von Hippel-Lindau 病的基因型-表型相关性。

Genotype-phenotype correlation in von Hippel-Lindau disease.

机构信息

Eye Centre, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Institute of Human Genetics, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

出版信息

Acta Ophthalmol. 2021 Dec;99(8):e1492-e1500. doi: 10.1111/aos.14843. Epub 2021 Mar 15.

DOI:10.1111/aos.14843

PMID:33720516

Abstract

BACKGROUND/AIMS: Retinal haemangioblastomas (RH) remain a major cause of visual impairment in patients with von Hippel-Lindau (VHL) disease. Identification of genotype-phenotype correlation is an important prerequisite for better management, treatment and prognosis.

METHODS

Retrospective, single-centre cohort study of 200 VHL patients. Genetic data and date of onset of RH, central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected. The number and locations of RH were recorded.

RESULTS

The first clinical finding occurred at an age of 26 ± 14 years (y) [mean ± SD]. In 91 ± 3% (95% CI 88-94) of the patients, at least one RH occur until the age of 60y. A total of 42 different rare VHL gene variants in 166 patients were detected. A higher age-related incidence of RH, CNSH, ccRCC and PNEN was detected in patients with a truncating variant (TV) compared to patients with a single amino-acid substitution/deletion (AASD) (all p < 0.01), while it is reverse for PPGL (p < 0.01). Patients with a TV showed 0.10 ± 0.15 RH per y during their lifetime compared to 0.05 ± 0.07 in patients with AASD (p < 0.02). The median enucleation/phthisis-free survival time in patients with a TV was 56y (95% CI 50-62) compared to 78y (95% CI 75-81) in patients with AASD (p < 0.02).

CONCLUSION

Compared to patients with AASD, patients with a TV develop RH, CNSH, ccRCC and PNEN earlier. They experience a higher number of RH and bear a higher risk of enucleation/phthisis. Thus, patients with a TV might be considered for a more intensive ophthalmological monitoring.

摘要

背景/目的：视网膜血管母细胞瘤（RH）仍然是 von Hippel-Lindau（VHL）病患者视力损害的主要原因。确定基因型-表型相关性是更好地管理、治疗和预测预后的重要前提。

方法

对 200 例 VHL 患者进行回顾性单中心队列研究。收集了遗传数据和 RH、中枢神经系统血管母细胞瘤（CNSH）、嗜铬细胞瘤/副神经节瘤（PPGL）、透明细胞肾细胞癌（ccRCC）和胰腺神经内分泌肿瘤（PNEN）的发病时间。记录 RH 的数量和位置。

结果

首次临床发现发生在 26±14 岁（y）[均值±标准差]。在 91±3%（95%置信区间 88-94）的患者中，至少有一个 RH 会在 60 岁之前出现。在 166 名患者中检测到 42 种不同的罕见 VHL 基因突变，其中包括 166 名患者。与单氨基酸替换/缺失（AASD）患者相比，截短变异（TV）患者的 RH、CNSH、ccRCC 和 PNEN 的发病年龄更高（均 p<0.01），而 PPGL 则相反（p<0.01）。与 AASD 患者相比，TV 患者在其一生中每 0.10±0.15 个 RH（p<0.02），而 AASD 患者为 0.05±0.07 个 RH。TV 患者的眼球摘除/眼球痨无进展生存率中位数为 56 年（95%置信区间 50-62），而 AASD 患者为 78 年（95%置信区间 75-81）（p<0.02）。