. Milk and other food allergies have been associated with eczema in WAS. Eczema may worsen in the presence of infection; it also follows the typical pattern of worsening in the winter. While the dermatitis often clinically mimics atopic dermatitis, it is generally more exfoliative. Conventional topical care with moisturizing creams and steroids has moderate benefit. Other atopic disorders, reactive airway disease (typically in toddlers), and allergic rhinitis (typically in school-aged children) are common.
• Autoimmune disorders, particularly autoimmune hemolytic anemia (AIHA), can be observed in patients of any age. In some cases, infections seem to aggravate AIHA. Arthritis, nephritis, and immune thrombocytopenia and neutropenia are also increased in incidence.
• Lymphomas and leukemias constitute the majority of malignancies, although various other malignancies are reported. Patients can present in mid childhood. The risk of malignancy seems to increase with age. The most common malignancy is non-Hodgkin lymphoma.

Physical

• Infants with WAS should be identified by petechiae, ecchymoses, and epistaxis, which are characteristic. The presence of lower extremity ecchymoses in the infant who is not yet walking indicates a platelet abnormality, as well as bloody diarrhea in the absence of an infectious etiology. Other manifestations may include hematemesis, melena, and hematuria.
• Eczema in patients with WAS is similar to that of atopic dermatitis, although it is often more exfoliative. The face, scalp, and flexural areas are most commonly involved. Secondary bacterial infections are common, as well as eczema herpeticum and molluscum.
• Patients usually experience normal growth for the first several years of life, even with episodes of severe acute infections. The older infant often has a dramatically increased incidence of otitis media, although it responds appropriately to oral antibiotics.
• Lymphadenopathy and splenomegaly are variably observed; they often seem appropriate for the presence of infection. Because they may be the presenting evidence for lymphoreticular malignancy, careful palpation and follow-up are essential.
• Clinical signs of anemia, paleness, tachycardia, and even jaundice can be caused by blood loss or AIHA. Renal failure, presumably secondary to glomerulonephritis, should also be considered as a potential cause for anemia.

Causes

The X-linked form of WAS is caused by mutations in WASP at Xp11.23. Some females with WAS also have a mutation in the WASP gene, but this has not been established in all cases. Theoretically, female carriers of WASP mutations could have clinical illness if extreme lyonization occurs, but nonrandom X inactivation is characteristic for carriers.

• Mutations can occur in any of the 12 exons of the WASP gene. Approximately one half of the reported mutations are single-base pair substitutions, often within CpG dinucleotide hot spots. Half of the mutations have been identified within the first 3 exons.
• Milder disease has been reported for mutations in exons 1 and 2, but because exceptions clearly exist, genotype-phenotype correlations are not reliable.

References

• Agammaglobulinemia
• Atopic Dermatitis
• Bruton Agammaglobulinemia
• DiGeorge Syndrome
• Histiocytosis
• Severe Combined Immunodeficiency

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