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Synonyms and related keywords: hypoimmunoglobulinemia M, hypogammaglobulinemia M, dysgammaglobulinemia M, dysimmunoglobulinemia M, dysgammaglobulinemia type V, gamma-M deficiency, selective IgM deficiency, selective immunoglobulin M deficiency, WAS, thrombocytopenia, eczema, autoimmune disease, hematologic malignancy

Background

Wiskott-Aldrich syndrome (WAS) is a condition with variable expression, but commonly includes immunoglobulin M (IgM) deficiency. WAS always causes persistent thrombocytopenia and, in its complete form, also causes small platelets, atopy, cellular and humoral immunodeficiency, and an increased risk of autoimmune disease and hematologic malignancy.¹ In one study of 154 patients with WAS, only 30% had a classic presentation with thrombocytopenia, small platelets, eczema, and immunodeficiency; although 84% had clinical signs and symptoms of thrombocytopenia, 20% had only hematologic abnormalities, 5% had only infectious manifestations, and none had eczema exclusively.² WAS is an X-linked recessive genetic condition; therefore, this disorder is found almost exclusively in boys. WAS has been the focus of intense molecular biology research, which recently led to the isolation of the affected gene product.³

Pathophysiology

WAS results from an X-linked genetic defect in a protein now termed Wiskott-Aldrich syndrome protein (WASp). The gene resides on Xp11.22-23, and its expression is limited to cells of hematopoietic lineage.³ The exact function of WASp is not fully elucidated, but it seems to function as a bridge between signaling and movement of the actin filaments in the cytoskeleton. Researchers identified many different mutations⁴ 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.³ This ultrastructural component of cellular architecture is involved fundamentally in intracellular and cell substrate interactions and signaling via its role in cell morphology and movement. The actin cytoskeleton is responsible for cellular functions such as growth, endocytosis, exocytosis, and cytokinesis.

Researchers propose several models of actin assembly; this topic is an extremely active area of cell biology research.⁵ Actin filament growth occurs by rapid monomer addition (polymerization) to the barbed leading end of a nucleated site. Nucleation, the rate-limiting step, is stimulated by a complex of actin-related protein Arp2/3 and WASp. Cdc42 GTPase also interacts with WASp to increase this nucleation. Next, gelsolin (activated by Ca⁺⁺) severs actin filaments to create barbed ends, but then must be uncapped from the filament by phosphatidylinositol 4,5-bisphosphonate and Rac to proceed with polymerization. WASp also interacts with Rac and, thus, is involved in regulation of this process at multiple interrelated sites. WAS neutrophils have been reported to manifest abnormal NAD(P)H autofluorescence, indicating defective intracellular energy flux. Presumably, WASp mutations interfere with the proper signaling and growth of cells of the hematopoietic lineage,resultinginthe platelet and immune defects observed clinically, although the exact mechanisms and defective pathways remain largely unknown.

Recently published research demonstrates that the Cdc42-WASp interaction is necessary for certain chemoattractant-induced T-cell chemotaxis.⁶ Further studies have now demonstrated abnormal migration and motility in multiple key cellular components of the immune system (specifically, dendritic cells and neutrophils, as well as both B and T lymphocytes).^{7, 8} With regard to WASp-deficient neutrophil adhesion and migration abnormalities, this may be caused by profound defects in clustering beta-2 integrins.⁹ Also of note, CD43 (a major T-cell sialoglycoprotein) is located on microvilli; disruption of WASp regulation of cytoskeletal structure may be the cause of the CD43 defects often observed in patients with WAS.¹⁰ WASp may also have a role in transcriptional signaling and regulation of NK cells, independent of its functions in cytoskeletal actin polymerization.¹¹

Studies of genotype-phenotype correlation in WAS and closely related conditions, with detailed analyses of WASp expression, have now linked absent WASp expression to classic WAS, mutant WASp expression to X-linked thrombocytopenia, and WASp with missense mutations at the Cdc42-binding site to X-linked neutropenia.^{12, 13, 14} Extensive study is also underway to further identify and characterize important WASp-associated proteins, such as WASp-interacting protein (WIP)^{15, 16, 17} and several Wiskott-Aldrich syndrome proteins verprolin homologous (WAVE).^{18, 19} 

Frequency

United States

Incidence is 4 cases per 1 million live male births, which remained relatively unchanged from 1947-1976.²⁰

International

A study from Switzerland reported the incidence of WAS is 4.1 cases per 1 million live births. The same study also examined the prevalence of WAS in several national registries (ie, Italy, Japan, Switzerland, Sweden) and found that this condition occurred in 2-8.8% of patients with primary immunodeficiencies, although this statistic is subject to ascertainment bias.²¹ A similar range has been documented in a national registry in Ireland, as well.²²

Mortality/Morbidity

• Median survival has increased from 8 months (patients born before 1935) to longer than 6 years (patients born after 1964).²⁰ In one recent 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
• The cause of death is largely infections or bleeding, but, 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.²⁰ Another study showed similar results, with the reported cause of death among patients who did not receive bone marrow transplants being infection (44%), bleeding (23%), or malignancy (26%).²
• With aggressive care (eg, splenectomy), longer survival is possible. Bone marrow transplant can be curative.²³ 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.^{24, 25}

Race

• One large series of 301 confirmed and probable cases of WAS from 149 families reported that 8 families were black and 4 families were Chicano. Of the 40 families whose ancestry was traced outside North America, 38 emigrated from Europe.²⁰

Sex

• WAS is an X-linked recessive genetic disorder. The abnormal gene is relatively rare, and affected individuals often do not survive childhood.
• WAS occurs almost exclusively in males, although it is also reported in females. One report of WAS in an 8-year-old girl found a WASp gene mutation on her paternal X chromosome associated with nonrandom inactivation of her maternal X chromosome.²⁶

Age

• WAS is a severe congenital immunodeficiency; therefore, it occurs primarily in children. However, 2 large case series reported patients in their fourth decade of life.^{20, 2}

History

• Male infants with WAS usually present with bleeding, commonly bloody diarrhea, prolonged bleeding from circumcision, purpura, or unusual bruising.
• One series of 154 patients found petechiae or purpura in 78%, serious gastrointestinal bleeding (hematemesis or melena) in 28%, epistaxis in 16%, and intracranial bleeding in 2% of patients.²
• Serious infections also occur. Encapsulated organisms are frequent pathogens that may cause life-threatening complications, including pneumonia, meningitis, and sepsis. Pneumocystis carinii and viral infections also may become troublesome.
• Atopic symptoms are frequently present, and eczema develops in 81% of these patients.² The eczema may improve as the patient gets older, although serious complications such as secondary infection (eg, cellulitis, abscess) or erythroderma can occur.²⁷

Physical

Watch for signs of bleeding, infection, malignancy, and atopy during the physical examination.

• Patients' general appearance and vital signs are important. Follow height and weight over time to monitor appropriate development.
• Examine the skin for any evidence of eczema, purpura (eg, thrombocytopenia), or superficial or deep infections (eg, impetigo, cellulitis, furuncles, abscesses).
• 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).
• Auscultate lungs carefully to check for wheezing (eg, asthma) and rales or rhonchi (eg, pulmonary infection such as bronchitis or pneumonia).
• Investigate for a possible malignancy if adenopathy or hepatosplenomegaly is present.
• Neurological examination is particularly relevant if meningitis, central nervous system lymphoma, or intracranial bleeding or infection is considered.

Causes

• WAS is caused by various mutations in the gene coding for the WASp. This mutation is expressed in hematopoietic cells (eg, lymphocytes) and impairs the normal function of WASp in actin polymerization.³
• 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.²⁸

Hypogammaglobulinemia
Immune Thrombocytopenic Purpura
Lymphoproliferative Syndrome, X-linked
Severe Combined Immunodeficiency
Thrombotic Thrombocytopenic Purpura

Other Problems to be Considered

Common variable immunodeficiency
X-linked thrombocytopenia
Omenn syndrome
Chediak-Higashi syndrome
Hematologic malignancy (various types)

Lab Studies

• Quantitative serum immunoglobulin levels
• • Measure quantitative serum immunoglobulin levels of all other classes (ie, immunoglobulin A [IgA], immunoglobulin G [IgG], immunoglobulin E [IgE]).
  • This measurement assists with accurate diagnosis because IgM deficiency may be part of a more extensive humoral immunodeficiency (eg, common variable immunodeficiency).
  • In classic WAS, IgM levels are low and IgG levels are relatively normal, but IgA and IgE levels may be elevated. On the other hand, in common variable immunodeficiency, a low IgG level is the hallmark of the disease, which is associated with low IgA levels, low IgM levels, or both.
• Functional testing of the humoral and cellular components of the immune system
• • Test humoral immune function by measuring the patient's ability to develop antibody responses to standard polysaccharide and protein antigen vaccines (eg, pneumococcal vaccine, tetanus toxoid), using preimmunization and postimmunization antibody titers.
  • Measure cellular immune function by examining lymphocyte proliferative responses to mitogens, alloantigen, and recall antigens and the patient's ability to react to anergy battery skin testing with delayed-type (type IV) hypersensitivity responses. The latter skin test antigens typically consist of candidal, mumps, trichophyton, and tetanus toxoid antigens.
  • In WAS, defects in a patient's response to polysaccharide vaccination and anergy are common. Responses to protein antigens and lymphocyte proliferation may also be impaired.²
• Complete blood cell count
• • Obtain a complete blood cell count with manual differential, lymphocyte enumeration, and peripheral blood smear. Enumeration of T- and B-cell subsets by flow cytometry may be helpful.
  • This test provides quantitative and morphologic information about cellular elements of the immune system and information about platelet numbers and morphology. T-cell deficiency may occur, although B-cell number is usually preserved (albeit with possibly significantly altered phenotypic expression). Thrombocytopenia and small platelets are present in patients with this disorder.^{2, 29} Patients with WAS may have unstable sialoglycoprotein CD43 (sialophorin) on the surface of lymphocytes¹⁰. One study of 154 patients with WAS revealed lymphopenia in 22% and low CD8⁺ T-cell counts in 61%.²
• Consider genetic testing for carrier status. Prenatal diagnosis via amniocentesis or chorionic villus sampling is possible.³⁰
• Patients may require other tests based on clinical presentation. Serious disorders (eg, bleeding, infection, malignancy) form part of this syndrome.

Imaging Studies

• If pneumonia is considered, obtain a chest radiograph.
• Use computed tomography to evaluate for splenomegaly, help rule out malignancy, help rule out intracranial bleeding, evaluate sinus infection, and/or evaluate for pulmonary infections.

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. If performed, megakaryocytes usually appear normal.²⁹
• If meningitis is considered, a lumbar puncture may be necessary.
• Recurrent otitis media may require tympanostomy tube placement.

Histologic Findings

Platelets in patients with WAS are small, with a decreased diameter and volume. One study of platelets in patients with WAS found an average diameter of 1.82 micrometer (normal = 2.23 micrometer)³¹, and another study found a mean volume of 3.8-5 fL, compared with 7.1-10.5 fL in individuals without WAS.²⁹

Medical Care

Patients require vigilant general medical or pediatric care. Promptly and aggressively treat infections and bleeding.

• Eczema may be severe. Manage the eczema in the usual fashion, with careful attention to skin care, moisturization, and appropriate (eg, route and potency) steroid therapy.²⁷
• Patients with thrombocytopenia may require intravenous immunoglobulin and/or corticosteroids. Patients with bleeding may require platelet and/or red blood cell transfusions.
• Surveillance for malignancy is an important aspect of care.
• Bone marrow transplantation may be curative if an appropriate histocompatible donor is available. However, this intervention carries substantial risks and mortality.²
• • Donor histocompatibility is a very important determinant of survival after bone marrow transplant for WAS. A survival rate of 80% was observed in patients who received HLA-identical transplants, but a survival rate of only 23% was observed in patients who received mismatched (haploidentical) transplants.³² A later study of outcome of bone marrow transplant in patients with WAS examined 170 patients and found a 70% 5-year survival rate for all patients who received transplants. This included a 5-year survival rate of 87% with HLA-identical sibling donors, 52% with other related donors, and 71% with unrelated donors.³³ More recent studies have shown continued improvement in graft success and survival rates, with rates now generally near 70-80% in case series from 1990-2005 in Italy²⁵ and 1985-2004 in Japan.²⁴ When a matched sibling donor is unavailable, umbilical cord blood stem cell transplantation has been used.³⁴
  • If bone marrow transplantation is successful, hematologic and immunologic defects are corrected and eczema resolves.^{23, 35}
  • Clinical trials of gene therapy to reconstitute WASp expression in autologous hematopoetic stem cells are now under development.³⁶

Surgical Care

Patients may require splenectomy to help control thrombocytopenia³⁷, although this intervention may increase the already elevated risk of infection from encapsulated organisms (eg, pneumococcal sepsis). Studies demonstrate that most patients who had a splenectomy achieve normal platelet counts, and their rates of serious bleeding decrease 5- to 6-fold.^{2, 23, 38}

Consultations

• Refer patients to an allergist/clinical immunologist and/or pediatric hematologist to exclude other comorbid immune defects and to ensure accurate diagnosis.
• Patients with associated thrombocytopenia, bleeding, and malignancies may require consultation with a hematologist or oncologist to assist with management.
• Patients with refractory infections may require consultation with an infectious diseases specialist.

Diet

Patients do not require dietary restrictions.

Activity

Patients with thrombocytopenia must take precautions to prevent bleeding (eg, fall precautions, protective headgear, no contact sports).

WAS is treated with a variety of therapeutic agents from several different categories, including antibiotics, antivirals, antifungals, chemotherapeutic agents, immunoglobulins, and corticosteroids. Agents are selected based on the patient's clinical presentation and response. When treating infections, if possible, identify the suspected pathogen before selecting antibiotic, antiviral, and/or antifungal agents. Antibiotics are indicated to treat bacterial infections and for prophylaxis in patients who have had a splenectomy. Antiviral and antifungal agents are indicated to treat viral and fungal infections, respectively. Chemotherapeutic agents are indicated to treat lymphoreticular and/or hematologic malignancies, but are also used as ablative agents, with or without total-body irradiation, prior to bone marrow transplantation. Immunoglobulins and systemic corticosteroids are indicated to treat thrombocytopenia. Use topical steroids to treat eczema.

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Name	Prednisone (Deltasone, Orasone, Sterapred)
Description	Immunosuppressant for treating autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Used to treat thrombocytopenia. Many different steroid treatment regimens are used to treat thrombocytopenia. Consider using other corticosteroids at equivalent doses (eg, prednisolone, methylprednisolone).
Adult Dose	1-2 mg/kg/d PO qd or divided bid/qid; taper over 2-3 wk as symptoms resolve
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tuberculous skin infections; GI disease
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
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abruptly discontinuing glucocorticoids may cause adrenal crisis if they have been administered qd for >14 d; hyperglycemia, edema, osteonecrosis, myopathy, upper GI bleeding, small intestine perforation, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Name	Methylprednisolone (Medrol, Solu-Medrol)
Description	Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Used to treat thrombocytopenia. Many different steroid treatment regimens are used to treat thrombocytopenia. Consider using other corticosteroids at equivalent doses (eg, dexamethasone, prednisolone).
Adult Dose	Pulse of high-dose IV at 15-30 mg/kg/d IV for 2-3 d is sometimes used or if PO therapy fails
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions	Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor for hypokalemia with concurrent diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Drug Name	Fluocinolone (Synalar)
Description	High-potency topical corticosteroid that inhibits cell proliferation. Immunosuppressive, antiproliferative, and anti-inflammatory. Used to treat eczema. Use lowest effective potency and dose. Consider using equivalent doses of other topical corticosteroid preparations (eg, hydrocortisone, mometasone). Topical steroids are preferred, but for rapid control of severe disease, consider a brief burst of moderate-dose PO steroids.
Adult Dose	Apply qd/bid as severity warrants
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; herpes simplex infection; fungal, viral, or tubercular skin lesions
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause adverse systemic effects if used over large areas, denuded areas, on occlusive dressings, or during prolonged treatment periods; may cause adverse local effects (eg, atrophy, depigmentation), particularly in areas such as the face, groin, and axillae

Drug Category: Immunoglobulins

Provide functional immunoglobulins in patients whose ability to respond to bacterial antigens is abnormal and may inhibit platelet sequestration by the reticuloendothelial system.

Drug Name	Immune globulin (Gamimune N, Gammagard S/D, Sandoglobulin)
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). See Hypogammaglobulinemia for dosing.
Adult Dose	400 mg/kg/d IV for 2-5 d or 1 g/kg/d for 1-2 d; may need to be repeated q10-21d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; do not use IgA-containing preparations on IgA-deficient patients; little data support routine use for immune defects in WAS in the absence of low serum IgG
Interactions	May impair response to vaccines
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Administer slowly to decrease infusion-related reactions (eg, chills, headache, rash); pretreatment with acetaminophen and antihistamines, and occasionally corticosteroids, may be necessary in certain cases; aseptic meningitis is reported infrequently, particularly with high-dose (>2 g/kg) therapy; hepatitis C is rarely transmitted, although all current preparations now include virucidal processes Possible risk of reversible and/or irreversible renal failure, particularly with sucrose-containing preparations in patients with renal insufficiency and with higher doses Do not use IgA-containing preparations in IgA-deficient patients because 17-40% have circulating anti-IgA antibodies and have risk of anaphylaxis Little data are available regarding pregnancy precautions, although 1 report described 2 patients with common variable immunodeficiency who were given IV immunoglobulin during the last trimester of pregnancy and delivered healthy newborns; IVIG may increase serum viscosity and thromboembolic events

Further Inpatient Care

• Patients with severe infections, bleeding, or malignancies may require hospitalization for intravenous antibiotics, for monitoring and/or transfusions, or for oncologic care, respectively.

Further Outpatient Care

• Patients must receive close pediatric or medical follow-up, specialized allergy or immunology care, and possibly hematology or oncology care.

In/Out Patient Meds

• Patients with WAS often need antibiotics for recurrent infections, either in an inpatient or outpatient setting. Patients who had a splenectomy usually require daily prophylactic antibiotics.^{23, 38}

Transfer

• Patients may need evaluation, and sometimes transfer, to a referral center with expertise in pediatric immunodeficiencies.

Deterrence/Prevention

• Genetic testing and prenatal diagnosis are options that may contribute to decreased occurrence of this condition.

Complications

• Complications from infection, bleeding, and malignancy characterize WAS.
• Autoimmune and rheumatologic conditions may also occur.³⁹ One study found these conditions in 40% of patients, and often multiple conditions coexisted in the same patient. Patients with autoimmune disease were significantly more likely to develop malignancy.² Another review of 55 patients with WAS from a single hospital in France, over 20 years, found autoimmune or inflammatory conditions in 72%, most commonly autoimmune hemolytic anemia, among multiple other conditions.⁴⁰

Prognosis

• Long-term prognosis had been poor; prior to use of stem cell transplantation, few patients survived beyond their teens and most succumbed to complications of bleeding, infection, or malignancy.⁴¹ Median survival in a cohort of patients born after 1964 was 6.5 years, although survival rates have continued to increase over time.²⁰
• With aggressive care, prognosis may substantially improve. One study projects median survival of 25 years for patients who undergo splenectomy, and even longer for patients who undergo successful bone marrow transplant.²³ Success rates of all categories of stem cell transplantation (HLA-identical, matched/related, matched/unrelated, umbilical cord blood) have also continued to climb over time.^{25, 24}

Patient Education

• Educate patients about the function of their platelets and their immune system and about signs and symptoms that require prompt medical attention, including those seen with infections, bleeding, and malignancy.
• Advise patients to appropriately restrict activities, depending on the severity of thrombocytopenia (eg, protective headgear may be indicated).
• Teach patients excellent general skin care and moisturization to manage eczema.
• Refer women known to be carriers for WAS for genetic counseling, and advise them that prenatal diagnosis is available.
• For excellent patient education resources, visit eMedicine's Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Eczema.

Medical/Legal Pitfalls

• Failure to measure quantitative levels of other immunoglobulin classes (ie, IgA, IgG, IgE) for accurate diagnosis and to help rule out other serious comorbid humoral immunodeficiency diseases (eg, common variable immunodeficiency) when discovering low or absent IgM levels
• Failure to fully evaluate cellular and humoral immunodeficiencies, platelet counts, and blood smears
• Failure to promptly and aggressively treat infections
• Failure to offer daily prophylactic antibiotics to patients after splenectomy (Data suggest higher death rates in these patients.)^{23, 38}
• Failure to inform patients and families about bleeding risks and appropriate activity restrictions that will help patients avoid this severe complication
• Failure to monitor for malignancy (Early detection may help treatment and survival.)
• Failure to consider appropriate bone marrow transplant options
• Failure to refer women known to be carriers for WAS for genetic counseling and failure to advise them that prenatal diagnosis is available

Special Concerns

• Detect carrier status by using a variety of genetic methods, including X-chromosome inactivation analysis⁴² and polymerase chain reaction and linkage analysis.⁴
• Pregnant women who are carriers for WAS can have prenatal diagnosis performed via amniocentesis or chorionic villous sampling.³⁰
• Patients who had a splenectomy usually require daily prophylactic antibiotics because they carry a substantial risk of sepsis.^{23, 38}
• Use of live virus vaccines poses a risk of infection in patients with immune deficiency such as WAS.