BACKGROUND von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL mutations include deletion, frameshift, nonsense and missense mutations. Synonymous mutations are expected to be phenotypically silent and their role in VHL disease remains poorly understood. CASE PRESENTATION We report a Caucasian male with a family history of pheochromocytoma and the synonymous VHL mutation c.414A > G (p.Pro138Pro). At 47-years, MRI revealed pheochromocytoma in the left adrenal gland and hemangioblastomas in the spine and brain. Pheochromocytoma was treated by adrenalectomy. Radiotherapy, followed by craniotomy and resection were needed to reduce hemangioblastomas to residual lesions. Two of three of the proband's children inherited the mutation and both presented with retinal hemangioblastomas without pheochromocytoma at age 7: one twin needed four laser treatments. Primary skin fibroblasts carrying the heterozygous mutation or wild type VHL were established from the family. Mutant fibroblasts downregulated full-length VHL mRNA and protein, and upregulated the short VHL mRNA isoform (a result of exon 2 skipping in splicing) at the mRNA level but not at the protein level. CONCLUSIONS Our study shows that the synonymous VHL mutation c.414A > G can within 7 years induce pediatric retinal hemangioblastoma in absence of pheochromocytoma. This highlights the need to include splicing-altering synonymous mutations into the screening for VHL disease. This is also the first report on detecting and validating a synonymous VHL mutation using patient-derived fibroblasts. The mutation c.414A > G translates to p.Pro138Pro, yet it is not functionally silent, because it causes aberrant splicing by skipping exon 2. The reduced but not completely abolished pVHL protein in a loss-of-heterozygosity genetic backdrop may underlie the etiology of VHL disease.

中文翻译：

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病例报告：同义的VHL突变（c.414A> G，p.Pro138Pro）通过剪接失调导致致病性家族性血管母细胞瘤。

背景技术von Hippel-Lindau（VHL）病是由VHL的种系突变导致的家族性瘤形成综合征。致病性VHL突变包括缺失，移码，无义和错义突变。预期同义突变在表型上是沉默的，其在VHL疾病中的作用仍知之甚少。病例介绍我们报道了一位白人，其具有嗜铬细胞瘤家族史，并具有同义的VHL突变c.414A> G（p.Pro138Pro）。在47岁时，MRI显示左肾上腺有嗜铬细胞瘤，而脊柱和大脑则有血管母细胞瘤。嗜铬细胞瘤通过肾上腺切除术治疗。需要放疗，然后进行开颅手术和切除术，以减少成血管母细胞瘤残留的病变。先证者中的三分之二' 的孩子们继承了这种突变，并且都出现了7岁时无嗜铬细胞瘤的视网膜血管母细胞瘤：一对双胞胎需要进行四次激光治疗。从该家庭建立了携带杂合突变或野生型VHL的原代皮肤成纤维细胞。突变的成纤维细胞在mRNA水平而非蛋白水平下调了全长VHL mRNA和蛋白质，并上调了短VHL mRNA同工型（外显子2剪接的结果）。结论我们的研究表明，在没有嗜铬细胞瘤的情况下，同义VHL突变c.414A> G可以在7年内诱导小儿视网膜血管母细胞瘤。这突出显示了在VHL疾病筛查中需要包括改变剪接的同义突变。这也是有关使用患者来源的成纤维细胞检测和验证同义VHL突变的第一份报告。突变c.414A> G可以翻译为p.Pro138Pro，但它在功能上不是沉默的，因为它会跳过第2外显子而引起异常剪接。杂合性丧失遗传背景中的pVHL蛋白减少但未完全消除，可能是其背后的原因。 VHL病的病因。