International Journal of Hematology

DOI: 10.1007/s12185-019-02595-0 Pages: 744-750

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

1. Wakayama Medical University, Department of Hematology/Oncology

2. Wakayama Medical University, Department of Diagnostic Pathology

3. Nagasaki University, Department of Human Genetics, Atomic Bomb Disease Institute

4. Kurume University School of Medicine, Department of Pathology

5. National Center for Child Health and Development, Department of Advanced Medicine for Infections

6. Wakayama Medical University, Department of Immunology, Institute of Advanced Medicine

7. Wakayama Medical University, Department of Dermatology

Correspondence to:
Shinobu Tamura
Tel: +81-73-441-0665



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.

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