Cases
Case 1 is a 10-year-old girl who was born to non-consanguineous healthy Japanese parents. As we previously reported, she had severe macrocytic anemia without reticulocytopenia (red blood cells [RBCs] 0.95 × 1012/L, hemoglobin level 43 g/L, mean corpuscular volume [MCV] 123 fL, reticulocytes 158 × 109/L, white blood cells [WBCs] 2.3 × 109/L, and platelets 396 × 109/L) from birth. Anemia did not improve with oral iron supplements or erythropoietin administration, and she had to undergo recurring RBC transfusions. The first bone marrow examination was performed when she was 6 months old, showing normal cellularity and marked dysplasia only in the erythroid lineage. G-banding karyotyping of the bone marrow aspirate showed a normal female karyotype (46, XX). She also developed chronic bloody diarrhea at the age of 2 months. Inflammatory bowel disease (IBD), unclassified type, was diagnosed based on endoscopic and pathological findings at the age of 8 months. She became corticosteroid dependent and required intravenous hyperalimentation to treat malnutrition. A follow-up bone marrow examination at the age of 17 months revealed hypercellularity and dysplasia of trilineage cells without excess blasts. However, bone marrow examination before HCT showed multilineage dysplasia and 7.5% blastic cells, reminiscent of progression to MDS with excess blast-1. As she remained transfusion dependent, HCT was performed at the age of 1 year and 10 months from an unrelated human leukocyte antigen (HLA)–matched donor (8/8 allele matched). She received myeloablative conditioning (MAC) composed of busulfan (1.2 mg/kg) four times daily on days −9 to −6 (total dose, 19.2 mg/kg) and cyclophosphamide (50 mg/kg) once daily from days −5 to −2 (total dose, 200 mg/kg). The infused bone marrow cells contained 3.0 × 106/kg of CD34-positive cells. Graft-versus-host disease (GVHD) prophylaxis was performed with tacrolimus and short-term methotrexate (15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, and +11). Engraftment was achieved on day +22 with full donor chimerism. She developed grade II acute skin GVHD on day +94 which resolved immediately after initiating corticosteroid treatment. However, she developed grade III gastrointestinal GVHD after discontinuing corticosteroid on day +140. The effect of reinitiated corticosteroid was insufficient, and infliximab was added. Her bloody stool and diarrhea gradually resolved, and corticosteroid was stopped approximately 1 year and 4 months after developing gastrointestinal GVHD. Infliximab was discontinued 3 years after discontinuing corticosteroid. Approximately ten years have passed since HCT, and she is doing well without active complications or transfusion demand and all her immunosuppressants have been discontinued. However, due to prolonged tube feeding associated with inflammation of the gastrointestinal tract, she is unable to ingest orally. After HCT, a novel compound heterozygous variant in POLE(p.[D1131fs];[T1891del]) was found by genetic analysis using her dermal fibroblasts.
Case 2 is a 3-year-old girl, a younger sister of Case 1. She also had severe macrocytic anemia without reticulocytopenia (RBCs 1.71 × 1012/L, hemoglobin level 54 g/L, MCV 117 fL, reticulocytes 30 × 109/L, WBCs 12.8 × 109/L, and platelets 306 × 109/L) from birth and became transfusion-dependent. Genetic analysis of her peripheral blood cells revealed the same variant of POLE as in Case 1. Bone marrow findings at 3 months of age were similar to those in Case 1, with dysplasia only in the erythroid without hypoplasia. Dysplasia of all three lineages was seen at 13 months of age (G-banding karyotyping showed a normal female karyotype (46, XX), with 8% blastic cells. These findings indicated MDS with excess blast-1. However, blastic cells decreased to 4.2% at 16 months of age. Unlike Case 1 she did not develop IBD. She remained transfusion dependent and there were fluctuations in the proportion of blasts. HCT was performed at the age of 1 year and 5 months from an unrelated HLA one allele mis-matched donor. She received conditioning composed of fludarabine (25 mg/m2) on days −8 to −4 (total dose, 125 mg/m2), melphalan (90 mg/m2) once daily from days −4 to −3 (total dose, 180 mg/ m2), anti-thymocyte globulin (2.5 mg/kg) once daily from days −7 to −6 (total dose, 5.0 mg/kg) and total body irradiation of 3 Gray on day 0. The infused bone marrow cells contained 6.3 × 106/kg of CD34-positive cells. GVHD prophylaxis was the same as in Case 1. Engraftment was achieved on day +16 with full donor chimerism. She developed grade III acute gastrointestinal GVHD on day +24 and was treated with immunosuppressive agents including corticosteroid, mycophenolate mofetil, and additional methotrexate. However, her symptoms were refractory and required addition of mesenchymal stem cell therapy. Meanwhile, pathological findings of her gastrointestinal biopsy revealed intestinal thrombotic microangiopathy and recombinant human soluble thrombomodulin was also administered. Her gastrointestinal symptoms gradually resolved, and each treatment was able to be tapered off without recurrence. Two years have passed since HCT, and she is doing well without active complications or transfusion demand and all her immunosuppressants have been discontinued.