Pediatric Wiskott-Aldrich Syndrome Workup

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD   more...
 
Updated: May 9, 2011
 

Laboratory Studies

CBC 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.

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.

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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.

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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.

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Procedures

No procedures are routinely performed.

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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.

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Contributor Information and Disclosures
Author

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Coauthor(s)

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

Robyn Siperstein, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Society for MOHS Surgery, and Sigma Xi

Disclosure: Nothing to disclose.

Specialty Editor Board

James M Oleske, MD, MPH  François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School

James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Allergy Asthma and Immunology, American Academy of HIV Medicine, American Academy of Hospice and Palliative Medicine, American Academy of Pain Management, American Academy of Pediatrics, American Association of Pediatrics, American Association of Public Health Physicians, American College of Preventive Medicine, American Pain Society, American Public Health Association, American Society for Microbiology, American Thoracic Society, Arab Board of Family Medicine, Association of Clinical Researchers and Educators (ACRE), Infectious Diseases Society of America, Infectious Diseases Society of America, Infectious Diseases Society of New Jersey, Medical Society of New Jersey, National Association of Pediatric Nurse Practitioners, Pediatric Infectious Diseases Society, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David J Valacer, MD  Consulting Staff, Hoffman La Roche Pharmaceuticals

David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, and New York Academy of Sciences

Disclosure: Nothing to disclose.

David Pallares, MD  Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville

David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD  Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Ann O'Neill Shigeoka, MD to the development and writing of this article.

References

  1. Blundell MP, Bouma G, Calle Y, Jones GE, Kinnon C, Thrasher AJ. Improvement of migratory defects in a murine model of Wiskott-Aldrich syndrome gene therapy. Mol Ther. May 2008;16(5):836-44. [Medline].

  2. Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr. Dec 1994;125(6 Pt 1):876-85. [Medline].

  3. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. Dec 1999;93(3):190-7. [Medline].

  4. Davis BR, Yan Q, Bui JH, Felix K, Moratto D, Muul LM, et al. Somatic mosaicism in the Wiskott-Aldrich syndrome: Molecular and functional characterization of genotypic revertants. Clin Immunol. Jan 31 2010;[Medline].

  5. Snapper SB, Meelu P, Nguyen D, Stockton BM, Bozza P, Alt FW. WASP deficiency leads to global defects of directed leukocyte migration in vitro and in vivo. J Leukoc Biol. Jun 2005;77(6):993-8. [Medline].

  6. Morales-Tirado V, Sojka DK, Katzman SD, Lazarski CA, Finkelman FD, Urban JF, et al. Critical requirement for the Wiskott-Aldrich syndrome protein in Th2 effector function. Blood. Dec 23 2009;[Medline].

  7. Notarangelo LD, Miao CH, Ochs HD. Wiskott-Aldrich syndrome. Curr Opin Hematol. Jan 2008;15(1):30-6. [Medline].

  8. Gulacsy V, Freiberger T, Shcherbina A, et al. Genetic characteristics of eighty-seven patients with the Wiskott-Aldrich syndrome. Mol Immunol. Feb 2011;48(5):788-92. [Medline].

  9. Albert MH, Notarangelo LD, Ochs HD. Clinical spectrum, pathophysiology and treatment of the Wiskott-Aldrich syndrome. Curr Opin Hematol. Nov 11 2010;[Medline].

  10. Kwan SP, Hagemann TL, Blaese RM, Rosen FS. A high-resolution map of genes, microsatellite markers, and new dinucleotide repeats from UBE1 to the GATA locus in the region Xp11.23. Genomics. Sep 1 1995;29(1):247-52. [Medline].

  11. Snapper SB, Rosen FS. The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Annu Rev Immunol. 1999;17:905-29. [Medline].

  12. Anton IM, Jones GE. WIP: a multifunctional protein involved in actin cytoskeleton regulation. Eur J Cell Biol. Apr 2006;85(3-4):295-304. [Medline].

  13. Konno A, Kirby M, Anderson SA, Schwartzberg PL, Candotti F. The expression of Wiskott-Aldrich syndrome protein (WASP) is dependent on WASP-interacting protein (WIP). Int Immunol. Feb 2007;19(2):185-92. [Medline].

  14. Soderling SH, Scott JD. WAVE signalling: from biochemistry to biology. Biochem Soc Trans. Feb 2006;34(Pt 1):73-6. [Medline].

  15. Takenawa T, Suetsugu S. The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol. Jan 2007;8(1):37-48. [Medline].

  16. Perry GH, Spector BD, Schuman LM. The Wiskitt-Aldrich syndrome inthe United States and Canada. J Pediatr. 1980;97:72.

  17. Ryser O, Morell A, Hitzig WH. Primary immunodeficiencies in Switzerland: first report of the national registry in adults and children. J Clin Immunol. Nov 1988;8(6):479-85. [Medline].

  18. Abuzakouk M, Feighery C. Primary immunodeficiency disorders in the Republic of Ireland: first report of the national registry in children and adults. J Clin Immunol. Jan 2005;25(1):73-7. [Medline].

  19. Mullen CA, Anderson KD, Blaese RM. Splenectomy and/or bone marrow transplantation in the management of the Wiskott-Aldrich syndrome: long-term follow-up of 62 cases. Blood. Nov 15 1993;82(10):2961-6. [Medline]. [Full Text].

  20. Kobayashi R, Ariga T, Nonoyama S, Kanegane H, Tsuchiya S, Morio T. Outcome in patients with Wiskott-Aldrich syndrome following stem cell transplantation: an analysis of 57 patients in Japan. Br J Haematol. Nov 2006;135(3):362-6. [Medline].

  21. Parolini O, Ressmann G, Haas OA, Pawlowsky J, Gadner H, Knapp W. X-linked Wiskott-Aldrich syndrome in a girl. N Engl J Med. Jan 29 1998;338(5):291-5. [Medline].

  22. Peacocke M, Siminovitch KA. Wiskott-Aldrich syndrome: new molecular and biochemical insights. J Am Acad Dermatol. Oct 1992;27(4):507-19. [Medline].

  23. Chandrakasan S, Singh S, Dogra S, Delaunay J, Proust A, Minz RW. Wiskott-Aldrich syndrome presenting with early onset recurrent acute hemorrhagic edema and hyperostosis. Pediatr Blood Cancer. Jul 1 2011;56(7):1130-2. [Medline].

  24. Ochs HD, Thrasher AJ. The Wiskott-Aldrich syndrome. J Allergy Clin Immunol. Apr 2006;117(4):725-38; quiz 739. [Medline].

  25. Thrasher AJ. New insights into the biology of Wiskott-Aldrich syndrome (WAS). Hematology Am Soc Hematol Educ Program. 2009;132-8. [Medline].

  26. Kang HJ, Shin HY, Ko SH, et al. Unrelated bone marrow transplantation with a reduced toxicity myeloablative conditioning regimen in Wiskott-Aldrich syndrome. J Korean Med Sci. Feb 2008;23(1):146-8. [Medline].

  27. Dupre L, Marangoni F, Scaramuzza S, et al. Efficacy of gene therapy for Wiskott-Aldrich syndrome using a WAS promoter/cDNA-containing lentiviral vector and nonlethal irradiation. Hum Gene Ther. Mar 2006;17(3):303-13. [Medline].

  28. Galy A, Roncarolo MG, Thrasher AJ. Development of lentiviral gene therapy for Wiskott Aldrich syndrome. Expert Opin Biol Ther. Feb 2008;8(2):181-90. [Medline].

  29. Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Drug Information Handbook 2008-2009. 16th ed. Cleveland, OH: Lexi-Comp Inc; 2008.

  30. Hooper JA. Intravenous Immunoglobulins: Evolution of Commercial IVIG Preparations. Immunol Allergy Clin North Am. Nov 2008;28(4):765-78. [Medline].

  31. Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health Syst Pharm. Aug 15 2005;62(16 Suppl 3):S5-11. [Medline].

  32. Siegel J. The product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. Nov 2005;25(11 Pt 2):78S-84S. [Medline].

  33. Kroger AT, Atkinson WL, Marcuse EK, Pickering LK. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. Dec 1 2006;55:1-48. [Medline]. [Full Text].

  34. Recommendations of the Advisory Committee on Immunization Practices (ACIP): use of vaccines and immune globulins for persons with altered immunocompetence. MMWR Recomm Rep. Apr 9 1993;42:1-18. [Medline]. [Full Text].

  35. Cianferoni A, Massaad M, Feske S, et al. Defective nuclear translocation of nuclear factor of activated T cells and extracellular signal-regulated kinase underlies deficient IL-2 gene expression in Wiskott-Aldrich syndrome. J Allergy Clin Immunol. Dec 2005;116(6):1364-71. [Medline].

  36. Dam T, Danelishvili L, Wu M, Bermudez LE. The fadD2 Gene Is Required for Efficient Mycobacterium avium Invasion of Mucosal Epithelial Cells. J Infect Dis. Apr 15 2006;193(8):1135-42. [Medline].

  37. de Saint Basile G, Lagelouse RD, Lambert N, et al. Isolated X-linked thrombocytopenia in two unrelated families is associated with point mutations in the Wiskott-Aldrich syndrome protein gene. J Pediatr. Jul 1996;129(1):56-62. [Medline].

  38. Derry JM, Kerns JA, Weinberg KI, et al. WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. Hum Mol Genet. Jul 1995;4(7):1127-35. [Medline].

  39. Derry JM, Ochs HD, Francke U. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome [published erratum appears in Cell 1994 Dec 2;79(5):following 922]. Cell. Aug 26 1994;78(4):635-44. [Medline].

  40. Dupuis-Girod S, Medioni J, Haddad E, et al. Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics. May 2003;111(5 Pt 1):e622-7. [Medline]. [Full Text].

  41. Eijkhout HW, van Der Meer JW, Kallenberg CG, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med. Aug 7 2001;135(3):165-74. [Medline]. [Full Text].

  42. Imai K, Morio T, Zhu Y, et al. Clinical course of patients with WASP gene mutations. Blood. Jan 15 2004;103(2):456-64. [Medline]. [Full Text].

  43. Lorenzi R, Brickell PM, Katz DR, et al. Wiskott-Aldrich syndrome protein is necessary for efficient IgG-mediated phagocytosis. Blood. May 1 2000;95(9):2943-6. [Medline]. [Full Text].

  44. Lutskiy MI, Shcherbina A, Bachli ET, Cooley J, Remold-O'Donnell E. WASP localizes to the membrane skeleton of platelets. Br J Haematol. Oct 2007;139(1):98-105. [Medline].

  45. Mullen CA, Anderson KD, Blaese RM. Splenectomy and/or bone marrow transplantation in the management of the Wiskott-Aldrich syndrome: long-term follow-up of 62 cases. Blood. Nov 15 1993;82(10):2961-6. [Medline].

  46. Ochs HD, Rosen FS. The Wiskott-Aldrich syndrome. In: Ochs HD, Smith CIE, Puck J, eds. Primary Immunodeficiency Diseases: a Molecular and Genetic Approach. New York, NY: Oxford University Press; 1999:292-305.

  47. Olivier A, Jeanson-Leh L, Bouma G, et al. A partial down-regulation of WASP is sufficient to inhibit podosome formation in dendritic cells. Mol Ther. Apr 2006;13(4):729-37. [Medline].

  48. Rengan R, Ochs HD, Sweet LI, et al. Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells. Blood. Feb 15 2000;95(4):1283-92. [Medline]. [Full Text].

  49. Samarin SN. WASP family proteins act between cytoskeleton and cellular signaling pathways. Biochemistry (Mosc). Dec 2005;70(12):1305-9. [Medline].

  50. Tsuboi S, Nonoyama S, Ochs HD. Wiskott-Aldrich syndrome protein is involved in alphaIIbbeta3-mediated cell adhesion. EMBO Rep. Mar 31 2006;[Medline].

  51. Tsuji Y, Imai K, Kajiwara M, et al. Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. Bone Marrow Transplant. Mar 2006;37(5):469-77. [Medline].

  52. Wietstruck PMA, Zuniga CP, Talesnik GE, Mendez RC, Barriga CF. [Hematopoietic stem cell transplantation for patients with Wiskott-Aldrich syndrome]. Rev Med Chil. Jul 2007;135(7):917-23. [Medline].

 
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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.
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).
Table. Immune Globulin, Intravenous[29, 30, 31, 32]
Brand(Manufacturer)Manufacturing ProcesspHAdditives (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 ConcentrationsIgA Content mcg/mL
Carimune NF



(CSL Behring)



Kistler-Nitschmann fractionation; pH 4 incubation, nanofiltration6.4-6.86% solution: 10% sucrose, < 20 mg NaCl/g proteinLyophilized powder 3%, 6%, 9%, 12%Trace
Flebogamma



(Grifols USA)



Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization5.1-6Sucrose free, contains 5% D-sorbitolLiquid 5%< 50
Gammagard Liquid 10%



(Baxter Bioscience)



Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation 4.6-5.10.25M glycineReady-for-use Liquid 10%37
Gamunex



(Talecris Biotherapeutics)



Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation4-4.5Contains no sugar, contains glycineLiquid 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 4.8-5.1Contains sorbitol (40 mg/mL); do not administer if fructose intolerantReady-for-use solution 5%< 10
Iveegam EN



(Baxter Bioscience)



Cohn-Oncley fraction II/III; ultrafiltration; pasteurization6.4-7.25% solution: 5% glucose, 0.3% NaClLyophilized 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 6.4-7.25% solution: 0.3% albumin, 2.25% glycine, 2% glucoseLyophilized 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 pasteurization5.1-610% maltoseLiquid 5%200
Panglobulin



(Swiss Red Cross for the American Red Cross)



Kistler-Nitschmann fractionation; pH 4, trace pepsin, nanofiltration6.6Per gram of IgG: 1.67 g sucrose, < 20 mg NaClLyophilized 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 filtration4.6-5L-proline (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose)Ready-for-use liquid 10%≤ 25
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