Genotype-phenotype correlations in Chinese von Hippel-Lindau disease patients

Abstract

von Hippel–Lindau (VHL) disease is caused by mutations in the VHL gene and demonstrates marked phenotypic variability. Genotype-phenotype correlations in Chinese VHL patients have been unclear. To establish genotype-phenotype correlations in Chinese VHL patients, we collected VHL mutations and phenotypes of 291 patients with VHL disease from 115 unrelated families. Genotype-phenotype correlations at mutation type level, mutation region level, and mutation codon level were analyzed by Kaplan-Meier curves and Cox regression models. We found missense mutations conferred an increased risk of pheochromocytoma developments, but a decreased risk of central nervous system hemangioblastomas (CHBs) and pancreatic lesions. Patients with VHL deletions were more prone to developing retinal angiomas. Renal cell carcinomas were more frequent in nonsense, frameshift or splice-site mutations. Mutations in Exon 2 conferred a higher risk and earlier diagnostic age of CHBs than mutations in other exons (HR = 1.684, 95% CI 1.082–2.620, p = 0.021; 27.0 ± 9.7 years versus 32.8 ± 11.7 years, p = 0.024), while patients with mutations in Exon 3 were more prone to developing pheochromocytomas (HR = 2.760, 95% CI 1.419–5.370, p = 0.003). Mutations at codon 80 or codon167 conferred significantly higher risks of pheochromocytomas than other mutations (HR = 4.678, 95% CI 1.392–15.724, p = 0.013; HR = 4.683, 95% CI 2.515–8.719, p < 0.001 respectively). In conclusion, VHL mutation types, mutation regions and mutation codons can act as phenotypic predictors of VHL disease. Mutation regions and mutation codons may aid in directed surveillance and monitoring of VHL patients.

Genotype and phenotype correlation in von Hippel–Lindau disease based on alteration of the HIF-α binding site in VHL protein

“…CHB (62.2%) was the most common manifestation in the patients, followed by PCT (46.0%), RCC (43.6%), RA (21.2%), and PHEO (13.5%), similar to our previous report. 29…”

Repurposing propranolol as an antitumor agent in von Hippel-Lindau disease

“…formation for RCCs, HBs, and pancreatic neuroendocrine tumors is believed to result from inappropriate upregulation of hypoxia response elements. 8,25 Patients with VHL harbor a quantitative or qualitative deficiency of the VHL protein, which, under normoxic conditions, fosters the degradation of hypoxia-inducible factors (HIFs). 8,17,36 In susceptible tissues, loss of heterozygosity of the wild-type VHL allele leads to constitutive, inappropriate upregulation of HIFs that upregulate expression of a variety of genes, including erythropoietin, vascular endothelial growth factor (VEGF), and transforming growth factor-alpha, which are believed to play important roles in tumorgenesis.…”

Extent of surgery for phaeochromocytomas in the genomic era

“…In line with the in vitro observations, missense mutations are more common than deletions or other genetic changes that completely abolish pVHL function in phaeochromocytomas, but this is not a pathognomonic trait of predictive value for patients who already have developed one or more adrenal tumours, and in whom the possibility of recurrence cannot be excluded. As only relatively low malignancy rates (1·6–7·7 per cent) have been reported for VHL‐related chromaffin tumours, adrenal‐sparing surgery seems to be a safe option, and has been performed successfully in both adults and children with VHL.…”

“…The initial manifestations usually present in the third or fourth decade of life, and patients may suffer from severe disabilities such as blindness, hearing problems, and postsurgical complications of pancreatic or adrenal insufficiency. Around 15–30 per cent of patients with VHL develop phaeochromocytomas, of which 40–50 per cent are bilateral.…”