eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology
Wiskott-Aldrich Syndrome
Updated: Feb 3, 2009
Introduction
Background
Wiskott-Aldrich syndrome (WAS) was first described by Wiskott in 1937 and was 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 a third of patients with the syndrome have the classic triad.1 Almost 90% of patients have manifestations of thrombocytopenia at presentation, 20% have only hematologic abnormalities, 5% have only infectious manifestations, and none have only eczema.2 Other symptoms may include autoimmune phenomena and malignancies.3
Wiskott-Aldrich syndrome occurs in males but can occur in females when the X chromosome that contains the functional allele is inactivated, although this is rare.
The gene for the Wiskott-Aldrich syndrome protein (WASp) is localized to Xp11.22-23 and consists of 12 exons that encode a 502 amino acid (53 kD) protein. WASp is a cytosolic protein expressed on all hematopoietic cell lineages and is essential for normal antibody function, T-cell responses, and platelet production.4 About 300 mutations have been found throughout the gene and can include base pair substitutions, insertions, and deletions. These mutations can result in different clinical phenotypes, including classic Wiskott-Aldrich syndrome, X-linked thrombocytopenia, intermittent thrombocytopenia, and neutropenia.5
Pathophysiology
WASP is a key regulator of actin polymerization in hematopoietic cells. As a cytoskeletal regulator, it is necessary for induction of normal immunity. WASp functions as a bridge between signaling and movement of the actin filaments in the cytoskeleton. 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 Wiskott-Aldrich syndrome reveal defects in the formation of microvilli, filopodia, phagocytic vacuoles, and podosomes, respectively; these structures depend on cytoskeletal reorganization of actin filaments. Researchers also identified many different mutations that interfere with the protein binding to Cdc42 and Rac GTPases, among other binding partners, most of which are involved in regulation of the actin cytoskeleton of lymphocytes.6,7 The actin cytoskeleton is responsible for cellular functions, such as growth, endocytosis, exocytosis, and cytokinesis.
Mutations of WASP are located throughout the gene and either inhibit or dysregulate normal WASp function. WASp facilitates the nuclear translocation of nuclear factor kappa-B
(NF-kB) and was shown to play an important role in lymphoid development and in the maturation and function of myeloid monocytic cells. 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 Wiskott-Aldrich syndrome.
Clot formation is interrupted by impaired formation of fibrin strands. WASp binds to calcium and integrin binding protein (CIB) on platelets. The complex of CIB and mutated WASp reduces alpha2-beta3 integrin mediated cell adhesion and causes defective platelet aggregation, resulting in bleeding.
Research has shown phenotype-genotype correlation. Classic Wiskott-Aldrich syndrome, X-linked thrombocytopenia, and X-linked neutropenia occurs when WASp is absent, when mutated WASp is expressed, and when missense mutations occur in the Cdc42-binding site, respectively. Although exceptions are noted and although predicting long-term prognosis based on these findings is difficult, this research may lead the way to curative hematopoietic stem cell transplantation and gene therapy.5 Further research is underway to identify WASp-associated proteins, such as WASp-interacting protein (WIP) and several Wiskott-Aldrich syndrome proteins verprolin homologous (WAVE).8,9,10,11
Frequency
United States
The estimated incidence of Wiskott-Aldrich syndrome in the United States is 1 in 250,000 live male births.12
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). A study from Switzerland reported the incidence of Wiskott-Aldrich syndrome is 4.1 cases per 1 million live births. The same study also examined the prevalence of Wiskott-Aldrich syndrome in several national registries (ie, Italy, Japan, Switzerland, Sweden) and found that this condition occurred in 2-8.8% of patients with primary immunodeficiencies.13 A similar range has been documented in a national registry in Ireland, as well.14
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. Median survival has increased from 8 months in patients born before 1935 to longer than 6 years in patients born after 1964.12 In one case series, 94 surviving patients ranged in age from 1-35 years, with a median of 11 years; the average age of patients who died was 8 years.2
In one study the reported cause of death among patients who did not receive bone marrow transplants were infection (44%), bleeding (23%), or malignancy (26%).2 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. Malignancies may occur in children but are more frequent in affected adults. Lymphomas occur in 26% of patients aged 20 years and older. In one series, 12% of patients developed malignancies, primarily lymphoreticular tumors, and leukemia. In that series, the relative risk of malignancy was more than 100-fold that of normal and the risk increased with age.12
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.15 Survival rates after stem cell transplant have continued to improve, particularly after more recent emphasis on performing these procedures as soon as possible after diagnosis.16
Race
Wiskott-Aldrich syndrome has been reported in individuals of European, African, and Asian ancestry; however, Blacks and Asians are less likely to be affected.One large series of 301 cases of Wiskott-Aldrich syndrome from 149 families reported that 8 families were black and 4 families were Chicano.12 Of the 40 families whose ancestry was traced outside North America, 38 emigrated from Europe.
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 Wiskott-Aldrich syndrome allele.17
Age
Age at presentation ranges from birth to 25 years. In one review, the average age of presentation was 21 months.2,12 Male infants present at birth with petechiae and ecchymoses. Infections usually begin in early infancy after maternal immunoglobulin G (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. However, only one third of patients with WASP mutations express the classic triad of Wiskott-Aldrich syndrome (WAS).
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 may occur at birth or later due to minor trauma. One series of 154 patients found petechiae or purpura in 78%, serious GI bleeding (hematemesis or melena) in 28%, epistaxis in 16%, and intracranial bleeding in 2% of patients.2
With the loss of maternally transported immunoglobulin G (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 are rare. Fungal infections are usually restricted to mucocutaneous candidiasis.
Atopic symptoms are frequently present, and eczema develops in 81% of these patients.2 Eczema ranges from mild to severe, and patients usually present earlier than immunocompetent infants. The eczema may improve as the patient gets older, although serious complications such as secondary infection (eg, cellulitis, abscess) or erythroderma can occur.18 Milk and other food allergies have been associated with eczema in Wiskott-Aldrich syndrome. Eczema may worsen in the presence of infection; it also follows the typical pattern of worsening in the winter. Although the dermatitis often clinically mimics atopic dermatitis, it is generally more exfoliative. Conventional topical care with moisturizing creams and steroids have moderate benefit. Other atopic disorders, reactive airway disease (typically in toddlers), and allergic rhinitis (typically in school-aged children) are also 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 most 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
Watch for signs of bleeding, infection, malignancy, and atopy during the physical examination. The patients' general appearance and vital signs are important. Follow height and weight over time to monitor appropriate development. Patients usually experience normal growth for the first several years of life, even with episodes of severe acute infections
Examine the skin for any evidence of eczema. The face, scalp, and flexural areas are most commonly involved. Superficial or deep infections such as secondary bacterial infections (eg, impetigo, cellulitis, furuncles, abscesses), eczema herpeticum, and molluscum contagiosum are common. Also check the skin for purpura (thrombocytopenia). The presence of lower extremity ecchymoses in infants who are not yet walking indicates a platelet abnormality. Examine for bloody diarrhea in the absence of an infectious etiology. Other manifestations may include hematemesis, melena, epistaxis, and hematuria.
During head and neck examinations, note any abnormalities of the tympanic membranes (eg, otitis media) or sinuses and mucous membranes (eg, sinonasal infections, pharyngitis, thrush). The older infant often has a dramatically increased incidence of otitis media, although it responds appropriately to oral antibiotics.
Carefully auscultate the lungs to check for wheezing (eg, asthma) and rales or rhonchi (eg, pulmonary infection such as bronchitis or pneumonia).
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.
Investigate for a possible malignancy if adenopathy or hepatosplenomegaly is present.
Causes
The WASP gene is located on the Xp11.22-23 region of the X chromosome and is inherited in a sex-linked fashion. A male child of a female carrier has a 50% chance of being affected; a female child has a 50% chance of being a carrier. Theoretically, female carriers of WASP mutations could have clinical illness if extreme lyonization occurs, but nonrandom X inactivation is characteristic for carriers. Wiskott-Aldrich syndrome is caused by various mutations in the gene that code for the WASp. This mutation is expressed in hematopoietic cells (eg, lymphocytes) and impairs the normal function of WASp in actin polymerization.7 Eczema appears to be related to the abnormal function of the T cells.
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.
A strong phenotype-genotype correlation was discovered, with classic Wiskott-Aldrich syndrome occurring when WASp is absent, X-linked thrombocytopenia occurring when mutated WASp is expressed, and X-linked neutropenia when missense mutations occur in the Cdc42-binding site; however, exceptions are noted.2,19
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Further Reading
Keywords
Wiskott-Aldrich syndrome, WAS, Wiskott-Aldrich-Huntley syndrome, eczema-thrombocytopenia syndrome, eczema-thrombocytopenia-diarrhea syndrome, eczema-thrombocytopenia immunodeficiency syndrome, X-linked thrombocytopenia, intermittent thrombocytopenia, neutropenia, lymphomas, leukemia, atopic dermatitis, otitis media, pneumonia, sepsis, meningitis, reactive airway disease, allergic rhinitis, Haemophilus influenzae type B, Hib, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, varicella-zoster virus, herpes simplex virus, autoimmune hemolytic anemia, AIHA, arthritis, nephritis, immune thrombocytopenia, non-Hodgkin lymphoma, impetigo, cellulitis, furuncles, abscesses, eczema herpeticum, molluscum, sinonasal infections, pharyngitis, thrush
