Von Hippel–Lindau (VHL) syndrome is a familial cancer syndrome caused by mutations in VHL gene. It is characterized by the formation of benign and malignant tumors like retinal angioma, cerebellar hemangioblastoma, spinal hemangioblastoma, renal cell carcinoma, pheochromocytoma, pancreatic and renal cysts, and endolymphatic sac tumors. Germline mutations in VHL gene have also been reported in isolated VHL-associated tumors. VHL gene is a small gene with 3 coding exons and can be easily tested even in a resource constraint setting.
To describe clinical presentation and estimate the diagnostic yield of in VHL and VHL-associated tumors.
This is a descriptive study in a hospital setting. Here, we describe the clinical and molecular data of 69 patients with suspected VHL or having VHL-associated tumors. Sanger sequencing of coding sequences and conserved splice sites of VHL gene were done in all patients. Multiplex ligation-dependent probe amplification (MLPA) of VHL gene to detect large deletions/duplications was performed for 18 patients with no pathogenic sequence variations.
Among tumor types at presentation, pheochromocytoma was seen in 49% (34/69), hemangioblastoma was seen in 30% (21/69), and renal cell carcinoma was seen in 7% (5/69). Rest had other tumors like paraganglioma, endolymphatic sac papillary tumors, cerebellar astrocytoma and pancreatic cyst. Seven patients (10%) had more than one tumor at the time of diagnosis. Pathogenic variations in VHL gene were identified in 31probands by Sanger sequencing; 18 were missense, 2 nonsense and 2 small indels. A heterozygous deletion of exon 3 was detected by MLPA in one patient among 18 patients for whom MLPA was done. Overall, the molecular yield was 46% cases (32/69). Family history was present in 7 mutation positive cases (22%). Overall, 11 families (16%) opted for pre-symptomatic mutation testing in the family.
Mutation testing is indicated in VHL and VHL-associated tumors. The testing facility is easy and can be adopted easily in developing countries like India. The yield is good, and with fairly high incidence of familial cases, molecular testing can help in pre-symptomatic testing and surveillance.