Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD; and.
Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.
Blood Adv. 2018 Jun 12;2(11):1243-1249. doi: 10.1182/bloodadvances.2018016964.
Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome and the prototypic telomere biology disorder (TBD). Leukocyte telomere length (TL) less than the first percentile for age, measured by flow cytometry with in situ hybridization (flow FISH), is diagnostic of DC. Androgens are a therapeutic option for DC/TBD-associated bone marrow failure (BMF). One report has shown an apparent increase in TL in patients while on treatment with the attenuated androgen danazol. The aim of this study was to compare TL over time in 10 androgen-treated and 16 untreated patients with DC. All subjects were enrolled in institutional review board-approved longitudinal cohort studies of inherited BMF. TL in 6-panel leukocyte subsets was measured by flow FISH. Generalized estimating equations (GEE) methodology was used to compare TL changes over time between groups. Unadjusted analyses showed annual median total lymphocyte TL attrition of -62 base pairs/year (bp/y) in androgen-treated patients with DC compared with -76 bp/y in untreated DC patients ( = .71). Longitudinal analysis using a GEE model, adjusted for age at sample collection, showed no statistically significant difference in TL change over time between treated and untreated patients ( = .24). The results were similar for each individual leukocyte subset evaluated. In summary, our data show the expected age-associated longitudinal telomere shortening in patients with DC, irrespective of androgen therapy. Caution is warranted when recommending androgen therapy for non-BMF manifestations of DC or TBDs until the biological mechanisms are better understood.
先天性角化不良症（DC）是一种遗传性骨髓衰竭综合征，也是典型的端粒生物学紊乱（TBD）。通过流式细胞术原位杂交（流式荧光原位杂交，flow FISH）测量，白细胞端粒长度（TL）低于年龄的第一百分位数可诊断为 DC。雄激素是治疗与 DC/TBD 相关的骨髓衰竭（BMF）的一种选择。有一份报告显示，在接受雄激素衰减剂达那唑治疗的患者中，TL 似乎有明显增加。本研究旨在比较 10 例雄激素治疗和 16 例未治疗的 DC 患者的 TL 随时间的变化。所有患者均参加了机构审查委员会批准的遗传性 BMF 纵向队列研究。通过流式荧光原位杂交法测量 6 个白细胞亚群的 TL。使用广义估计方程（GEE）方法比较两组之间随时间的 TL 变化。未调整分析显示，接受雄激素治疗的 DC 患者的总淋巴细胞 TL 每年平均损失 -62 个碱基对/年（bp/y），而未接受雄激素治疗的 DC 患者为 -76 bp/y（ =.71）。使用 GEE 模型进行纵向分析，调整样本采集时的年龄，治疗和未治疗患者的 TL 随时间的变化无统计学差异（ =.24）。评估的每个白细胞亚群的结果均相似。总之，无论是否接受雄激素治疗，我们的数据均显示 DC 患者的预期与年龄相关的纵向端粒缩短。在更好地了解生物学机制之前，对于非 BMF 表现的 DC 或 TBD 推荐雄激素治疗时应谨慎。
