Clinical Guidance

Von Hippel-Lindau syndrome (VHL) is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and renal cell carcinoma; pheochromocytoma and paraganglioma; pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. Some clustering of tumors occurs, resulting in the designation of specific VHL phenotypes. The manifestations and severity are highly variable both within and between families, even among those with the same pathogenic variant. Hemangioblastomas. Central nervous system (CNS) hemangioblastoma is the prototypic lesion of VHL . Multiple CNS tumors, occurring either synchronously or metachronously, are common. Roughly 80% develop in the brain and 20% in the spinal cord.

Diagnostic Criteria

Clinical diagnostic criteria for von Hippel-Lindau syndrome (VHL) have been proposed and vary slightly between Dutch or Danish guidelines . Suggestive Findings VHL should be suspected in individuals with or without a family history of VHL who have: • Retinal angioma, especially in a young individual • Multiple spinal or cerebellar hemangioblastoma, or a single hemangioblastoma diagnosed at age ≤50 years • Adrenal or extra-adrenal pheochromocytoma • Renal cell carcinoma diagnosed at age ≤40 years • Multiple renal and pancreatic cysts • Multiple neuroendocrine tumors of the pancreas • Endolymphatic sac tumors • Less commonly, multiple papillary cystadenomas of the epididymis or broad ligament Establishing the Diagnosis The clinical diagnosis of VHL can be established in proband according to Danish or Dutch guidelines , or the molecular diagnosis can be established by identification of a heterozygous pathogenic (or likely pathogenic) variant in VHL on molecular genetic testing . Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making . Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous VHL variant of uncertain significance does not establish or rule out the diagnosis. Table 1. Von Hippel-Lindau Syndrome Clinical Diagnostic Criteria

Management Guidelines

The first von Hippel-Lindau syndrome (VHL) care pathway was recently published by a multidisciplinary team from the Netherlands .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with VHL, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Surveillance Guidelines

In the United States, the VHL Alliance has worked extensively with health care professionals to assemble guidelines that are generally accepted worldwide (see VHL Resources – Active Surveillance Guidelines). Additional guidelines originate from Denmark and the Netherlands . Individuals with VHL and first-degree relatives who have not undergone DNA-based testing need regular clinical surveillance by a physician or medical team familiar with VHL . Table 5. Von Hippel-Lindau Syndrome: Recommended Surveillance