International Journal of Hematology

, Volume 83, Issue 1, pp 51–54 | Cite as

A Novel Perforin Gene Mutation in a Japanese Family with Hemophagocytic Lymphohistiocytosis

  • Ikuyo Ueda
  • Shigeyoshi Hibi
  • Tohru Sugimoto
  • Akira Morimoto
  • Urara Kohdera
  • Tohru Inaba
  • Ken Yamamoto
  • Eiichi Ishii
  • Shinsaku Imashuku
Case Report


A 4-month-old girl with clinical features of hemophagocytic lymphohistiocytosis (HLH) was successfully treated with immunochemotherapy but died at the age of 1 year and 3 months, before hematopoietic stem cell transplantation could be performed. Her family history showed death during infancy of the eldest sister, suggesting a diagnosis of familial HLH (FHL). Direct sequencing of the DNA extracted from the patient’s spleen tissue obtained at autopsy revealed a novel perforin gene mutation: a homozygous 1289G insertion (Asp430 frameshift and termination at amino acid residue 457), which has not previously been reported in FHL patients.

Key words

Familial hemophagocytic lymphohistiocytosis Perforin Mutation Natural killer activity 


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  1. 1.
    Arico M, Danesino C, Pende D, Moretta L. Pathogenesis of hemo- phagocytic lymphohistiocytosis. Br J Haematol. 2001;114:761–769.CrossRefGoogle Scholar
  2. 2.
    Henter JI. Biology and treatment of familial hemophagocytic lymphohistiocytosis: importance of perforin in lymphocyte-mediated cytotoxicity and triggering of apoptosis. Med Pediatr Oncol. 2002; 38:305–309.CrossRefGoogle Scholar
  3. 3.
    Stark B, Cohen IJ, Pecht M, et al. Immunologic dysregulation in a patient with familial hemophagocytic lymphohistiocytosis. Cancer. 1987;60:2629–2636.CrossRefGoogle Scholar
  4. 4.
    Ishii E, Ohga S, Imashuku S, et al. Review of hemophagocytic lymphohistiocytosis (HLH) in children with focus on Japanese experience. Crit Rev Oncol Hematol. 2005;53:209–223.CrossRefGoogle Scholar
  5. 5.
    Arico M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis: report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. 1996;10:197–203.PubMedGoogle Scholar
  6. 6.
    Henter JI, Samuelsson-Horne A, Arico M, et al.. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100:2367–2373.CrossRefGoogle Scholar
  7. 7.
    Imashuku S. Advances in the management of hemophagocytic lymphohistiocytosis. Int J Hematol. 2000;72:1–11.PubMedGoogle Scholar
  8. 8.
    Farquhar JW, Claireux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952;136:519–525.CrossRefGoogle Scholar
  9. 9.
    Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286:1957–1959.CrossRefGoogle Scholar
  10. 10.
    Feldmann J, Callebaut I, Raposo G, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell.2003;115:461–473.CrossRefGoogle Scholar
  11. 11.
    zur Stadt U, Schmidt S, Kasper B, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. 2005;14:827–834.CrossRefGoogle Scholar
  12. 12.
    Yamamoto K, Ishii E, Horiuchi H, et al. Mutations of syntaxin 11 and SNAP23 genes as causes of familial hemophagocytic lymphohistiocytosis were not found in Japanese people. J Hum Genet. In press.Google Scholar
  13. 13.
    zur Stadt U, Beutel K, Oyen F, et al. UNC13D and PRF1 mutations in childhood patients with hemophagocytic lymphohistiocytosis. In: Program and abstracts of the 20th Annual Meeting of the Histiocyte Society; September 12-14,{dy2004}; Stockholm, Sweden.Google Scholar
  14. 14.
    Ueda I, Morimoto A, Inaba T, et al. Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan. Br J Haematol. 2003;121:503–510.CrossRefGoogle Scholar
  15. 15.
    Janka GE, Schneider EM. Modern management of children with hemophagocytic lymphohistiocytosis. Br J Haematol. 2004;124:4–14.CrossRefGoogle Scholar
  16. 16.
    Katano H, Cohen JI. Perforin and lymphohistiocytic proliferative disorders. Br J Haematol. 2005;128:739–750.CrossRefGoogle Scholar
  17. 17.
    Clementi R, Locatelli F, Dupre L, et al. A proportion of patients with lymphoma may harbor mutations of the perforin gene. Blood. 2005;105:4424–4428.CrossRefGoogle Scholar
  18. 18.
    Muralitharan S, Al Lamki Z, Dennison D, et al. An inframe perforin gene deletion in familial hemophagocytic lymphohistiocytosis is associated with perforin expression. Am J Hematol. 2005;78: 59–63.CrossRefGoogle Scholar
  19. 19.
    Ishii E, Ueda I, Shirakawa R, et al. Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Blood. 2005;105:3442–3448.CrossRefGoogle Scholar
  20. 20.
    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;99:61–66.CrossRefGoogle Scholar
  21. 21.
    Molleran Lee S, Villanueva J, Sumegi J, et al. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J Med Genet. 2004;41:137–144.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Clementi R, zur Stadt U, Savoldi G, et al. Six novel mutations in the PRF1 gene in children with haemophagocytic lymphohistiocytosis. J Med Genet. 2001;38:643–646.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    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. In press.Google Scholar
  24. 24.
    Voskoboinik I, Thia MC, Trapani JA. A functional analysis of the putative polymorphisms A91V and N252S, and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis. Blood. 2005;105:4700–4706.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2006

Authors and Affiliations

  • Ikuyo Ueda
    • 1
  • Shigeyoshi Hibi
    • 1
  • Tohru Sugimoto
    • 1
  • Akira Morimoto
    • 1
  • Urara Kohdera
    • 2
  • Tohru Inaba
    • 3
  • Ken Yamamoto
    • 4
  • Eiichi Ishii
    • 5
  • Shinsaku Imashuku
    • 6
  1. 1.Department of PediatricsKyoto Prefectural University of MedicineHirokoji-Kawaramachi, Kamigyo-ku, KyotoJapan
  2. 2.Department of PediatricsKansai Medical CollegeMoriguchiJapan
  3. 3.Departments of Molecular Genetics and Laboratory MedicineKyoto Prefectural University of MedicineKyotoJapan
  4. 4.Department of Molecular Genetics, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
  5. 5.Department of PediatricsSaga UniversitySagaJapan
  6. 6.Division of PediatricsTakasago-seibu HospitalTakasagoJapan

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