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Update on Pathogenesis and Systemic Aspects

Aronow, Mary E. MD*; Wiley, Henry E. MD; Gaudric, Alain MD; Krivosic, Valerie MD; Gorin, Michael B. MD, PhD§; Shields, Carol L. MD; Shields, Jerry A. MD; Jonasch, Eric W. MD**; Singh, Arun D. MD††; Chew, Emily Y. MD

doi: 10.1097/IAE.0000000000002555

Purpose: To provide an update summarizing the biologic pathways governing von Hippel–Lindau (VHL) disease pathogenesis and to provide an overview of systemic manifestations as well as screening recommendations.

Methods: A PubMed search of the English language literature was reviewed using the following search terms: von Hippel–Lindau, von Hippel–Lindau disease, and VHL. Of 6,696 publications, the most current and pertinent information related to the pathogenesis and systemic aspects of VHL disease were included in this review.

Results: von Hippel–Lindau disease is one of the most frequently occurring multisystem familial cancer syndromes. The disease results from germline mutation in the VHL tumor suppressor gene on the short arm of chromosome 3. Mutation in the VHL gene affects multiple cellular processes including transcriptional regulation, extracellular matrix formation, apoptosis, and, in particular, the cellular adaptive response to hypoxia. As a result, there is widespread development of vascular tumors affecting the retina, brain, and spine, as well as a spectrum of benign and malignant tumors and/or cysts in visceral organs.

Conclusion: The ophthalmologist plays a key role in VHL disease diagnosis, as retinal hemangioblastoma is frequently the first disease manifestation. Screening guidelines for individuals with known VHL disease, and those at risk of VHL disease, help to ensure early detection of potentially vision-threatening and life-threatening disease.

This update summarizes the biologic pathways governing von Hippel–Lindau disease pathogenesis and provides an overview of systemic manifestations as well as screening recommendations.

*Retina Service, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts;

National Eye Institute, National Institutes of Health, Bethesda, Maryland;

Department of Ophthalmology, Hôpital Lariboisière, AP-HP, Université Paris 7, Sorbonne Paris Cité, Paris, France;

§Jules Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, California;

Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania;

**Department of Genitourinary Medical Oncology, University of Texas Maryland Anderson Cancer Center, Houston, Texas; and

††Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.

Reprint requests: Mary E. Aronow, MD, 243 Charles Street, Boston, MA 02114; e-mail:

A. Gaudric: BAYER: reimbursement of Congress fees and travel. NOVARTIS: reimbursement of Congress fees and travel, honoraria for an educational web site. THROMBOGENICS: honoraria for participation to a data monitoring committee. M. B. Gorin: Funding from the VHL Alliance, Harold and Pauline Price Foundation, and Research to Prevent Blindness.

None of the authors has any financial/conflicting interests to disclose.

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© 2019 by Ophthalmic Communications Society, Inc.