Genotype-Phenotype Heterogeneity in Von Hippel-Lindau Disease: A Single-Center Multidisciplinary Study

Introduction: Von Hippel-Lindau (VHL) disease is an autosomal dominant familial cancer syndrome caused by germline mutations in the VHL tumor suppressor gene, leading to various neoplasms including hemangioblastomas, renal cell carcinoma (RCC), and pheochromocytomas. This study evaluates the clinical, radiological, and genetic profiles of two unrelated families: family A, in whom genotype–phenotype correlations were systematically analyzed, and family B, characterized by a novel de novo pathogenic variant. Methods Patients suspected of VHL were analyzed using exome sequencing and targeted family testing. Variants were interpreted according to ACMG/AMP 2015 guidelines and interpreted in line with the ClinGen recommendations for the VHL gene. Clinical follow-ups included multidisciplinary evaluations including detailed ophthalmologic screenings. Results The study primarily focuses on Family A, where 21 members carry the c.499C > T (p.Arg167Trp) variant. This variant revealed remarkable phenotypic heterogeneity, as family members presented with clinical manifestations consistent with multiple VHL subtypes across the established disease spectrum. In reported cases in the literature, pheochromocytoma is the most frequent manifestation (72%), whereas RCC is the least common (4.5%). In Family B, the study identified a novel frameshift mutation, c.449_462dup (p.Val155IlefsTer9), which has not been previously reported. Notably, this patient also carried a pathogenic BRCA2 variant, representing a rare case of Multilocus Inherited Neoplasia Allele Syndrome (MINAS). Furthermore, the administration of belzutifan, a HIF-2α inhibitor, showed promising results in stabilizing renal cystic lesions in the Family B proband. Conclusion Our findings highlight that even identical mutations, such as c.499C > T, can result in a wide spectrum of clinical outcomes, likely due to genetic, epigenetic, or environmental modifiers. The identification of novel variants and MINAS cases emphasizes the need for comprehensive genetic screening. Lifelong, multidisciplinary surveillance remains critical for the early detection and management of VHL-associated lesions to prevent morbidity.