Department of Hematology, Kitano Hospital, 2-4-20, Ougimachi, Kita-ku, Osaka, Japan.
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Int J Hematol. 2022 Mar;115(3):428-434. doi: 10.1007/s12185-021-03251-2. Epub 2021 Oct 26.
Shwachman-Diamond syndrome (SDS) is an autosomal recessive inherited disorder characterized by bone marrow failure, exocrine pancreatic dysfunction, and skeletal abnormalities. SDS is typically caused by a pathogenic mutation in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. Patients with SDS have an increased risk of developing acute myeloid leukemia (AML) and myelodysplastic syndromes. We identified germline biallelic SBDS mutations (p.K62X and p.I167M) in a 50-year-old AML patient who had never experienced the typical symptoms of SDS. The K62X mutation is one of the most common pathogenic mutations, whereas the significance of the I167M mutation was unclear. Based on cellular experiments, we concluded that the I167M mutation contributed to the development of AML, and chemotherapy including topoisomerase inhibitors, which induce DNA double-strand breaks, may have been toxic to this patient. Our experience indicates that some asymptomatic Shwachman-Bodian-Diamond syndrome mutations contribute to the development of leukemia, and that careful treatment selection may be warranted for patients harboring these mutations.
Shwachman-Diamond 综合征（SDS）是一种常染色体隐性遗传性疾病，其特征为骨髓衰竭、外分泌胰腺功能障碍和骨骼异常。SDS 通常由 Shwachman-Bodian-Diamond 综合征（SBDS）基因的致病性突变引起。SDS 患者发生急性髓系白血病（AML）和骨髓增生异常综合征的风险增加。我们在一名 50 岁 AML 患者中鉴定出 SBDS 基因的胚系双等位基因突变（p.K62X 和 p.I167M），该患者从未出现 SDS 的典型症状。K62X 突变是最常见的致病性突变之一，而 I167M 突变的意义尚不清楚。基于细胞实验，我们得出结论，I167M 突变导致了 AML 的发生，包括拓扑异构酶抑制剂在内的化疗药物可能对该患者有毒性。我们的经验表明，一些无症状的 Shwachman-Bodian-Diamond 综合征突变有助于白血病的发生，对于携带这些突变的患者，可能需要谨慎选择治疗方法。
