Blood Journal
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The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2

  1. Birthe Jessen1,
  2. Sebastian F. N. Bode1,
  3. Sandra Ammann1,
  4. Subarna Chakravorty2,
  5. Graham Davies3,
  6. Jana Diestelhorst4,
  7. Melissa Frei-Jones5,
  8. William A. Gahl6,
  9. Bernadette R. Gochuico6,
  10. Matthias Griese4,
  11. Gillian Griffiths7,
  12. Gritta Janka8,
  13. Christoph Klein4,
  14. Tamara Kögl9,
  15. Karin Kurnik4,
  16. Kai Lehmberg8,
  17. Andrea Maul-Pavicic1,
  18. Andrew D. Mumford10,
  19. David Pace11,
  20. Nima Parvaneh12,
  21. Nima Rezaei13,
  22. Geneviève de Saint Basile14,
  23. Annette Schmitt-Graeff15,
  24. Klaus Schwarz16,
  25. Gulsun T. Karasu17,
  26. Barbara Zieger18,
  27. Udo zur Stadt19,
  28. Peter Aichele9, and
  29. Stephan Ehl1
  1. 1Centre of Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Germany;
  2. 2Department of Medicine, Imperial College London, United Kingdom;
  3. 3Immunology Department, Great Ormond Street Hospital for Children, London, United Kingdom;
  4. 4Department of Pediatrics, Dr von Hauner Children’s Hospital, Ludwig Maximilian University, Munich, Germany;
  5. 5The University of Texas Health Science Center San Antonio, San Antonio, TX;
  6. 6Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD;
  7. 7Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, United Kingdom;
  8. 8University Medical Center Hamburg Eppendorf, Department of Pediatric Hematology and Oncology, Hamburg, Germany;
  9. 9Department of Immunology, Institute of Medical Microbiology and Hygiene, University of Freiburg, Germany;
  10. 10Bristol Heart Institute, University of Bristol, Bristol, United Kingdom;
  11. 11Department of Paediatrics, Mater Dei Hospital, Tal-Qroqq, Msida, Malta;
  12. 12Pediatric Infectious Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran;
  13. 13Research Center for Immunodeficiencies, Children's Medical Center, and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran;
  14. 14INSERM U768, Université Paris Descartes, Hôpital Necker-Enfants Malades, Paris, France;
  15. 15Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany;
  16. 16Institute for Transfusion Medicine, University of Ulm, Ulm, Germany;
  17. 17Division of Hematology and Medical Oncology, Akdeniz University Faculty of Medicine, Antalya, Turkey;
  18. 18Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany; and
  19. 19Center for Diagnostic, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Key Points

  • Hermansky-Pudlak syndrome type 2 confers a moderate risk for hemophagocytic lymphohistiocytosis.


Genetic disorders of lymphocyte cytotoxicity predispose patients to hemophagocytic lymphohistiocytosis (HLH). Reduced lymphocyte cytotoxicity has been demonstrated in Hermansky-Pudlak syndrome type 2 (HPS2), but only a single patient was reported who developed HLH. Because that patient also carried a potentially contributing heterozygous RAB27A mutation, the risk for HLH in HPS2 remains unclear. We analyzed susceptibility to HLH in the pearl mouse model of HPS2. After infection with lymphocytic choriomeningitis virus, pearl mice developed all key features of HLH, linked to impaired virus control caused by a moderate defect in CTL cytotoxicity in vivo. However, in contrast to perforin-deficient mice, the disease was transient, and all mice fully recovered and controlled the infection. An additional heterozygous Rab27a mutation did not aggravate the cytotoxicity defect or disease parameters. In the largest survey of 22 HPS2 patients covering 234 patient years, we identified only 1 additional patient with HLH and 2 with incomplete transient HLH-like episodes, although cytotoxicity or degranulation was impaired in all 16 patients tested. HPS2 confers a risk for HLH that is lower than in Griscelli or Chediak-Higashi syndrome, probably because of a milder defect in cytotoxicity. Preemptive hematopoietic stem cell transplantation does not appear justified in HPS2.

  • Submitted October 22, 2012.
  • Accepted January 21, 2013.
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