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Comparative Study
. 2021 Dec;99(8):e1492-e1500.
doi: 10.1111/aos.14843. Epub 2021 Mar 15.

Genotype-phenotype correlation in von Hippel-Lindau disease

Michael Reich  1 , Sabine Jaegle  2 , Elke Neumann-Haefelin  3 , Jan-Helge Klingler  4 , Charlotte Evers  1 , Moritz Daniel  1 , Felicitas Bucher  1 , Franziska Ludwig  1 , Simone Nuessle  1 , Julia Kopp  2 , Daniel Boehringer  1 , Thomas Reinhard  1 , Wolf A Lagrèze  1 , Clemens Lange  1 , Hansjuergen Agostini  1 , Stefan J Lang  1
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Free article
Comparative Study

Genotype-phenotype correlation in von Hippel-Lindau disease

Michael Reich et al. Acta Ophthalmol. 2021 Dec.
Free article

Abstract

Background/aims: Retinal haemangioblastomas (RH) remain a major cause of visual impairment in patients with von Hippel-Lindau (VHL) disease. Identification of genotype-phenotype correlation is an important prerequisite for better management, treatment and prognosis.

Methods: Retrospective, single-centre cohort study of 200 VHL patients. Genetic data and date of onset of RH, central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected. The number and locations of RH were recorded.

Results: The first clinical finding occurred at an age of 26 ± 14 years (y) [mean ± SD]. In 91 ± 3% (95% CI 88-94) of the patients, at least one RH occur until the age of 60y. A total of 42 different rare VHL gene variants in 166 patients were detected. A higher age-related incidence of RH, CNSH, ccRCC and PNEN was detected in patients with a truncating variant (TV) compared to patients with a single amino-acid substitution/deletion (AASD) (all p < 0.01), while it is reverse for PPGL (p < 0.01). Patients with a TV showed 0.10 ± 0.15 RH per y during their lifetime compared to 0.05 ± 0.07 in patients with AASD (p < 0.02). The median enucleation/phthisis-free survival time in patients with a TV was 56y (95% CI 50-62) compared to 78y (95% CI 75-81) in patients with AASD (p < 0.02).

Conclusion: Compared to patients with AASD, patients with a TV develop RH, CNSH, ccRCC and PNEN earlier. They experience a higher number of RH and bear a higher risk of enucleation/phthisis. Thus, patients with a TV might be considered for a more intensive ophthalmological monitoring.

Keywords: VHL; genotype -phenotype correlation; haemangioblastoma; retina; von Hippel-Lindau disease.

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References

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