Volume 29, Issue 166, December 2025

Phenotypic variability in von Hippel-Lindau disease, efficacy of therapy, and prognosis. A review of the literature

Żanna Gawrysz^1♦, Stanisław Derewjanko², Karolina Capar², Joanna Gaik², Julia Woźniak², Zofia Cholewa²

¹Department of Plastic and Burns Surgery, Multispecialty Hospital in Nowa Sól, ul. Chałubińskiego 7, 67-000 Nowa Sól, Poland
²Collegium Medicum of the University of Zielona Gora, ul. Zyty 28, 65-046 Zielona Góra, Poland

^♦Corresponding author
Department of Plastic and Burns Surgery, Multispecialty Hospital in Nowa Sól, ul. Chałubińskiego 7, 67-000 Nowa Sól, Poland

ABSTRACT

Von Hippel-Lindau disease is an inherited cancer predisposition that occurs due to an incorrect structure or a lack of the von Hippel-Lindau protein. Von Hippel-Lindau disease is known to have a noteworthy phenotypic variability and an elevated risk of developing tumors. A multitude of publications have demonstrated the correlation of the severity of a disease with a patient's genotype. Missense mutations in exon three are associated with one of the most severe outcomes, including the elevated risk of clear cell renal cell carcinoma and pancreatic neuroendocrine tumors. Deletions in exon one significantly raise the risk of developing pheochromocytomas. The review proved the importance of tailoring the therapeutic strategy to the genetic profile of the patient. Belzutifan shows high efficacy in treating patients with mutations in exon three. The development of gene therapy, which is currently in preclinical testing, could become a groundbreaking approach to treatment. Heterogeneity of VHL gene mutations leads to high phenotypic variability in the disease. It directly modulates the disease course, treatment efficacy, and prognosis. Early molecular diagnostics and personalized therapy based on the genetic profile are critical for improving patient care. Further studies and the improvement of modern therapeutic approaches, including gene therapy, are necessary.

Keywords: VHL, Hif pathway, hypoxia, genotype-phenotype correlation, treatment

Medical Science, 2025, 29, e229ms3682

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Published: 23 December 2025