Fanconi anemia (FA) is a DNA repair disorder resulting from mutations in genes encoding for FA DNA repair complex components and is characterized by variable congenital abnormalities, bone marrow failure (BMF), and high incidences of malignancies. FA mosaicism arises from reversion or other compensatory mutations in hematopoietic cells and may be associated with BMF reversal and decreased blood cell sensitivity to DNA-damaging agents (clastogens); this sensitivity is a phenotypic and diagnostic hallmark of FA. Uncertainty regarding the clinical significance of FA mosaicism persists; in some cases, patients have survived multiple decades without BMF or hematologic malignancy, and in others hematologic failure occurred despite the presence of clastogen-resistant cell populations. Assessment of mosaicism is further complicated because clinical evaluation is frequently based on clastogen resistance in lymphocytes, which may arise from reversion events both in lymphoid-specific lineages and in more pluripotent hematopoietic stem/progenitor cells (HSPCs). In this review, we describe diagnostic methods and outcomes in published mosaicism series, including the substantial intervals (1-6 years) over which blood counts normalized, and the relatively favorable clinical course in cases where clastogen resistance was demonstrated in bone marrow progenitors. We also analyzed published FA mosaic cases with emphasis on long-term clinical outcomes when blood count normalization was identified. Blood count normalization in FA mosaicism likely arises from reversion events in long-term primitive HSPCs and is associated with low incidences of BMF or hematologic malignancy. These observations have ramifications for current investigational therapeutic programs in FA intended to enable gene correction in long-term repopulating HSPCs.

中文翻译：

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范可尼贫血中的镶嵌现象：对已发表病例的简要回顾和评估，重点关注血细胞计数正常化的临床过程。


范可尼贫血 (FA) 是一种 DNA 修复障碍，由编码 FA DNA 修复复合体成分的基因突变引起，其特点是可变的先天性异常、骨髓衰竭 (BMF) 和高发病率的恶性肿瘤。 FA 嵌合现象由造血细胞的逆转或其他补偿性突变引起，可能与 BMF 逆转和血细胞对 DNA 损伤剂（断裂剂）敏感性降低有关；这种敏感性是 FA 的表型和诊断标志。 FA 嵌合体的临床意义仍然存在不确定性；在某些情况下，患者可以存活数十年而没有出现 BMF 或血液恶性肿瘤，而在其他情况下，尽管存在断裂剂抗性细胞群，但仍发生了血液学衰竭。嵌合体的评估更加复杂，因为临床评估通常基于淋巴细胞中的断裂剂抗性，这可能是由淋巴特异性谱系和多能造血干/祖细胞（HSPC）中的逆转事件引起的。在这篇综述中，我们描述了已发表的嵌合体系列中的诊断方法和结果，包括血细胞计数正常化的相当长的时间间隔（1-6年），以及在骨髓祖细胞中证明断裂剂耐药性的情况下相对有利的临床过程。我们还分析了已发表的 FA 镶嵌病例，重点关注确定血细胞计数正常化后的长期临床结果。 FA 嵌合体中的血细胞计数正常化可能是由长期原始 HSPC 的逆转事件引起的，并且与 BMF 或血液恶性肿瘤的低发生率相关。 这些观察结果对 FA 中当前的研究性治疗计划产生了影响，该计划旨在实现长期重新增殖 HSPC 中的基因校正。