Clinical characteristics: Von Hippel-Lindau syndrome (VHL) is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma and paraganglioma; pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cystadenomas. Retinal hemangioblastomas may be the initial manifestation of VHL and can cause vision loss. Cerebellar hemangioblastomas may be associated with headache, vomiting, gait disturbances, or ataxia. Spinal hemangioblastomas and related syrinx usually present with pain. Sensory and motor loss may develop with cord compression. Renal cell carcinoma occurs in about 70% of individuals with VHL and is the leading cause of mortality. Pheochromocytomas can be asymptomatic but may cause sustained or episodic hypertension. Pancreatic lesions often remain asymptomatic and rarely cause endocrine or exocrine insufficiency. Endolymphatic sac tumors can cause hearing loss of varying severity, which can be a presenting symptom. Cystadenomas of the epididymis are relatively common. They rarely cause problems, unless bilateral, in which case they may result in infertility.

Diagnosis/testing: The diagnosis of VHL is established in a proband who fulfills existing diagnostic clinical criteria. Identification of a heterozygous germline VHL pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Management: Targeted therapies: Pazopanib is an FDA-approved treatment for advanced renal cell carcinoma. Belzutifan is approved in many countries for the treatment of adults with VHL who do not require immediate surgery for associated renal cell carcinoma, central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors.

Supportive care: Surgical resection for most CNS hemangioblastomas; early treatment for retinal hemangioblastomas; cryoablation or radiofrequency ablation for renal cell carcinoma; kidney transplantation following bilateral nephrectomy; removal of pheochromocytomas (partial adrenalectomy when possible); consider removal of pancreatic neuroendocrine tumors; consider surgical removal of endolymphatic sac tumors (particularly small tumors in order to preserve hearing and vestibular function); cystadenomas of the epididymis or broad ligament need treatment when symptomatic or threatening fertility; psychosocial support and care coordination as needed.

Surveillance: For individuals with VHL and at-risk relatives of unknown genetic status: annual clinical evaluation for neurologic symptoms, vision problems, and hearing disturbances beginning in the first decade of life; brain and total spine MRI every two years starting at age 11 years; ophthalmology evaluation beginning at age one year; abdominal MRI every two years starting at age 15 years; annual blood pressure starting in the first decade of life; annual plasma or 24-hour urine for fractionated metanephrines starting at age five years; audiology assessment every two to three years starting at age 11 years; MRI of the internal auditory canal in asymptomatic individuals between age 15 and 20 years; assessment of psychosocial needs at each visit.

Agents/circumstances to avoid: Tobacco products should be avoided, as they are considered a risk factor for kidney cancer; chemicals and industrial toxins known to affect VHL-involved organs should be avoided; contact sports should be avoided if adrenal or pancreatic lesions are present.

Evaluation of relatives at risk: If the pathogenic variant in a family is known, molecular genetic testing can be used to clarify the genetic status of at-risk family members to eliminate the need for surveillance of family members who have not inherited the pathogenic variant.

Pregnancy management: Intensified surveillance for cerebellar hemangioblastoma and pheochromocytoma prior to conception and during pregnancy; MRI without contrast of the cerebellum at four months' gestation.

Genetic counseling: VHL is inherited in an autosomal dominant manner. Approximately 80% of individuals with VHL have an affected parent and about 20% have VHL as the result of a pathogenic variant that occurred as a de novo event in the affected individual or as a postzygotic de novo event in a mosaic, apparently unaffected parent. The offspring of an individual with VHL are at a 50% risk of inheriting the VHL pathogenic variant. Once the VHL pathogenic variant has been identified in an affected family member, testing of at-risk asymptomatic family members, prenatal testing, and preimplantation genetic testing for VHL are possible.