Wiskott Aldrich Sendromu: Kısa Derleme

Abstract

Wiskott Aldrich Sendromu (WAS) X’e bağlı resesif kalıtılan, nadir görülen genetik bir hastalıktır. WAS proteini (WASp) genindeki mutasyondan kaynaklanmaktadır. WAS proteini aktin hücre iskeleti organizasyonu ve sinyalizasyonunda rol oynar, bunun yanında bağışıklık sistemi hücrelerinin işlevlerinde kritik bir rol sahibidir. Hastalığın karakteristik klinik triadı mikrotrombositopeni, egzama ve immun yetmezliktir. Hastaların kliniği WASP mutasyonunun tipine göre şiddetli fenotipten (klasik WAS) daha hafif olanlara (X'e bağlı trombositopeni (XLT) ve X'e bağlı nötropeni) kadar değişiklik göstermektedir. WAS hastalarında bakteriyal, fungal ve viral enfeksiyonlara yatkınlıkla beraber, otoimmun hastalık (otoimmun hemolitik anemi, vaskülit, inflamatuar barsak hastalığı) ve malignite (özellikle lenfoma) riski artmıştır. WAS hastalarında tedavi yönetimi, klinik fenotipe göre bireyselleştirilmelidir. Enfeksiyonlara yönelik profilaktik antibiyoterapi ve intravenöz immünoglobulin replasman tedavisi uygulanmaktadır. Allojenik hematopoietik kök hücre nakli ise WAS'lı hastalar için altta yatan immün yetmezlik ve trombositopeninin düzeltilmesini sağlayan altın standart tedavidir. Son zamanlarda hematopoietik kök hücre gen tedavisi de potansiyel terapötik strateji olarak gündeme gelmiştir. Otolog gen tedavisi, allojenik kök hücre nakli için donörü olmayan hastalara umut verici bir alternatif olarak görünmektedir.

Keywords

• Wiskott-Aldrich sendromu
• trombositopeni
• egzama
• immünyetmezlik

Wiskott Aldrich Syndrome: Short Review

Abstract

Wiskott Aldrich Syndrome (WAS) is a rare X-linked recessive genetic disorder. It is caused by a mutation in the WAS protein (WASp) gene. The WAS protein plays a role in actin cytoskeleton organization and signaling, as well as a critical role in the function of immune system cells. The characteristic clinical triad of the disease is microthrombocytopenia, eczema and immunodeficiency. The clinical picture of the patients varies from severe phenotype (classical WAS) to milder ones (X-linked thrombocytopenia (XLT) and X-linked neutropenia) depending on the type of WASP mutation. WAS patients have an increased risk of autoimmune disease (autoimmune hemolytic anemia, vasculitis, inflammatory bowel disease) and malignancy (especially lymphoma), along with a predisposition to bacterial, fungal and viral infections. Treatment management in WAS patients should be individualized according to the clinical phenotype. Prophylactic antibiotics and intravenous immunoglobulin replacement therapy are used for infections. Allogeneic hematopoietic stem cell transplantation is the gold standard treatment for patients with WAS, providing correction of underlying immunodeficiency and thrombocytopenia. Recently, hematopoietic stem cell gene therapy has also come to the fore as a potential therapeutic strategy. Autologous gene therapy appears to be a promising alternative to allogeneic stem cell transplantation for patients without a donor.

Keywords

• Wiskott Aldrich syndrome
• thrombocytopenia,
• eczema
• immunodeficiency

References

1. Wiskott A. Familiarer, angeborener morbus werlhofii? Monatsschr Kinderheilkd. 1937; 68: 212-6.
2. Aldrich RA, Steinberg AG, Campbell DC. Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea. Pediatrics. 1954; 13(2): 133-9.
3. Kwan SP, Sandkuyl LA, Blaese M, Kunkel LM, Bruns G, Parmley R, et al. Genetic mapping of the wiskott-aldrich syndrome with two highly-linked polymorphic DNA markers. Genomics. 1988; 3(1): 39-43.
4. Notarangelo LD, Mazza C, Giliani S, D’Aria C, Gandellini F, Ravelli C, et al. Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia. Blood. 2002; 99: 2268-9.
5. Devriendt K, Kim AS, Mathijs G, Frints SG, Schwartz M, Van Den Oord JJ, et al. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet. 2001; 27: 313-7.
6. Stradal TE, Rottner K, Disanza A, Confalonieri S, Innocenti M, Scita G. Regulation of actin dynamics by WASP and WAVE family proteins. Trends Cell Biol. 2004; 14: 303-11.
7. Kwan SP, Lehner T, Hagemann T, Lu B, Blaese M, Ochs H,et al, Localization of the gene for the Wiskott-Aldrich syndrome between two flanking markers, TIMP and DXS255, on Xp11.22-Xp11.3. Genomics. 1991; 10: 29-33.
8. Derry JM, Ochs HD, Francke U. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell. 1994; 78: 635-44.

9. Ochs HD, Thrasher AJ, The Wiskott-Aldrich syndrome, J Allergy Clin Immunol. 2006; 117(4): 725-38.
10. Notarangeloa LD, Miaob CH, Ochs HD. Wiskott-Aldrich Syndrome. Curr Opin Hematol. 2008; 15(1): 30-6.
11. Villa A, Notarangelo L, Macchi P, Mantuano E, Cavagni G, Brugnoni D, et al. X-linked thrombocytopenia and Wiskott-Aldrich syndrome are allelic diseases with mutations in the WASP gene. Nat Genet. 1995; 9: 414-7.
12. Devriendt K, Kim AS, Mathijs G, Frints SG, Schwartz M, Van Den Oord JJ, et al. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet. 2001; 27: 313-7.
13. Jin Y, Mazza C, Christie JR, Giliani S, Fiorini M, Mella P, et al. Mutations of the Wiskott-Aldrich syndrome protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood. 2004; 104: 4010-9.
14. Imai K, Morio T, Zhu Y, Jin Y, Itoh S, Kajiwara M, et al. Clinical course of patients with WASP gene mutations. Blood. 2004; 103: 456-64.
15. Ochs HD, Rosen FS. Wiskott-Aldrich syndrome. In: Ochs HD, Smith CIE, Puck JM, editors. Primary immunodeficiency diseases: a molecular and genetic approach, 2nd ed. New York: Oxford University Press; 2007. pp. 454-69.
16. Thrasher AJ, Kinnon C. The Wiskott–Aldrich syndrom, Clin Exp Immunol. 2000; 120(1): 2-9.
17. Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr. 1994; 125: 876-85.
18. Baharin MF, Dhaliwal JS, Sarachandran SV, Idris SZ, Yeoh SL. A rare case of Wiskott-Aldrich syndrome with normal platelet size: a case report. J Med Case Rep. 2016; 10(1): 188.
19. Patel PD, Samanich JM, Mitchell WB, Manwani D. A unique presentation of Wiskott-Aldrich syndrome in relation to platelet size. Pediatr Blood Cancer. 2011; 56(7): 1127-9.
20. Haddad E, Cramer E, Riviere C, Rameau P, Louache F, Guichard J, et al. The thrombocytopenia of Wiskott Aldrich syndrome is not related to a defect in proplatelet formation. Blood. 1999; 94(2): 509-18.
21. Ochs HD, Slichter SJ, Harker LA, Von Behrens WE, Clark RA, Wedgwood RJ. The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets. Blood. 1980; 55(2): 243-52.
22. 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; 82(10): 2961-6.
23. Litzman J, Jones A, Hann I, Chapel H, Strobel S, Morgan G. Intravenous immunoglobulin, splenectomy, and antibiotic prophylaxis in Wiskott-Aldrich syndrome. Arch Dis Child. 1996; 75(5): 436-9.
24. Prislovsky A, Zeng X, Sokolic RA, Garabedian EN, Anur P, Candotti F, et al. Platelets from WAS patients show an increased susceptibility to ex vivo phagocytosis. Platelets. 2013; 24(4): 288-96.
25. Grottum KA, Hovig T, Holmsen H, Abrahamsen AF, Jeremic M, Seip M. Wiskott-Aldrich syndrome: qualitative platelet defects and short platelet survival. Br J Haematol. 1969; 17(4): 373-88.
26. Baldini MG. Nature of the platelet defect in the Wiskott-Aldrich syndrome. Ann N Y Acad Sci. 1972; 201: 437-44.
27. Semple JW, Siminovitch KA, Mody M, Milev Y, Lazarus AH, Wright JF, et al. Flow cytometric analysis of platelets from children with the Wiskott- Aldrich syndrome reveals defects in platelet development, activation and structure. Br J Haematol. 1997; 97(4): 747-54.
28. Zhang ZY, Xiao HQ, Jiang LP, Zhou Y, Zhao Q, Yu J, et al. Analysis of clinical and molecular characteristics of Wiskott-Aldrich syndrome in 24 patients from 23 unrelated Chinese families. Pediatr Allergy Immunol. 2010; 21(3): 522-32.
29. Park JY, Kob M, Prodeus AP, Rosen FS, Shcherbina A, Remold-O'Donnell E. Early deficit of lymphocytes in Wiskott-Aldrich syndrome: possible role of WASP in human lymphocyte maturation. Clin Exp Immunol. 2004; 136(1): 104-10.
30. Rawlings SL, Crooks GM, Bockstoce D, Barsky LW, Parkman R, Weinberg KI. Spontaneous apoptosis in lymphocytes from patients with Wiskott-Aldrich syndrome: correlation of accelerated cell death and attenuated bcl-2 expression. Blood. 1999; 94(11): 3872-82.
31. Rengan R, Ochs HD, Sweet LI, Keil ML, Gunning WT, Lachant NA, et al. Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells. Blood. 2000 ; 95(4): 1283-92.
32. Park JY, Shcherbina A, Rosen FS, Prodeus AP, Remold-O'Donnell E. Phenotypic perturbation of B cells in the Wiskott-Aldrich syndrome. Clin Exp Immunol. 2005; 139(2): 297-305.
33. Schurman SH, Candotti F. Autoimmunity in Wiskott-Aldrich syndrome. Curr Opin Rheumatol. 2003; 15(4): 446-53.
34. Cotelingam JD, Witebsky FG, Hsu SM, Blaese RM, Jaffe ES. Malignant lymphoma in patients with the Wiskott-Aldrich syndrome. Cancer Investig. 1985; 3(6): 515-22.
35. Picard C, Mellouli F, Duprez R, Chedeville G, Neven B, Fraitag S, et al. Kaposi’s sarcoma in a child with Wiskott-Aldrich syndrome. Eur J Pediatr. 2006; 165(7): 453-7.
36. Yoshimi A, Kamachi Y, Imai K, Watanabe N, Nakadate H, Kanazawa T, et al. Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia. Pediatr Blood Cancer. 2013; 60(5): 836-41.
37. Ochs HD, Filipovich AH, Veys P, Cowan MJ, Kapoor N. Wiskott-Aldrich syndrome: diagnosis, clinical and laboratory manifestations, and treatment. Biology of Blood and Marrow Transplantation. 2009; 15(1 Suppl): 84-90.
38. Rivers E, Worth A, Thrasher AJ, Burns SO. How I manage patients with Wiskott Aldrich syndrome. 2019; 185 (4): 647-55.
39. Candotti F. Clinical Manifestations and Pathophysiological Mechanisms of the Wiskott-Aldrich Syndrome. J Clin Immunol. 2018; 38(1): 13-27.
40. Mathew P, Cooper MD. Effect of intravenous gammaglobulin (IVIG) on the platelet count in patients with Wiskott–Aldrich syndrome. Pediatr Allergy Immunol. 1995; 6(2): 91-4.
41. Lum LG, Tubergen DG, Corash L, Blaese RM. Splenectomy in the management of the thrombocytopenia of the Wiskott–Aldrich syndrome. N Engl J Med. 1980; 302: 892-6.