Abstract
Backgroundvon 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 presentationWe 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.ConclusionsOur 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.
Highlights
Background von HippelLindau (VHL) disease is a rare autosomal dominant neoplasia syndrome affecting 1 in 36,000 births
Our study shows that the synonymous von Hippel-Lindau (VHL) mutation c.414A > G can within 7 years induce pediatric retinal hemangioblastoma in absence of pheochromocytoma
The mutation c.414A > G translates to p.Pro138Pro, yet it is not functionally silent, because it causes aberrant splicing by skipping exon 2
Summary
Background von HippelLindau (VHL) disease is a rare autosomal dominant neoplasia syndrome affecting 1 in 36,000 births. Affected individuals have significantly heightened chance of developing lesions in the central nervous system (CNS) including hemangioblastoma (HGB) of cerebellum, spinal cord, brainstem and retina, as well as visceral tumors such as pheochromocytoma (PHEO), renal cell carcinoma (RCC), and pancreatic neuroendocrine tumors [1, 4, 5]. VHL disease has a characteristic genotype-phenotype correlation: Type 1 has a very low risk of PHEO and is most commonly caused by VHL exon deletion, truncation, frameshift and nonsense mutations; Type 2 has a higher risk of PHEO and is characterized by VHL missense mutations [1, 2, 5]. Type 2 is further categorized into 2A (low risk of RCC), 2B (high risk of RCC), and 2C (only PHEO) [1, 2, 5]. VHLassociated tumors frequently lose the function of the remaining wild-type VHL allele in the process called loss of heterozygosity (LOH) [1, 2]
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