Genotype-phenotype correlation in von Hippel-Lindau disease

Area of Science:

• Genetics
• Ophthalmology
• Oncology

Background:

• Von Hippel-Lindau (VHL) disease is a genetic disorder predisposing individuals to tumors, including retinal haemangioblastomas (RH), a major cause of visual impairment.
• Understanding genotype-phenotype correlations in VHL disease is crucial for effective management, treatment, and prognosis.

Purpose of the Study:

• To investigate the genotype-phenotype correlation in VHL disease, focusing on the impact of different VHL gene variants on the development and progression of haemangioblastomas and other associated neoplasms.
• To determine if specific VHL gene variants are associated with an earlier onset, higher incidence, or increased severity of clinical manifestations, particularly RH.

Main Methods:

• A retrospective, single-center cohort study involving 200 patients with VHL disease.
• Collection of genetic data and clinical information, including the onset and characteristics of RH, CNS haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC), and pancreatic neuroendocrine neoplasms (PNEN).

Main Results:

• A total of 42 distinct VHL gene variants were identified in 166 patients.
• Patients with truncating variants (TV) exhibited a significantly earlier age of onset and higher incidence of RH, CNSH, ccRCC, and PNEN compared to those with amino-acid substitution/deletion variants (AASD).
• Patients with TV had a higher number of RH per year and a shorter median disease-free survival time, increasing the risk of enucleation or phthisis.

Conclusions:

• Truncating variants in the VHL gene are associated with an earlier onset and increased risk of developing RH, CNSH, ccRCC, and PNEN.
• Patients with truncating variants experience a greater burden of RH and a higher risk of vision-threatening complications, necessitating more intensive ophthalmological monitoring.
• These findings underscore the importance of genetic profiling for personalized surveillance and management strategies in VHL disease.