Skip to main content
SpringerLink
Log in
Book cover

Hematological Disorders in Children pp 247–261Cite as

Primary Hemophagocytic Lymphohistiocytosis

  • Chapter
  • First Online:

  • 919 Accesses

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal syndrome of dysregulated immune reaction that mostly affects infants and young children. HLH represents the extreme end of uncontrolled inflammatory reaction and can occur in various clinical settings. It is classified into primary and secondary forms based on the underlying etiology. Since the first report of causative gene for primary HLH in 1999, it has been clarified that a defect in lymphocyte cytotoxic function leads to abnormal activation of T cells and subsequent release of inflammatory cytokines. Herein, recent advances in genetics, pathophysiology, diagnostic procedure, and clinical management of primary HLH are reviewed.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Janka GE, Lehmberg K. Hemophagocytic syndromes—an update. Blood Rev. 2014;28(4):135–42. doi:10.1016/j.blre.2014.03.002.

    Article  PubMed  Google Scholar 

  2. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31. doi:10.1002/pbc.21039.

    Article  PubMed  Google Scholar 

  3. Bode SF, Ammann S, Al-Herz W, Bataneant M, Dvorak CC, Gehring S, et al. The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis. Haematologica. 2015;100(7):978–88. doi:10.3324/haematol.2014.121608.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sieni E, Cetica V, Hackmann Y, Coniglio ML, Da Ros M, Ciambotti B, et al. Familial hemophagocytic lymphohistiocytosis: when rare diseases shed light on immune system functioning. Front Immunol. 2014;5:167. doi:10.3389/fimmu.2014.00167.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957–9.

    Article  CAS  PubMed  Google Scholar 

  6. Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell. 2003;115(4):461–73.

    Article  CAS  PubMed  Google Scholar 

  7. zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter JI, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. 2005;14(6):827–34. doi:10.1093/hmg/ddi076.

    Article  CAS  PubMed  Google Scholar 

  8. Cote M, Menager MM, Burgess A, Mahlaoui N, Picard C, Schaffner C, et al. Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J Clin Invest. 2009;119(12):3765–73. doi:10.1172/JCI40732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. zur Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J, et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet. 2009;85(4):482–92. doi:10.1016/j.ajhg.2009.09.005.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Nagle DL, Karim MA, Woolf EA, Holmgren L, Bork P, Misumi DJ, et al. Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nat Genet. 1996;14(3):307–11. doi:10.1038/ng1196-307.

    Article  CAS  PubMed  Google Scholar 

  11. Barbosa MD, Nguyen QA, Tchernev VT, Ashley JA, Detter JC, Blaydes SM, et al. Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature. 1996;382(6588):262–5. doi:10.1038/382262a0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Menasche G, Pastural E, Feldmann J, Certain S, Ersoy F, Dupuis S, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet. 2000;25(2):173–6. doi:10.1038/76024.

    Article  CAS  PubMed  Google Scholar 

  13. Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, et al. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II. Blood. 2006;108(1):81–7. doi:10.1182/blood-2005-11-4413.

    Article  CAS  PubMed  Google Scholar 

  14. Introne W, Boissy RE, Gahl WA. Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome. Mol Genet Metab. 1999;68(2):283–303. doi:10.1006/mgme.1999.2927.

    Article  CAS  PubMed  Google Scholar 

  15. Meeths M, Bryceson YT, Rudd E, Zheng C, Wood SM, Ramme K, et al. Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations. Pediatr Blood Cancer. 2010;54(4):563–72. doi:10.1002/pbc.22357.

    PubMed  Google Scholar 

  16. Jessen B, Bode SF, Ammann S, Chakravorty S, Davies G, Diestelhorst J, et al. The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2. Blood. 2013;121(15):2943–51. doi:10.1182/blood-2012-10-463166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Badolato R, Prandini A, Caracciolo S, Colombo F, Tabellini G, Giacomelli M, et al. Exome sequencing reveals a pallidin mutation in a Hermansky-Pudlak-like primary immunodeficiency syndrome. Blood. 2012;119(13):3185–7. doi:10.1182/blood-2012-01-404350.

    Article  CAS  PubMed  Google Scholar 

  18. Sayos J, Wu C, Morra M, Wang N, Zhang X, Allen D, et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature. 1998;395(6701):462–9. doi:10.1038/26683.

    Article  CAS  PubMed  Google Scholar 

  19. Coffey AJ, Brooksbank RA, Brandau O, Oohashi T, Howell GR, Bye JM, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet. 1998;20(2):129–35. doi:10.1038/2424.

    Article  CAS  PubMed  Google Scholar 

  20. Rigaud S, Fondaneche MC, Lambert N, Pasquier B, Mateo V, Soulas P, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006;444(7115):110–4. doi:10.1038/nature05257.

    Article  CAS  PubMed  Google Scholar 

  21. Veillette A, Perez-Quintero LA, Latour S. X-linked lymphoproliferative syndromes and related autosomal recessive disorders. Curr Opin Allergy Clin Immunol. 2013;13(6):614–22. doi:10.1097/ACI.0000000000000008.

    Article  CAS  PubMed  Google Scholar 

  22. Dupre L, Andolfi G, Tangye SG, Clementi R, Locatelli F, Arico M, et al. SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. Blood. 2005;105(11):4383–9. doi:10.1182/blood-2004-08-3269.

    Article  CAS  PubMed  Google Scholar 

  23. Snow AL, Marsh RA, Krummey SM, Roehrs P, Young LR, Zhang K, et al. Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency. J Clin Invest. 2009;119(10):2976–89. doi:10.1172/JCI39518.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Vince JE, Wong WW, Gentle I, Lawlor KE, Allam R, O’Reilly L, et al. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity. 2012;36(2):215–27. doi:10.1016/j.immuni.2012.01.012.

    Article  CAS  PubMed  Google Scholar 

  25. Yabal M, Muller N, Adler H, Knies N, Gross CJ, Damgaard RB, et al. XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. Cell Rep. 2014;7(6):1796–808. doi:10.1016/j.celrep.2014.05.008.

    Article  CAS  PubMed  Google Scholar 

  26. Wada T, Kanegane H, Ohta K, Katoh F, Imamura T, Nakazawa Y, et al. Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency. Cytokine. 2014;65(1):74–8. doi:10.1016/j.cyto.2013.09.007.

    Article  CAS  PubMed  Google Scholar 

  27. Rohr J, Beutel K, Maul-Pavicic A, Vraetz T, Thiel J, Warnatz K, et al. Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases. Haematologica. 2010;95(12):2080–7. doi:10.3324/haematol.2010.029389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118(22):5794–8. doi:10.1182/blood-2011-07-370148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Horne A, Trottestam H, Arico M, Egeler RM, Filipovich AH, Gadner H, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2008;140(3):327–35. doi:10.1111/j.1365-2141.2007.06922.x.

    Article  PubMed  Google Scholar 

  30. Deiva K, Mahlaoui N, Beaudonnet F, de Saint BG, Caridade G, Moshous D, et al. CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis. Neurology. 2012;78(15):1150–6. doi:10.1212/WNL.0b013e31824f800a.

    Article  CAS  PubMed  Google Scholar 

  31. Ueda I, Ishii E, Morimoto A, Ohga S, Sako M, Imashuku S. Correlation between phenotypic heterogeneity and gene mutational characteristics in familial hemophagocytic lymphohistiocytosis (FHL). Pediatr Blood Cancer. 2006;46(4):482–8. doi:10.1002/pbc.20511.

    Article  PubMed  Google Scholar 

  32. Jessen B, Kogl T, Sepulveda FE, de Saint Basile G, Aichele P, Ehl S. Graded defects in cytotoxicity determine severity of hemophagocytic lymphohistiocytosis in humans and mice. Front Immunol. 2013;4:448. doi:10.3389/fimmu.2013.00448.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Pagel J, Beutel K, Lehmberg K, Koch F, Maul-Pavicic A, Rohlfs AK, et al. Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). Blood. 2012;119(25):6016–24. doi:10.1182/blood-2011-12-398958.

    Article  CAS  PubMed  Google Scholar 

  34. Latour S, Aguilar C. XIAP deficiency syndrome in humans. Semin Cell Dev Biol. 2015;39:115–23. doi:10.1016/j.semcdb.2015.01.015.

    Article  CAS  PubMed  Google Scholar 

  35. Pachlopnik Schmid J, Canioni D, Moshous D, Touzot F, Mahlaoui N, Hauck F, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood. 2011;117(5):1522–9. doi:10.1182/blood-2010-07-298372.

    Article  PubMed  Google Scholar 

  36. Dotta L, Parolini S, Prandini A, Tabellini G, Antolini M, Kingsmore SF, et al. Clinical, laboratory and molecular signs of immunodeficiency in patients with partial oculo-cutaneous albinism. Orphanet J Rare Dis. 2013;8:168. doi:10.1186/1750-1172-8-168.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Yasumi T, Hori M, Hiejima E, Shibata H, Izawa K, Oda H, et al. Laboratory parameters identify familial haemophagocytic lymphohistiocytosis from other forms of paediatric haemophagocytosis. Br J Haematol. 2015;170(4):532–8. doi:10.1111/bjh.13461.

    Article  PubMed  Google Scholar 

  38. Bryceson YT, Pende D, Maul-Pavicic A, Gilmour KC, Ufheil H, Vraetz T, et al. A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood. 2012;119(12):2754–63. doi:10.1182/blood-2011-08-374199.

    Article  CAS  PubMed  Google Scholar 

  39. Kogawa K, Lee SM, Villanueva J, Marmer D, Sumegi J, Filipovich AH. Perforin expression in cytotoxic lymphocytes from patients with hemophagocytic lymphohistiocytosis and their family members. Blood. 2002;99(1):61–6.

    Article  CAS  PubMed  Google Scholar 

  40. Abdalgani M, Filipovich AH, Choo S, Zhang K, Gifford C, Villanueva J, et al. Accuracy of flow cytometric perforin screening for detecting patients with FHL due to PRF1 mutations. Blood. 2015;126(15):1858–60. doi:10.1182/blood-2015-06-648659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Murata Y, Yasumi T, Shirakawa R, Izawa K, Sakai H, Abe J, et al. Rapid diagnosis of FHL3 by flow cytometric detection of intraplatelet Munc13-4 protein. Blood. 2011;118(5):1225–30. doi:10.1182/blood-2011-01-329540.

    Article  CAS  PubMed  Google Scholar 

  42. Marsh RA, Villanueva J, Zhang K, Snow AL, Su HC, Madden L, et al. A rapid flow cytometric screening test for X-linked lymphoproliferative disease due to XIAP deficiency. Cytometry B Clin Cytom. 2009;76(5):334–44. doi:10.1002/cyto.b.20473.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Marsh RA, Bleesing JJ, Filipovich AH. Using flow cytometry to screen patients for X-linked lymphoproliferative disease due to SAP deficiency and XIAP deficiency. J Immunol Methods. 2010;362(1–2):1–9. doi:10.1016/j.jim.2010.08.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhao M, Kanegane H, Kobayashi C, Nakazawa Y, Ishii E, Kasai M, et al. Early and rapid detection of X-linked lymphoproliferative syndrome with SH2D1A mutations by flow cytometry. Cytometry B Clin Cytom. 2011;80(1):8–13. doi:10.1002/cyto.b.20552.

    Article  PubMed  Google Scholar 

  45. Hori M, Yasumi T, Shimodera S, Shibata H, Hiejima E, Oda H, et al. A CD57+ CTL degranulation assay effectively identifies familial hemophagocytic lymphohistiocytosis type 3 patients. J Clin Immunol. 2017;37(1):92–9. doi:10.1007/s10875-016-0357-3.

    Article  CAS  PubMed  Google Scholar 

  46. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041–52. doi:10.1182/blood-2011-03-278127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cetica V, Sieni E, Pende D, Danesino C, De Fusco C, Locatelli F et al. Genetic predisposition to hemophagocytic lymphohistiocytosis: report on 500 patients from the Italian registry. J Allergy Clin Immunol. 2016;137(1):188–96, e4. doi:10.1016/j.jaci.2015.06.048.

  48. Nagai K, Yamamoto K, Fujiwara H, An J, Ochi T, Suemori K, et al. Subtypes of familial hemophagocytic lymphohistiocytosis in Japan based on genetic and functional analyses of cytotoxic T lymphocytes. PLoS One. 2010;5(11):e14173. doi:10.1371/journal.pone.0014173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yoon HS, Kim HJ, Yoo KH, Sung KW, Koo HH, Kang HJ, et al. UNC13D is the predominant causative gene with recurrent splicing mutations in Korean patients with familial hemophagocytic lymphohistiocytosis. Haematologica. 2010;95(4):622–6. doi:10.3324/haematol.2009.016949.

    Article  CAS  PubMed  Google Scholar 

  50. Meeths M, Chiang SC, Wood SM, Entesarian M, Schlums H, Bang B, et al. Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D. Blood. 2011;118(22):5783–93. doi:10.1182/blood-2011-07-369090.

    Article  CAS  PubMed  Google Scholar 

  51. Rudd E, Goransdotter Ericson K, Zheng C, Uysal Z, Ozkan A, Gurgey A, et al. Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies. J Med Genet. 2006;43(4):e14. doi:10.1136/jmg.2005.035253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Marsh RA, Satake N, Biroschak J, Jacobs T, Johnson J, Jordan MB, et al. STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. Pediatr Blood Cancer. 2010;55(1):134–40. doi:10.1002/pbc.22499.

    PubMed  Google Scholar 

  53. Spessott WA, Sanmillan ML, McCormick ME, Patel N, Villanueva J, Zhang K, et al. Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion. Blood. 2015;125(10):1566–77. doi:10.1182/blood-2014-11-610816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nagai K, Ochi F, Terui K, Maeda M, Ohga S, Kanegane H, et al. Clinical characteristics and outcomes of Chediak-Higashi syndrome: a nationwide survey of Japan. Pediatr Blood Cancer. 2013;60(10):1582–6. doi:10.1002/pbc.24637.

    Article  PubMed  Google Scholar 

  55. Karim MA, Suzuki K, Fukai K, Oh J, Nagle DL, Moore KJ, et al. Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome. Am J Med Genet. 2002;108(1):16–22.

    Article  PubMed  Google Scholar 

  56. Cetica V, Hackmann Y, Grieve S, Sieni E, Ciambotti B, Coniglio ML et al. Patients with Griscelli syndrome and normal pigmentation identify RAB27A mutations that selectively disrupt MUNC13-4 binding. J Allergy Clin Immunol. 2015;135(5):1310–8, e1. doi:10.1016/j.jaci.2014.08.039.

  57. Booth C, Gilmour KC, Veys P, Gennery AR, Slatter MA, Chapel H, et al. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood. 2011;117(1):53–62. doi:10.1182/blood-2010-06-284935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Speckmann C, Lehmberg K, Albert MH, Damgaard RB, Fritsch M, Gyrd-Hansen M, et al. X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis. Clin Immunol. 2013;149(1):133–41. doi:10.1016/j.clim.2013.07.004.

    Article  CAS  PubMed  Google Scholar 

  59. Trottestam H, Horne A, Arico M, Egeler RM, Filipovich AH, Gadner H, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577–84. doi:10.1182/blood-2011-06-356261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Marsh RA, Allen CE, McClain KL, Weinstein JL, Kanter J, Skiles J, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 2013;60(1):101–9. doi:10.1002/pbc.24188.

    Article  CAS  PubMed  Google Scholar 

  61. Mahlaoui N, Ouachee-Chardin M, de Saint Basile G, Neven B, Picard C, Blanche S, et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics. 2007;120(3):e622–8. doi:10.1542/peds.2006-3164.

    Article  PubMed  Google Scholar 

  62. Ouachee-Chardin M, Elie C, de Saint Basile G, Le Deist F, Mahlaoui N, Picard C, et al. Hematopoietic stem cell transplantation in hemophagocytic lymphohistiocytosis: a single-center report of 48 patients. Pediatrics. 2006;117(4):e743–50. doi:10.1542/peds.2005-1789.

    Article  PubMed  Google Scholar 

  63. Marsh RA, Vaughn G, Kim MO, Li D, Jodele S, Joshi S, et al. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood. 2010;116(26):5824–31. doi:10.1182/blood-2010-04-282392.

    Article  CAS  PubMed  Google Scholar 

  64. Nishi M, Nishimura R, Suzuki N, Sawada A, Okamura T, Fujita N, et al. Reduced-intensity conditioning in unrelated donor cord blood transplantation for familial hemophagocytic lymphohistiocytosis. Am J Hematol. 2012;87(6):637–9. doi:10.1002/ajh.23190.

    Article  PubMed  Google Scholar 

  65. Sawada A, Ohga S, Ishii E, Inoue M, Okada K, Inagaki J, et al. Feasibility of reduced-intensity conditioning followed by unrelated cord blood transplantation for primary hemophagocytic lymphohistiocytosis: a nationwide retrospective analysis in Japan. Int J Hematol. 2013;98(2):223–30. doi:10.1007/s12185-013-1391-z.

    Article  PubMed  Google Scholar 

  66. Marsh RA, Rao K, Satwani P, Lehmberg K, Muller I, Li D, et al. Allogeneic hematopoietic cell transplantation for XIAP deficiency: an international survey reveals poor outcomes. Blood. 2013;121(6):877–83. doi:10.1182/blood-2012-06-432500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lehmberg K, Albert MH, Beier R, Beutel K, Gruhn B, Kroger N, et al. Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis. Haematologica. 2014;99(1):180–4. doi:10.3324/haematol.2013.094730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ono S, Okano T, Hoshino A, Yanagimachi M, Hamamoto K, Nakazawa Y, et al. Hematopoietic stem cell transplantation for XIAP deficiency in Japan. J Clin Immunol. 2017;37(1):85–91. doi:10.1007/s10875-016-0348-4.

    Article  CAS  PubMed  Google Scholar 

  69. Jessen B, Maul-Pavicic A, Ufheil H, Vraetz T, Enders A, Lehmberg K, et al. Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome. Blood. 2011;118(17):4620–9. doi:10.1182/blood-2011-05-356113.

    Article  CAS  PubMed  Google Scholar 

  70. Carmo M, Risma KA, Arumugam P, Tiwari S, Hontz AE, Montiel-Equihua CA, et al. Perforin gene transfer into hematopoietic stem cells improves immune dysregulation in murine models of perforin deficiency. Mol Ther. 2015;23(4):737–45. doi:10.1038/mt.2014.242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Takahiro Yasumi, Hirofumi Shibata, Saeko Shimodera & Toshio Heike

Authors
  1. Takahiro Yasumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hirofumi Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saeko Shimodera
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toshio Heike
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takahiro Yasumi .

Editor information

Editors and Affiliations

  1. Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan

    Eiichi Ishii

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

Yasumi, T., Shibata, H., Shimodera, S., Heike, T. (2017). Primary Hemophagocytic Lymphohistiocytosis. In: Ishii, E. (eds) Hematological Disorders in Children. Springer, Singapore. https://doi.org/10.1007/978-981-10-3886-0_12

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-3886-0_12

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-3885-3

  • Online ISBN: 978-981-10-3886-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation