Pediatric Wiskott-Aldrich Syndrome 

Updated: Apr 03, 2019
Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD 

Overview

Practice Essentials

Wiskott-Aldrich syndrome (see the image below) is an X-linked recessive immunodeficiency disorder characterized in one third of patients by the triad of recurrent bacterial sinopulmonary infections, eczema (atopiclike dermatitis), and a bleeding diathesis caused by thrombocytopenia and platelet dysfunction.[1]

This 10-month-old infant presented with bloody dia This 10-month-old infant presented with bloody diarrhea at age 4 months followed by recurrent otitis media infections. A maternal uncle had Wiskott-Aldrich Syndrome (WAS). Note the mild malar eczema and pretibial ecchymoses in this nonambulatory child. His diagnosis was confirmed by immunologic parameters, thrombocytopenia, and low platelet volume.

Signs and symptoms

The characteristic triad of bleeding, eczema, and recurrent infections in Wiskott-Aldrich syndrome generally become evident during the first year of life, with petechiae and ecchymoses of the skin and oral mucosa and bloody diarrhea being the first clinical signs. Although only one third of patients with WASP (Wiskott-Aldrich syndrome protein) mutations express the classic triad at presentation, other manifestations include the following:

  • Thrombocytopenia (almost 90%)[2]

  • Only hematologic abnormalities (20%)[2]

  • Only infectious manifestations (5%)[2]

  • Only eczema (0%)[2]

  • Autoimmune phenomena[3]

  • Malignancies[3]

See Clinical Presentation for more detail.

Diagnosis

Examination for Wiskott-Aldrich disease includes evaluation for/of the following:

  • Signs of bleeding, infection, malignancy, and atopy

  • General appearance and vital signs

  • Height and weight growth parameters

  • Head and neck assessment

  • Dermatologic assessment

  • Pulmonary assessment

  • Neurologic assessment

Laboratory Tests

Laboratory studies used in the evaluation of Wiskott-Aldrich syndrome include the following:

  • CBC count: Often supports the diagnosis

  • Quantitative serum immunoglobulin levels

  • Functional testing of the humoral and cellular components of the immune system

  • Delayed-type hypersensitivity skin tests

  • Genetic testing

Other tests that may be appropriate, depending on the clinical situation, include the following:

  • Cultures (eg, blood) and sensitivities

  • Renal function tests

  • Hepatic function tests

  • Major histocompatibility tests of the patient, parents, and siblings to determine feasibility for stem cell transplantation

  • Screening of patient and potential donor for infectious agents (eg, HIV, CMV, hepatitis viruses)

Imaging studies

Radiography, particularly of the chest, is part of the assessment for new infections. However, CT and MRI studies are not usually utilized for Wiskott-Aldrich syndrome unless stem cell reconstitution procedures have been performed and posttransplantation complications have developed.

Procedures

Consider obtaining a bone marrow biopsy to assist diagnosis in complex cases or to evaluate for hematologic malignancy. However, patients generally do not require bone marrow biopsy.

See Workup for more detail.

Management

Wiskott-Aldrich syndrome has a variable disease severity, depending on the genotype.[4] Accordingly, treatment strategies range from conservative to early definitive intervention, including antibiotics, antivirals, antifungals, chemotherapeutic agents, immunoglobulins, and corticosteroids. Agents are selected based on the patient's clinical presentation and response.

Pharmacotherapy

Medications used in the treatment of Wiskott-Aldrich disease include the following:

  • Antibiotics (eg, amoxicillin, amoxicillin/clavulanate, cefuroxime, ceftriaxone, vancomycin, nafcillin)

  • Inhaled bronchodilators (eg, albuterol, salmeterol, beclomethasone, fluticasone)

  • Hyperimmune globulins (eg, varicella-zoster immune globulin)

  • Immunizations (eg, vaccines, including diphtheria and tetanus toxoids [DT or Td], acellular pertussis, conjugated HIB, conjugated pneumococcal vaccine, unconjugated meningococcal A and C, hepatitis B [HBV], influenza)

  • Corticosteroids (eg, prednisone, methylprednisolone, fluocinolone)

  • Immunoglobulins (eg, immune globulin)

Surgery

Surgical intervention may be necessary for complications of bleeding, such as the following:

  • Neurosurgery if subdural hematoma forms

  • Surgical evacuation of hematomas

  • Surgical intervention to halt blood loss after any minor trauma

  • Splenectomy as an option in cases of coexisting severe thrombocytopenia and frequent bleeding when stem cell reconstitution is not considered

Additional treatments

Supportive care in patients with Wiskott-Aldrich syndrome includes the following:

  • Transfusions of platelets and/or red blood cells

  • Bone marrow transplantation

  • Infusions of intravenous immunoglobulin G

See Treatment and Medication for more detail.

Background

Wiskott-Aldrich syndrome (WAS) was first described by Wiskott in 1937 and was further characterized by Aldrich in 1954. It is a rare 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.[5] However, only a third of patients with the syndrome have the classic triad.[6] 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] WAS platelets are usually smaller than those of idiopathic thrombocytopenia, but a macrothrombocytopenia has been described in WAS.[7]  Other symptoms may include autoimmune phenomena and malignancies.[3]  

An infant with WAS is seen in the image below.

This 10-month-old infant presented with bloody dia This 10-month-old infant presented with bloody diarrhea at age 4 months followed by recurrent otitis media infections. A maternal uncle had Wiskott-Aldrich Syndrome (WAS). Note the mild malar eczema and pretibial ecchymoses in this nonambulatory child. His diagnosis was confirmed by immunologic parameters, thrombocytopenia, and low platelet volume.

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. There may be multiple revertant genotypes in patients with Wiskott-Aldrich syndrome.[8]

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.[9] It also regulates actin polymerization, transcription, and a selective, post-transcriptional role in Th2 effector function.[10] 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.[11, 12]

The type of specific mutation, its location within the gene, and its effect on protein expression appear to determine an individual patient's clinical phenotype.[13]

For more information, see Dermatologic Manifestations of Wiskott-Aldrich Syndrome and Wiskott-Aldrich Syndrome.

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.[14, 15] 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. Low T cell numbers resembling T-B+ SCID has been described in WAS.[16]

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.[11] Further research is underway to identify WASp-associated proteins, such as WASp-interacting protein (WIP) and several Wiskott-Aldrich syndrome proteins verprolin homologous (WAVE).[17, 18, 19, 20]

Epidemiology

Frequency

The estimated incidence of Wiskott-Aldrich syndrome in the United States is 1 in 250,000 live male births.[21]

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.[22]  A similar range has been documented in a national registry in Ireland, as well.[23]

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.[21]  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.[24]

Age

Age at presentation ranges from birth to 25 years. In one review, the average age of presentation was 21 months.[2, 21]  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. Monoclonal gammopathy is rare and may be of uncertain significance in these children.[25] Lymphomas occur in 26% of patients aged 20 years and older.

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.[21] 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.[21]

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.[26] 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.[27]

 

Presentation

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 (see the image below) 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]

This 1-year-old boy was hospitalized because of re This 1-year-old boy was hospitalized because of respiratory syncytial virus bronchiolitis but was noted to have eczema and petechiae (note arrow). His history was significant for a subdural hematoma for which trauma was denied; at that time the platelet count was 212,000. His diagnosis of Wiskott-Aldrich Syndrome (WAS) was confirmed by the detection of a missense mutation (Phe 128 Ser).

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.[28] 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. Aggressive mature B-cell lymphoproliferative disease may be evident in children and adults with WAS.[29]

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 (see the image below) 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.

This 10-month-old infant presented with bloody dia This 10-month-old infant presented with bloody diarrhea at age 4 months followed by recurrent otitis media infections. A maternal uncle had Wiskott-Aldrich Syndrome (WAS). Note the mild malar eczema and pretibial ecchymoses in this nonambulatory child. His diagnosis was confirmed by immunologic parameters, thrombocytopenia, and low platelet volume.

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.

Neurological examination is particularly relevant if meningitis, CNS lymphoma, or intracranial bleeding or infection is considered.

Cutaneous vasculitis may be rarely seen as recurrent acute hemorrhagic edema of infancy.[30]

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,[31] 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.[15] 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, 32]

 

DDx

Diagnostic Considerations

This disorder should be considered in male infants with persistent unexplained thrombocytopenia, especially if the platelet size is small, recognizing that the clinical presentation is variable.[33] Physicians must distinguish between infants with bleeding and thrombocytopenia and infants with neonatal alloimmune thrombocytopenia. The presence of small platelets with mean platelet value (MPV) less than 6 fL characterizes Wiskott-Aldrich syndrome (WAS), whereas the other 2 disorders usually have large MPVs because of the young age of the platelets. However, the MPV is difficult to measure in the presence of profound thrombocytopenia (platelet count < 10,000/dL).

X-linked thrombocytopenia is a mild phenotype of Wiskott-Aldrich syndrome with mutations in WASP that confer thrombocytopenia, possibly eczema, but no significant immunologic deficit. Sites for the WASP mutations in X-linked thrombocytopenia are somewhat different; thus, mutational analysis as well as clinical and laboratory data contribute to the final diagnosis of X-linked thrombocytopenia versus Wiskott-Aldrich syndrome (WAS). Differentiating this phenotype is important because stem cell reconstitution is not appropriate therapy for this clinically mild nonfatal disease.

The differential diagnosis of generalized eczema in infants includes Wiskott-Aldrich syndrome, as well as atopic dermatitis, seborrheic dermatitis, severe combined immunodeficiency (SCID), Langerhans cell histiocytosis, seborrheic dermatitis, Omenn syndrome, and ataxia-telangiectasia (AT).

AT presents with symptoms of eczema and recurrent infections; however, in contrast to Wiskott-Aldrich syndrome, patients with AT have decreased levels of immunoglobulin A (IgA) and, often, immunoglobulin E (IgE), and cerebellar ataxia is an early feature.

Wiskott-Aldrich syndrome is sometimes confused with Bruton agammaglobulinemia (X-linked agammaglobulinemia [XLA]) when the infant presents with recurrent otitis media, and when quantitative immunoglobulin levels show low immunoglobulin G (IgG). Patients with XLA are unlikely to have bleeding related to thrombocytopenia. Typically, Wiskott-Aldrich syndrome is associated with low immunoglobulin M (IgM) levels and normal-to-high immunoglobulin A (IgA) levels, whereas all immunoglobulin levels are undetectable in XLA. T-cell and B-cell population patterns are also characteristically different (normal CD19+ B cells and high CD4:CD8 ratios in Wiskott-Aldrich syndrome compared with absent CD19+ B cells and normal-to-elevated T cells in XLA).

X-linked hyperimmunoglobulin M (XHIM) syndrome may clinically resemble Wiskott-Aldrich syndrome, although bleeding manifestations are absent. Laboratory study findings should distinguish between them. Wiskott-Aldrich syndrome is associated with low IgM, high IgA, and high immunoglobulin E (IgE) levels; XHIM has normal-to-high IgM, low IgA, and low IgE levels. The pattern of T-cell abnormalities also differs as follows: high CD4:CD8 because of low CD8 in Wiskott-Aldrich syndrome compared with a normal ratio with lymphopenia in XHIM.

Other T-cell disorders occur early in infancy but without bleeding manifestations. Wiskott-Aldrich syndrome and other T-cell disorders share an increased incidence of dermatitis. X-linked severe combined immunodeficiency (X-SCID) is usually clinically different because of the early presence of more significant opportunistic and viral infections. Fluorocytometric analysis of T-cell and B-cell populations is used to distinguish Wiskott-Aldrich syndrome from X-SCID and other forms of SCID, such as major histocompatibility (MHC) class II deficiency ("bare lymphocyte" syndrome).

See Table 1 in Severe Combined Immunodeficiency.

Differential Diagnoses

 

Workup

Laboratory Studies

Complete blood counts often support the diagnosis of Wiskott-Aldrich syndrome (WAS). MPV is a routine component of the automated CBC count. Platelets are less than 70,000/mL. The mean platelet volume (MPV) is less than 5 fL. Eosinophilia may be evident.[34, 35]

Always interpret quantitative immunoglobulin levels based on age-related reference range values. Classic Wiskott-Aldrich syndrome is associated with low immunoglobulin M (IgM) and immunoglobulin G (IgG) levels, with normal-to-high immunoglobulin A (IgA) and immunoglobulin E (IgE) levels. However, young infants in particular may not show classic immunoglobulin abnormalities because Wiskott-Aldrich syndrome is associated with attrition in immunologic functions.

Specific antibody defects are most likely in response to polysaccharide antigens. Therefore, isohemagglutinins, IgM directed against the ABO blood group antigens, are typically absent; isohemagglutinins are age-related and are not detectable until infants are older than approximately 6 months. IgG directed against unconjugated pneumococcal antigens are determined postvaccination but are not produced by healthy children younger than 2 years. T-dependent antibody responses to tetanus, diphtheria, and conjugated Hib vaccines vary in Wiskott-Aldrich syndrome. Immune attrition in antibody responses occurs in older patients.

Classic Wiskott-Aldrich syndrome is associated with anergy to delayed-type hypersensitivity (DTH) skin tests. Conventional antigens for DTH testing are tetanus, diphtheria, and Candida; however, immunocompetent infants must have been exposed to the antigen 4-6 weeks prior to testing in order for a positive response to be present. In vitro tests for T-cell function show normal responses in young patients with Wiskott-Aldrich syndrome using nonspecific mitogens such as phytohemagglutinin, concanavalin A, and pokeweed as the stimulus. Defects in T-cell responses are more consistent using allogeneic lymphocytes or periodate as the stimulus. As with humoral responses, Wiskott-Aldrich syndrome is associated with immune attrition of cell-mediated immunity over time.

Autoantibodies may be detected in autoimmune hemolytic anemia (AIHA), immune neutropenia, or immune thrombocytopenia. Such antibodies are the same as those observed in immunocompetent patients.

When a T-cell disorder is suspected, the Immune Deficiency Foundation has a consultative service for physicians. Laboratories in Seattle (the University of Washington), Boston (Children's Hospital), and New York City are funded to provide molecular analysis (Jeffrey Modell Foundation), or they can assist in contacting other research facilities.

Prenatal evaluation of high-risk pregnant women with Wiskott-Aldrich syndrome may be accomplished by karyotyping, gene analysis, and Wiskott-Aldrich syndrome protein detection using cord blood.[36]

Imaging Studies

Radiography, particularly of the chest, is part of the assessment for new infections.

CT and MRI studies are usually not part of Wiskott-Aldrich syndrome management unless stem cell reconstitution procedures have been performed and posttransplantation complications have developed.

Other Tests

Appropriate cultures and sensitivities are essential to manage acute infections. Blood cultures are especially important in splenectomized patients with Wiskott-Aldrich syndrome, but any patient has increased risk for bacteremia with polysaccharide-coated bacteria.

Monitor renal function and hepatic function at regular intervals.

Workup to determine feasibility for stem cell transplantation requires major histocompatibility (MHC) tests of the patient, parents, and siblings. Screen both the patient and potential donor for infectious agents, including human immunodeficiency virus (HIV), cytomegalovirus (CMV), and hepatitis viruses. Pulmonary, hepatic, and neurologic evaluations of the patient are required to assess chronic organ dysfunction.

Blinded food trials are the criterion standard for determination of food hypersensitivity. However, no adequately studied reports exist of the incidence of food sensitivity or the effect of food restriction on the eczematous dermatitis of Wiskott-Aldrich syndrome. The radioallergosorbent assay test (RAST) for food sensitivity is insensitive, and findings often do not correlate with clinical symptoms.

Procedures

No procedures are routinely performed.

Histologic Findings

Older patients with Wiskott-Aldrich syndrome have involution of lymphoid tissues, but depletion of lymphocytes is subtle in younger patients who show only poor development of the follicular areas.

Lymphoid tissues of the gut usually are relatively normal.

The thymus may be small but shows normal architecture, including Hassall corpuscles.

T cells are remarkable for the lack of surface microvilli on which CD43 are expressed in normal lymphocytes.

Specialized techniques can be used to detect poor filopodia formation in platelets and poor F-actin capping at phagocytic vacuoles in phagocytes.

 

Treatment

Medical Care

The Wiskott-Aldrich syndrome (WAS) disease severity is variable, although somewhat predictable from genotype.[4] Accordingly, treatment strategies range from conservative to early definitive intervention.

Optimally, donor cells should match the patient at all 6 major histocompatibility (MHC) sites because an incomplete match carries a higher risk for complications (particularly graft versus host disease [GVHD]) in Wiskott-Aldrich syndrome compared with patients with most other primary immunodeficiency diseases. Matched-related bone marrow transplantation from a sibling has been successful in almost 90% of patients with Wiskott-Aldrich syndrome, with full T-cell, B-cell, and platelet engraftment.

Because a patient with Wiskott-Aldrich syndrome has some degree of cell-mediated immunity, the patient must receive a preparative regime of immunosuppressive therapy, typically cyclophosphamide, busulfan, and, possibly, total body irradiation, to allow donor cells to engraft. Recently, fludarabine-based myeloablative conditioning regimens have been developed with promising results of good engraftment and low treatment-related toxicities.[37] In utero transplantation is not an option because of the need for pretransplant immunosuppression.

Gene therapy is becoming available.[38] In mice, one study successfully transferred the WASP gene into hematopoietic stem cells, using the WASP –containing lentiviral vector, combined with nonlethal irradiation.[39] Another murine study showed that the WASp transgene expression can be successfully maintained long-term in recipients and that it is associated with a significant repair of migratory defects.[6] Phase I and II clinical studies are starting soon in several European countries to assess the safety and efficacy of this lentiviral vector in Wiskott-Aldrich syndrome and early results are promising.[40, 38, 41] Although the WASP gene is cloned, its exact identity and function are not fully understood, leading to concern that overexpression of WASP could cause clinical illness.

Management of infection includes antibiotics and possibly intravenous immunoglobulin G (IVIG). The decision to use prophylactic antibiotics and/or IVIG is made case-by-case, based on incidence and severity of infection in the individual patient. Postsplenectomy, prophylactic antibiotics are mandatory, although the patients who undergo splenectomy remain at considerable risk for overwhelming sepsis despite of prophylaxis. Immunizations are mandatory with conjugated polysaccharide Hib and pneumococcal vaccines and with the unconjugated meningococcal vaccines.

Postexposure prophylaxis for varicella is indicated. Varicella-zoster immune globulin is administered within 48 hours if possible, although it may be effective until 96 hours postexposure. Beyond that time, acyclovir is recommended during the incubation period. Patients with severe eczema are at risk for both disseminated varicella-zoster infection and eczema herpeticum. The appropriate treatment for both is oral acyclovir.

Manage acute bleeding with platelet transfusions and packed erythrocytes. All blood products should be leukocyte-free and screened to avoid transmission of cytomegalovirus (CMV), in addition to regular screening for human immunodeficiency virus (HIV) and hepatitis viruses. Minimizing exposure to allogeneic cells in the patient for whom stem cell reconstitution is planned is important because such exposure increases graft rejection rates. Platelets have a shorter survival in Wiskott-Aldrich syndrome than in healthy individuals. Recurrent episodes of significant bleeding have been managed by splenectomy when immune reconstitution was not an option. Splenectomy is a controversial procedure because it increases the risk of infection with encapsulated organisms.

Treat eczema with conventional topical moisturizing creams and topical steroids. Milk and other potential food allergens may be eliminated from the diet on a trial basis to observe for improvement. Eczema often waxes and wanes with no apparent trigger, although some patients seem to improve during antibiotic therapy. Allergic rhinitis and asthma are treated in the same manner as in an immunocompetent individual. Eczema herpeticum is treated with oral acyclovir.

Manage autoimmune hemolytic anemia (AIHA) and other autoimmune disorders as in immunocompetent individuals. Interestingly, high-dose IVIG is unlikely to have benefit in AIHA or immune thrombocytopenia.

For more information, see Dermatologic Manifestations of Wiskott-Aldrich Syndrome and Wiskott-Aldrich Syndrome.

Surgical Care

Surgical intervention is likely to be necessary for complications of bleeding. If subdural hematoma formation occurs, the neurosurgeon must work closely with the clinical immunologist and the blood bank for an optimal outcome. Bleeding after any minor trauma may require surgical evacuation of hematomas or intervention to halt blood loss. Platelet and erythrocyte transfusions must be available immediately and maintained during and after surgery. Consider blood products cautiously when stem cell therapy is planned. Splenectomy is an option for patients in whom severe thrombocytopenia and frequent bleeding coexist and for whom stem cell reconstitution is not considered. However, splenectomy creates an additional risk for overwhelming fatal sepsis and leaves the patient at continued risk for the complication of malignancy.

Consultations

A hematologist and an oncologist are the most common consultations needed when AIHA, immune neutropenia, or lymphoreticular malignancies develop. Support from blood banking can be critical when active bleeding occurs. Bone marrow transplantation teams now are an obligatory component of Wiskott-Aldrich syndrome management. Because the outcome of stem cell reconstitution is best in children younger than 2 years, early consultation is essential.

Unlike other primary immunodeficiencies, unusual infections are relatively rare in Wiskott-Aldrich syndrome. Autoimmune disorders that require consultation include arthritis (usually transient) and renal compromise.

Diet

Offer most patients a normal nutritious diet. In the presence of significant eczema, the physician may try eliminating common foods associated with allergy; although milk is the most likely culprit, nuts, eggs, and legumes may also be at fault.

Activity

Encourage normal levels of physical activities, with the notable exception of sports that risk CNS trauma because of the presence of thrombocytopenia. Toddlers should wear helmets, although this is difficult to enforce. Most patients can attend school or work under normal circumstances. Advise patients to avoid exposure to varicella.

 

Medication

Medication Summary

Otitis media is treated with conventional first-line antibiotics (eg, amoxicillin, amoxicillin/clavulanate, cefuroxime axetil). Intramuscular injection of antibiotics is avoided because of the risk of excessive bleeding. The duration of antibiotic therapy should follow conventional recommendations for the specific infection being treated.

Most medical care is provided on an outpatient basis with the caveat that episodes of bacteremia and sepsis present higher risks for patients with Wiskott-Aldrich syndrome (WAS), and signs and symptoms may be subtle because of an inadequate inflammatory response resulting from phagocytic and humoral immune defects.

Administration of tetanus and diphtheria toxoids and the acellular pertussis and conjugated Hib and pneumococcal vaccines is essential and usually results in a protective, although subnormal, antibody response. The attenuated varicella vaccine has been administered without complication. Live measles and poliovirus vaccines are contraindicated. Influenza and hepatitis vaccines should be safe, but experience in administering them to patients with Wiskott-Aldrich syndrome is limited.

IVIG has been administered to selected patients with frequent bacterial infections.

Some patients may benefit from conventional inhaler therapies for reactive airway disease.

Replacement therapy with intravenous immunoglobulin in patients with primary immune deficiencies

The consensus among clinical immunologists is that a dose of intravenous immunoglobulin (IVIG) of 400-600 mg/kg/mo or a dose that maintains trough serum immunoglobulin G (IgG) levels greater than 500 mg/dL is desirable. Patients with meningoencephalitis require much higher doses (1 g/kg) and perhaps intrathecal therapy. Measurement of preinfusion (trough) serum IgG levels every 3 months until a steady state is achieved and then every 6 months if the patient is stable may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons who have a high catabolism of infused IgG, more frequent infusions (eg, every 2-3 wk) of smaller doses may maintain the serum level in the reference range. The rate of elimination of IgG may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher dosages or shorter intervals may be required.

For replacement therapy for patients with primary immune deficiency, all brands of IVIG are probably equivalent, although differences in viral inactivation processes are noted (eg, solvent detergent versus pasteurization and liquid versus lyophilized). The choice of brands may depend on the hospital or home care formulary and the local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion in order to review for adverse events or other consequences.

Recording all side effects that occur during the infusion is crucial. Monitoring liver and renal function test results periodically, approximately 3-4 times yearly, is also recommended. The US Food and Drug Administration (FDA) recommends that for patients at risk for renal failure (eg, preexisting renal insufficiency, diabetes, volume depletion, sepsis, paraproteinemia, age >65 y, use of nephrotoxic drugs), recommended doses should not be exceeded and infusion rates and concentrations should be the minimum levels that are practicable.

The initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in the initial treatments is high, especially in patients with infections and those who form immune complexes. In patients with active infection, infusion rates may need to be slower and the dose halved (ie, 200-300 mg/kg), with the remaining dose administered the next day to achieve a full dose. Treatment should not be discontinued. After achieving reference range serum IgG levels, adverse reactions are uncommon unless patients have active infections.

With the new generation of IVIG products, adverse effects are much reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions are dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with more profound immunodeficiency or patients with active infections have more severe reactions.

Anticomplementary activity of IgG aggregates in the IVIG and the formation of immune complexes are thought to be related to the adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with Fc receptors and trigger the release of inflammatory mediators is another cause. Most adverse reactions are rate related. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with ibuprofen (5-10 mg/kg every 6-8 h), acetaminophen (15 mg/kg per dose), diphenhydramine (1 mg/kg per dose), and/or hydrocortisone (6 mg/kg per dose, maximum 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe adverse effects, analgesics and antihistamines may be repeated.

Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products using sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis are suggestive of osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should not exceed 3 mg sucrose per kg/min. Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents. For patients at increased risk, monitoring BUN and creatinine levels before starting the treatment and prior to each infusion is necessary. If renal function deteriorates, the product should be discontinued.

Immunoglobulin E (IgE) antibodies to immunoglobulin A (IgA) have been reported to cause severe transfusion reactions in IgA-deficient patients. A few reports suggest true anaphylaxis in patients with selective IgA deficiency and common variable immunodeficiency who developed IgE antibodies to IgA after treatment with immunoglobulin. However, in actual experience this is very rare. In addition, this is not a problem for patients with X-linked agammaglobulinemia (XLA) (Bruton disease) or severe combined immunodeficiency (SCID). Exercise caution in patients with IgA deficiency (< 7 mg/dL) who need IVIG because of IgG subclass deficiencies. IVIG preparations with very low concentrations of contaminating IgA are advised (see the Table below).

Table. Immune Globulin, Intravenous [42, 43, 44, 45] (Open Table in a new window)

Brand(Manufacturer)

Manufacturing Process

pH

Additives (IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs].)

Parenteral Form and Final Concentrations

IgA Content mcg/mL

Carimune NF

(CSL Behring)

Kistler-Nitschmann fractionation; pH 4 incubation, nanofiltration

6.4-6.8

6% solution: 10% sucrose, < 20 mg NaCl/g protein

Lyophilized powder 3%, 6%, 9%, 12%

Trace

Flebogamma

(Grifols USA)

Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization

5.1-6

Sucrose free, contains 5% D-sorbitol

Liquid 5%

< 50

Gammagard Liquid 10%

(Baxter Bioscience)

Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation

4.6-5.1

0.25M glycine

Ready-for-use Liquid 10%

37

Gamunex

(Talecris Biotherapeutics)

Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation

4-4.5

Contains no sugar, contains glycine

Liquid 10%

46

Gammaplex

(Bio Products)

Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation

4.8-5.1

Contains sorbitol (40 mg/mL); do not administer if fructose intolerant

Ready-for-use solution 5%

< 10

Iveegam EN

(Baxter Bioscience)

Cohn-Oncley fraction II/III; ultrafiltration; pasteurization

6.4-7.2

5% solution: 5% glucose, 0.3% NaCl

Lyophilized powder 5%

< 10

Polygam S/D

Gammagard S/D

(Baxter Bioscience for the American Red Cross)

Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated

6.4-7.2

5% solution: 0.3% albumin, 2.25% glycine, 2% glucose

Lyophilized powder 5%, 10%

< 1.6 (5% solution)

Octagam

(Octapharma USA)

9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events

Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization

5.1-6

10% maltose

Liquid 5%

200

Panglobulin

(Swiss Red Cross for the American Red Cross)

Kistler-Nitschmann fractionation; pH 4, trace pepsin, nanofiltration

6.6

Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl

Lyophilized powder 3%, 6%, 9%, 12%

720

Privigen Liquid 10%

(CSL Behring)

Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration

4.6-5

L-proline (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose)

Ready-for-use liquid 10%

≤ 25

Antibiotics

Class Summary

Amoxicillin, amoxicillin/clavulanate, and cefuroxime axetil are the PO drugs of choice for the common extracellular bacteria that cause sinopulmonary infections. Ceftriaxone administered intravenously is the first-line antibiotic for suspected bacteremia or sepsis and for pneumonia. It covers penicillin-resistant pneumococci. Intramuscular administration is avoided because of bleeding caused by thrombocytopenia. Nafcillin is chosen for invasive S aureus. Vancomycin is needed for penicillin-allergic patients and for treatment of methicillin-resistant S aureus. Vancomycin-resistant S aureus, GISA, may require fluoroquinolones, linezolid or Synercid.

Prophylactic antibiotics for patients with splenectomies are penicillin or amoxicillin; a macrolide can be used for penicillin-allergic patients.

Amoxicillin (Trimox, Amoxil, Biomox)

Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.

Amoxicillin/clavulanate (Augmentin)

Drug combination treats bacteria resistant to beta-lactam antibiotics.

For children >3 mo, base dosing protocol on amoxicillin content. Because of different amoxicillin–clavulanic acid ratios in 250-mg tab (250/125) vs 250-mg tab (250/62.5), do not use 250-mg tab until child weighs >40 kg.

Cefuroxime axetil (Ceftin)

Second-generation cephalosporin maintains gram-positive activity that first-generation cephalosporins have. Adds activity against Proteus mirabilis, H influenzae, E coli, K pneumoniae, and Moraxella catarrhalis.

Ceftriaxone (Rocephin)

Third-generation cephalosporin with broad-spectrum activity; efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins.

Vancomycin (Lyphocin, Vancocin, Vancoled)

Potent antibiotic directed against gram-positive organisms and active against Enterococcus species. Indicated for patients who cannot receive or who have not responded to penicillins and cephalosporins or who have infections with resistant staphylococci.

To avoid toxicity, current recommendation is to assay vancomycin trough levels after third dose drawn 0.5 h before next dosing. Use creatinine clearance to adjust dose in patients with renal impairment.

Nafcillin

DOC for acute pneumonia and deep-seated abscesses caused by S aureus.

Bronchodilators, Inhaled

Class Summary

These agents are used to relieve bronchoconstriction and decrease the inflammatory response in the respiratory tree. Both pulmonary and nasal inhalers may be needed. Children 4 years and older may use inhalers effectively. Inhaler use is hampered in young children and others unable to understand the technique of administration and in older individuals unable to achieve a forceful inhalation. Adding a spacer is customary to improve coordination in children. Steroid inhalation is followed by rinsing the mouth to avoid thrush, and a spacer is highly recommended for use with steroid pressurized metered dose inhalers for all patients.

Albuterol (Proventil HFA, Ventolin HFA)

Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility.

Salmeterol (Serevent Diskus)

By relaxing the smooth muscle fibers of the bronchioles it can relieve bronchospasms. Effect may also facilitate expectoration.

Beclomethasone (QVAR)

Inhibits bronchoconstriction mechanisms and produces direct smooth muscle relaxation. May decrease number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness.

Some patients may require higher doses of inhaled beclomethasone. Available as 40-mcg and 80-mcg per inhalation.

Fluticasone (Flovent HFA)

Has extremely potent vasoconstrictive and anti-inflammatory activity. Has a weak hypothalamic-pituitary-adrenocortical axis inhibitory potency when applied topically.

Some patients may require higher doses of inhaled fluticasone.

Hyperimmune Globulins

Class Summary

A limited number of immunoglobulin preparations have been developed to provide prophylaxis against specific microorganisms. For primary immunodeficiency diseases including Wiskott-Aldrich syndrome, VZIG has proven efficacy to prevent primary varicella when administered within 48-72 hours postexposure. It may modify varicella when administered up to 96 hours later.

Varicella-zoster immune globulin (VariZIG)

Contains IgG varicella-zoster antibodies. Provides passive immunization to exposed individuals at high risk of complications from varicella. Administration recommended within 48 h postexposure but may be efficacious up to 96 h postexposure. The US product VZIG was discontinued by the manufacturer. An investigational product (VariZIG) is currently available via IND (contact FFF Enterprises at 800-843-7477).

Immunizations

Class Summary

Vaccines that contain viral components (not live viruses) should be administered to patients with Wiskott-Aldrich syndrome because a protective antibody response is often obtained. Injection technique is critical because of the risk of bleeding and hematoma at the injection site. Live virus vaccines are contraindicated with the possible exception of varicella-zoster virus. For current Advisory Committee on Immunization Practices (ACIP) recommended immunizations schedule for immunocompromised individuals, see the Centers for Disease Control and Prevention (CDC) guidelines.[46, 47]

Vaccines

Diphtheria and tetanus toxoids (DT or Td), acellular pertussis, conjugated HIB, conjugated pneumococcal vaccine, unconjugated meningococcal A and C, hepatitis B (HBV), and influenza. CDC/AAP recommendations undergo continuing reevaluation.

 

Follow-up

Further Inpatient Care

In general, admit a patient with Wiskott-Aldrich syndrome (WAS) with bleeding or pulmonary infection because the extent of bleeding may be difficult to ascertain or bleeding may be difficult to control.

Similarly, infections such as pneumonia may be accompanied by sepsis or require respiratory support; inpatient management is usually wise.

The patient's risk for bleeding and the presence of any chronic illness complicate diagnosis and treatment of malignancies.

Transfer

Because any primary immunodeficiency disease is associated with a great complexity of medical problems, most clinical immunologists strongly think an immunologist should manage these patients. High early mortality rates and a high rate of complications in Wiskott-Aldrich syndrome suggest frequent monitoring by a clinical immunologist is essential.

Transfers are most likely to a bone marrow transplantation unit for stem cell reconstitution. These units customarily provide social services and psychological support for the patient and family in addition to the requisite medical care.

Deterrence/Prevention

Families carrying known mutations in the WASP gene should have prenatal diagnosis using mutation analysis. Identifying an affected infant in utero allows consideration of caesarian delivery to avoid bleeding at birth. Most importantly, prenatal diagnosis allows consideration of early stem cell reconstitution and identification of a donor as early as possible.

A critical point to remember is that platelet count alone does not establish the diagnosis of Wiskott-Aldrich syndrome in all infants; mean platelet volume (MPV) must be assessed. Immune functions may not show a classic pattern, making input from a clinical immunologist essential for accurate identification. In some cases, only determination of DNA mutational analysis allows discrimination among Wiskott-Aldrich syndrome, the more minor disorder of X-linked thrombocytopenia, and a non–Wiskott-Aldrich syndrome diagnosis.

Complications

Complications from bleeding and infection now have decreased because of better recognition and prompt intervention. Most immune cytopenias can also be treated effectively.

Chronic renal disease has become better recognized and must be considered, especially in an older child or young adult with a history of hematuria accompanying acute (often viral) infections.

Malignancies respond poorly to conventional therapy, and bone marrow transplantation in the presence of malignancy has failed.

Complications from bone marrow and other stem cell reconstitution procedures are a significant problem. These complications, largely because of graft versus host disease (GVHD), include infections resulting from immune dysfunction related to GVHD, chronic dermatitis, chronic pulmonary disease, and neurologic impairment. GVHD-related disorders are well-recognized problems in patients with Wiskott-Aldrich syndrome. Minor issues after successful reconstitution have included donor-transmitted allergic rhinitis and even such changes as obesity. These minor problems can cause significant emotional turmoil for both patient and donor.

Prognosis

About one fourth of patients who do not receive stem cell reconstitution die from bleeding, another fourth from malignancies, and the remaining 50% from infections. Average age of surviving patients with Wiskott-Aldrich syndrome in 1994 was 11 years, whereas death during the 1960s occurred within 4 years. More recent studies show average age of survival to be around 15 years. Autoimmune disease is a poor prognosis factor in these patients and should be treated promptly.[48]

Hematopoietic stem cell transplantation is the most reliable curative approach for patients with HLA-matched family or unrelated donors.[49]  The outlook for successfully transplanted patients is much more optimistic; the first patient to receive complete immunologic reconstitution after a 1968 bone marrow transplantation still survives without immunologic or clinical abnormalities.

Patient Education

As with any patient who has an immune deficiency, the patient and family must seek immediate medical care at the slightest indication of an infection. This issue is critical for the splenectomized patient with Wiskott-Aldrich syndrome who has a high risk of dying from overwhelming postsplenectomy sepsis, usually caused by S pneumoniae infection. Bleeding (eg, epistaxis, into joints, progressive hematomas) must be recognized and treated. Patient and family must be made aware of the risk for complications, including specific autoimmune disorders and malignancies.

An important resource for education and support for patients and families with any primary immunodeficiency disease is the Immune Deficiency Foundation (some states have local chapters).

Immune Deficiency Foundation

25 W Chesapeake Ave, Suite 206

Towson, MD 21204

Consultation calls: 1-877-666-0866

The Jeffrey Modell Foundation also provides educational support and raises funds for research.

The Jeffrey Modell Foundation

747 3rd Avenue

New York, NY 10017

Phone: 1-800-JEFF-844

For patient education resources, see the Skin, Hair, and Nails Center, as well as Eczema.

 

Questions & Answers

Overview

What is Wiskott-Aldrich syndrome?

What are the signs and symptoms of Wiskott-Aldrich syndrome?

How is Wiskott-Aldrich syndrome diagnosed?

What are the treatment options for Wiskott-Aldrich syndrome?

Which medications are used in the treatment of Wiskott-Aldrich syndrome?

Which surgical interventions are used to treat bleeding complications in Wiskott-Aldrich syndrome?

What is included in supportive care for Wiskott-Aldrich syndrome?

How is Wiskott-Aldrich syndrome characterized?

What is the role of genetics in the etiology of Wiskott-Aldrich syndrome?

What is the pathophysiology of Wiskott-Aldrich syndrome?

What is the prevalence of Wiskott-Aldrich syndrome in the US?

What is the global prevalence of Wiskott-Aldrich syndrome?

What are the racial predilections of Wiskott-Aldrich syndrome?

What are the sexual predilections of Wiskott-Aldrich syndrome?

At what age does Wiskott-Aldrich syndrome typically present?

What is the mortality and morbidity associated with Wiskott-Aldrich syndrome?

Presentation

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

Which physical findings are characteristic of Wiskott-Aldrich syndrome?

What causes Wiskott-Aldrich syndrome?

DDX

How is Wiskott-Aldrich syndrome differentiated from neonatal alloimmune thrombocytopenia?

How is the Wiskott-Aldrich syndrome phenotype X-linked thrombocytopenia diagnosed?

Which conditions are included in the differential diagnoses of Wiskott-Aldrich syndrome and generalized eczema?

How is ataxia-telangiectasia (AT) differentiated from Wiskott-Aldrich syndrome?

How is X-linked agammaglobulinemia (XLA) differentiated from Wiskott-Aldrich syndrome?

How is X-linked hyperimmunoglobulin M (XHIM) syndrome differentiated from Wiskott-Aldrich syndrome?

How is Wiskott-Aldrich syndrome differentiated from other T-cell disorders?

What are the differential diagnoses for Pediatric Wiskott-Aldrich Syndrome?

Workup

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

What is the role of imaging studies in the workup of Wiskott-Aldrich syndrome?

Which test are performed in the long-term monitoring of Wiskott-Aldrich syndrome?

What is included in the workup to determine feasibility for stem cell transplantation in Wiskott-Aldrich syndrome?

How is food hypersensitivity assessed in Wiskott-Aldrich syndrome?

Which procedures are performed in the workup of pediatric Wiskott-Aldrich syndrome?

Which histologic findings are characteristic of Wiskott-Aldrich syndrome?

Treatment

How is Wiskott-Aldrich syndrome treated?

What is the role of gene therapy in the treatment of Wiskott-Aldrich syndrome?

How are infections managed in Wiskott-Aldrich syndrome?

How is acute bleeding managed in Wiskott-Aldrich syndrome?

How is eczema treated in Wiskott-Aldrich syndrome?

How are autoimmune disorders managed in Wiskott-Aldrich syndrome?

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

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

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

Which activity modifications are used in the treatment of Wiskott-Aldrich syndrome?

Medications

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

What is the role of IV immunoglobulin replacement therapy in the treatment of Wiskott-Aldrich syndrome?

Which medications in the drug class Immunizations are used in the treatment of Pediatric Wiskott-Aldrich Syndrome?

Which medications in the drug class Hyperimmune Globulins are used in the treatment of Pediatric Wiskott-Aldrich Syndrome?

Which medications in the drug class Bronchodilators, Inhaled are used in the treatment of Pediatric Wiskott-Aldrich Syndrome?

Which medications in the drug class Antibiotics are used in the treatment of Pediatric Wiskott-Aldrich Syndrome?

Follow-up

When is inpatient care indicated for the treatment of Wiskott-Aldrich syndrome?

When is patient transfer indicated for the treatment of Wiskott-Aldrich syndrome?

How is Wiskott-Aldrich syndrome diagnosed prenatally?

What are the possible complications of Wiskott-Aldrich syndrome?

What is the prognosis of Wiskott-Aldrich syndrome?

What is included in patient education about Wiskott-Aldrich syndrome?