DNA polymerase epsilon (POLE) plays a critical role in DNA replication, DNA damage repair, and cell cycle regulation. POLE2, a subunit of this enzyme complex, is associated with an extremely rare deficiency characterized by facial dysmorphism, combined immunodeficiency, and autoimmune disease. To date, only a single case has been reported by Frugoni et al (1). There are no previous reports of hematopoietic stem cell transplantation (HSCT) for POLE2 deficiency. We report the case of an 18-month-old female with POLE2 deficiency who developed a hepatocellular malignant neoplasm (HMN) following HSCT from an HLA-matched sibling donor.
The patient presented with recurrent respiratory infections and was referred to our hospital due to pancytopenia. Clinical evaluation revealed decreased counts of CD8+ T cells and CD56+ cells, diminished natural killer (NK) cell activity, and low T cell receptor excision circle (TREC) levels. Given a family history of fatal immunodeficiency in her older sister, genetic analysis was performed, confirming POLE2 deficiency in both siblings. While both parents carried a monoallelic HLA deletion, the younger sister was wild type and was selected as the donor. Neutrophil engraftment was achieved on day 20 post-transplantation. Although the patient developed stage 4 acute gastrointestinal graft-versus-host disease (GVHD) on day 35, it was successfully managed without secondary infectious complications. After HSCT, CD3+, CD8+, and CD56+ cell counts recovered and NK cell activity normalized, whereas recovery of CD19+ cells remained absent. At 25 months after HSCT, the patient was diagnosed with HMN.
POLE is increasingly recognized for its role in genomic stability, and its mutations are frequently linked to an elevated risk of malignancies, particularly colorectal cancer. In this case, the POLE2 mutation likely contributed to post-transplantation oncogenesis. Since POLE-mutated tumors often exhibit a high tumor mutational burden (TMB), which suggests potential efficacy of immune checkpoint inhibitors, we intended to perform comprehensive cancer genomic profiling to evaluate the TMB in this patient. These findings may inform future therapeutic strategies.
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