Pediatric Wiskott-Aldrich Syndrome Treatment & Management
- Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD more...
The Wiskott-Aldrich syndrome (WAS) disease severity is variable, although somewhat predictable from genotype. 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. In utero transplantation is not an option because of the need for pretransplant immunosuppression.
Gene therapy is becoming available. In mice, one study successfully transferred the WASP gene into hematopoietic stem cells, using the WASP –containing lentiviral vector, combined with nonlethal irradiation. 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. 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.[35, 33, 36] 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.
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.
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.
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.
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.
Loyola Presa JG, de Carvalho VO, Morrisey LR, Bonfim CM, Abagge KT, Vasselai A, et al. Cutaneous manifestations in patients with Wiskott-Aldrich syndrome submitted to haematopoietic stem cell transplantation. Arch Dis Child. 2013 Apr. 98(4):304-7. [Medline].
Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr. 1994 Dec. 125(6 Pt 1):876-85. [Medline].
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. 1999 Dec. 93(3):190-7. [Medline].
Thrasher AJ. New insights into the biology of Wiskott-Aldrich syndrome (WAS). Hematology Am Soc Hematol Educ Program. 2009. 132-8. [Medline].
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. 2008 May. 16(5):836-44. [Medline].
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. 2010 Jan 31. [Medline].
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. 2005 Jun. 77(6):993-8. [Medline].
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. 2009 Dec 23. [Medline].
Notarangelo LD, Miao CH, Ochs HD. Wiskott-Aldrich syndrome. Curr Opin Hematol. 2008 Jan. 15(1):30-6. [Medline].
Gulacsy V, Freiberger T, Shcherbina A, et al. Genetic characteristics of eighty-seven patients with the Wiskott-Aldrich syndrome. Mol Immunol. 2011 Feb. 48(5):788-92. [Medline].
Albert MH, Notarangelo LD, Ochs HD. Clinical spectrum, pathophysiology and treatment of the Wiskott-Aldrich syndrome. Curr Opin Hematol. 2010 Nov 11. [Medline].
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. 1995 Sep 1. 29(1):247-52. [Medline].
Snapper SB, Rosen FS. The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Annu Rev Immunol. 1999. 17:905-29. [Medline].
Anton IM, Jones GE. WIP: a multifunctional protein involved in actin cytoskeleton regulation. Eur J Cell Biol. 2006 Apr. 85(3-4):295-304. [Medline].
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. 2007 Feb. 19(2):185-92. [Medline].
Soderling SH, Scott JD. WAVE signalling: from biochemistry to biology. Biochem Soc Trans. 2006 Feb. 34(Pt 1):73-6. [Medline].
Takenawa T, Suetsugu S. The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol. 2007 Jan. 8(1):37-48. [Medline].
Perry GH, Spector BD, Schuman LM. The Wiskitt-Aldrich syndrome inthe United States and Canada. J Pediatr. 1980. 97:72.
Ryser O, Morell A, Hitzig WH. Primary immunodeficiencies in Switzerland: first report of the national registry in adults and children. J Clin Immunol. 1988 Nov. 8(6):479-85. [Medline].
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. 2005 Jan. 25(1):73-7. [Medline].
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. 1993 Nov 15. 82(10):2961-6. [Medline]. [Full Text].
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. 2006 Nov. 135(3):362-6. [Medline].
Parolini O, Ressmann G, Haas OA, Pawlowsky J, Gadner H, Knapp W. X-linked Wiskott-Aldrich syndrome in a girl. N Engl J Med. 1998 Jan 29. 338(5):291-5. [Medline].
Peacocke M, Siminovitch KA. Wiskott-Aldrich syndrome: new molecular and biochemical insights. J Am Acad Dermatol. 1992 Oct. 27(4):507-19. [Medline].
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. 2011 Jul 1. 56(7):1130-2. [Medline].
Takimoto T, Takada H, Ishimura M, Kirino M, Hata K, Ohara O, et al. Wiskott-Aldrich syndrome in a girl caused by heterozygous WASP mutation and extremely skewed X-chromosome inactivation: a novel association with maternal uniparental isodisomy 6. Neonatology. 2015. 107(3):185-90. [Medline].
Ochs HD, Thrasher AJ. The Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2006 Apr. 117(4):725-38; quiz 739. [Medline].
Suri D, Singh S, Rawat A, Gupta A, Kamae C, Honma K, et al. Clinical profile and genetic basis of Wiskott-Aldrich syndrome at Chandigarh, North India. Asian Pac J Allergy Immunol. 2012 Mar. 30(1):71-8. [Medline].
Navabi B, Upton JE. Primary immunodeficiencies associated with eosinophilia. Allergy Asthma Clin Immunol. 2016. 12:27. [Medline].
Patiroglu T, Klein C, Gungor HE, Ozdemir MA, Witzel M, Karakukcu M, et al. CLINICAL FEATURES AND GENETIC ANALYSIS OF SIX PATIENTS WITH WISKOTT-ALDRICH SYNDROME REPORTING TWO NOVEL MUTATIONS: EXPERIENCE OF ERCIYES UNIVERSITY, KAYSERI, TURKEY. Genet Couns. 2016. 27 (1):9-24. [Medline].
Zhao Q, Zhang ZY, Zhao XD, Jiang LP, Zhao Y, Yang XQ. [Analysis of prenatal diagnosis for seven high-risk fetuses with Wiskott-Aldrich syndrome]. Zhonghua Er Ke Za Zhi. 2012 Jan. 50(1):15-9. [Medline].
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. 2008 Feb. 23(1):146-8. [Medline].
Hacein-Bey Abina S, Gaspar HB, Blondeau J, Caccavelli L, Charrier S, Buckland K, et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA. 2015 Apr 21. 313(15):1550-63. [Medline].
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. 2006 Mar. 17(3):303-13. [Medline].
Galy A, Roncarolo MG, Thrasher AJ. Development of lentiviral gene therapy for Wiskott Aldrich syndrome. Expert Opin Biol Ther. 2008 Feb. 8(2):181-90. [Medline].
Castiello MC, Scaramuzza S, Pala F, Ferrua F, Uva P, Brigida I, et al. B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2015 Mar 16. [Medline].
Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Drug Information Handbook 2008-2009. 16th ed. Cleveland, OH: Lexi-Comp Inc; 2008.
Hooper JA. Intravenous Immunoglobulins: Evolution of Commercial IVIG Preparations. Immunol Allergy Clin North Am. 2008 Nov. 28(4):765-78. [Medline].
Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health Syst Pharm. 2005 Aug 15. 62(16 Suppl 3):S5-11. [Medline].
Siegel J. The product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005 Nov. 25(11 Pt 2):78S-84S. [Medline].
Kroger AT, Atkinson WL, Marcuse EK, Pickering LK. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006 Dec 1. 55:1-48. [Medline]. [Full Text].
Recommendations of the Advisory Committee on Immunization Practices (ACIP): use of vaccines and immune globulins for persons with altered immunocompetence. MMWR Recomm Rep. 1993 Apr 9. 42:1-18. [Medline]. [Full Text].
Chen N, Zhang ZY, Liu DW, Liu W, Tang XM, Zhao XD. The clinical features of autoimmunity in 53 patients with Wiskott-Aldrich syndrome in China: a single-center study. Eur J Pediatr. 2015 Apr 16. [Medline].
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. 2005 Dec. 116(6):1364-71. [Medline].
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. 2006 Apr 15. 193(8):1135-42. [Medline].
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. 1996 Jul. 129(1):56-62. [Medline].
Derry JM, Kerns JA, Weinberg KI, et al. WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. Hum Mol Genet. 1995 Jul. 4(7):1127-35. [Medline].
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. 1994 Aug 26. 78(4):635-44. [Medline].
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. 2003 May. 111(5 Pt 1):e622-7. [Medline]. [Full Text].
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. 2001 Aug 7. 135(3):165-74. [Medline]. [Full Text].
Imai K, Morio T, Zhu Y, et al. Clinical course of patients with WASP gene mutations. Blood. 2004 Jan 15. 103(2):456-64. [Medline]. [Full Text].
Lorenzi R, Brickell PM, Katz DR, et al. Wiskott-Aldrich syndrome protein is necessary for efficient IgG-mediated phagocytosis. Blood. 2000 May 1. 95(9):2943-6. [Medline]. [Full Text].
Lutskiy MI, Shcherbina A, Bachli ET, Cooley J, Remold-O'Donnell E. WASP localizes to the membrane skeleton of platelets. Br J Haematol. 2007 Oct. 139(1):98-105. [Medline].
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. 1993 Nov 15. 82(10):2961-6. [Medline].
Ochs HD, Rosen FS. The Wiskott-Aldrich syndrome. Ochs HD, Smith CIE, Puck J, eds. Primary Immunodeficiency Diseases: a Molecular and Genetic Approach. New York, NY: Oxford University Press; 1999. 292-305.
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. 2006 Apr. 13(4):729-37. [Medline].
Rengan R, Ochs HD, Sweet LI, et al. Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells. Blood. 2000 Feb 15. 95(4):1283-92. [Medline]. [Full Text].
Samarin SN. WASP family proteins act between cytoskeleton and cellular signaling pathways. Biochemistry (Mosc). 2005 Dec. 70(12):1305-9. [Medline].
Tsuboi S, Nonoyama S, Ochs HD. Wiskott-Aldrich syndrome protein is involved in alphaIIbbeta3-mediated cell adhesion. EMBO Rep. 2006 Mar 31. [Medline].
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. 2006 Mar. 37(5):469-77. [Medline].
Wietstruck PMA, Zuniga CP, Talesnik GE, Mendez RC, Barriga CF. [Hematopoietic stem cell transplantation for patients with Wiskott-Aldrich syndrome]. Rev Med Chil. 2007 Jul. 135(7):917-23. [Medline].
Xie JW, Zhang ZY, Wu JF, Liu DW, Liu W, Zhao Y, et al. In vivo reversion of an inherited mutation in a Chinese patient with Wiskott-Aldrich syndrome. Hum Immunol. 2015 Apr 8. [Medline].
|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|
|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|
|Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization||5.1-6||Sucrose free, contains 5% D-sorbitol||Liquid 5%||< 50|
|Gammagard Liquid 10%
|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|
|Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation||4-4.5||Contains no sugar, contains glycine||Liquid 10%||46|
|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|
|Cohn-Oncley fraction II/III; ultrafiltration; pasteurization||6.4-7.2||5% solution: 5% glucose, 0.3% NaCl||Lyophilized powder 5%||< 10|
(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)|
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|
(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%
|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|