# Mosaic Form of von Hippel–Lindau Syndrome: Case Report and Literature Review

## TL;DR

This paper reports a rare case of mosaic von Hippel–Lindau syndrome and reviews literature on its diagnosis and management.

## Contribution

The study presents a novel case of mosaic VHLS diagnosed using advanced genetic methods and summarizes insights for managing similar cases.

## Key findings

- A mosaic form of VHLS was identified with a 2% mutant allele proportion in blood DNA.
- NGS with high coverage was effective in detecting low-level mosaicism in VHLS.
- Literature review highlights clinical severity and diagnostic challenges of mosaic VHLS.

## Abstract

von Hippel–Lindau syndrome (VHLS) is a hereditary cancer syndrome with CNS hemangioblastomas, clear cell renal carcinoma, pheochromocytoma, retinal angiomas, and a number of other manifestations. VHLS is caused by a mutation in the VHL gene and is inherited in an autosomal dominant manner. However, some cases of VHLS develop de novo, and among them, there are rare patients with a mosaic form of the disease. Genetic testing in mosaic patients is prone to false-negative results due to the low copy number of a mutant allele in DNA isolated from the blood. We describe a case of molecular genetic diagnostics of VHLS in a 39-year-old patient using various methods, including mutation analysis in asynchronous primary tumors and repeated DNA analysis from blood using NGS with high coverage for the mutant position. As a result, the patient was diagnosed with a mosaic form of VHLS caused by the variant c.481C>T (p.Arg161Ter), the proportion of which in the blood DNA was 2%. We also summarized the literature data on the mosaic form of VHLS: the severity of clinical manifestations, the features of differential diagnostics of VHLS with a negative result of routine molecular genetic VHL testing, and specific options of active surveillance and treatment for mutation carriers.