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Identification of a novel CCDC22 mutation in a patient with severe Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia

  • Yusuke Yamashita
  • Akinori Nishikawa
  • Yoshifumi Iwahashi
  • Masakazu Fujimoto
  • Izumi Sasaki
  • Hiroyuki Mishima
  • Akira Kinoshita
  • Hiroaki Hemmi
  • Nobuo Kanazawa
  • Kouichi Ohshima
  • Ken-Ichi Imadome
  • Shin-ichi Murata
  • Koh-ichiro Yoshiura
  • Tsuneyasu Kaisho
  • Takashi Sonoki
  • Shinobu TamuraEmail author
Case Report

Abstract

Aggressive natural killer cell leukemia (ANKL) is a rare neoplasm characterized by the systemic infiltration of Epstein–Barr virus (EBV)-associated NK cells, and rapidly progressive clinical course. We report the case of a 45-year-old man with intellectual disability who developed ANKL, and describe the identification of a novel genetic mutation of coiled-coil domain-containing 22 (CCDC22). He presented with persistent fever, severe pancytopenia, and hepatosplenomegary. Following bone marrow aspiration, numerous hemophagocytes were identified. High EBV viral load was detected in NK cells fractionation by qPCR. The initial diagnosis was EBV-related hemophagocytic lymphohistiocytosis (EBV–HLH). A combination of immunosuppressive drugs and chemotherapy was administered, but was unsuccessful in controlling the disease. Therefore, he was treated with HLA-matched related allogeneic hematopoietic stem cell transplantation. However, his condition deteriorated within 30 days, resulting in fatal outcome. Autopsy revealed many EBV-infected NK cells infiltrating major organs, consistent with ANKL. Furthermore, whole-exome sequencing identified a novel missense mutation of the CCDC22 gene (c.112G>A, p.V38M), responsible for X-linked intellectual disability (XLID). CCDC22 has been shown to play a role in NF-κB activation. Our case suggests that CCDC22 mutation might be implicated in pathogenesis of EBV–HLH and NK-cell neoplasms as well as XLID via possibly affecting NF-κB signaling.

Keywords

Aggressive natural killer cell leukemia EBV-related hemophagocytic lymphohistiocytosis Allogeneic hematopoietic stem cell transplantation CCDC22 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

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Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  • Yusuke Yamashita
    • 1
  • Akinori Nishikawa
    • 1
  • Yoshifumi Iwahashi
    • 2
  • Masakazu Fujimoto
    • 2
  • Izumi Sasaki
    • 6
  • Hiroyuki Mishima
    • 3
  • Akira Kinoshita
    • 3
  • Hiroaki Hemmi
    • 6
  • Nobuo Kanazawa
    • 7
  • Kouichi Ohshima
    • 4
  • Ken-Ichi Imadome
    • 5
  • Shin-ichi Murata
    • 2
  • Koh-ichiro Yoshiura
    • 3
  • Tsuneyasu Kaisho
    • 6
  • Takashi Sonoki
    • 1
  • Shinobu Tamura
    • 1
    Email author
  1. 1.Department of Hematology/OncologyWakayama Medical UniversityWakayamaJapan
  2. 2.Department of Diagnostic PathologyWakayama Medical UniversityWakayamaJapan
  3. 3.Department of Human Genetics, Atomic Bomb Disease InstituteNagasaki UniversityNagasakiJapan
  4. 4.Department of PathologyKurume University School of MedicineFukuokaJapan
  5. 5.Department of Advanced Medicine for InfectionsNational Center for Child Health and DevelopmentTokyoJapan
  6. 6.Department of Immunology, Institute of Advanced MedicineWakayama Medical UniversityWakayamaJapan
  7. 7.Department of DermatologyWakayama Medical UniversityWakayamaJapan

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