Clinical characteristics: Von Hippel-Lindau (VHL) syndrome is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma, pancreatic cysts, and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. 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. Retinal hemangioblastomas may be the initial manifestation of VHL syndrome and can cause vision loss. 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: Treatment of manifestations: Intervention for most CNS lesions (remove brain and spinal lesions completely when large and/or symptomatic); treat retinal (but not optic nerve) angiomas prospectively; early surgery (nephron-sparing or partial nephrectomy when possible) for renal cell carcinoma; renal transplantation following bilateral nephrectomy; remove pheochromocytomas (partial adrenalectomy when possible); monitor pancreatic cysts and neuroendocrine tumors and consider removal of 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.
Prevention of secondary complications: Early detection and removal of tumors to prevent/minimize secondary deficits such as hearing loss, vision loss, neurologic symptoms, and the need for renal replacement therapy.
Surveillance: For individuals with VHL syndrome, those with a VHL pathogenic variant, and at-risk relatives of unknown genetic status:
Starting at age one year: Annual evaluation for neurologic symptoms, vision problems, and hearing disturbance; annual blood pressure monitoring; annual ophthalmology evaluation.
Starting at age five years: Annual plasma or 24-hour urine for fractionated metanephrines; audiology assessment every two to three years; thin-slice MRI with contrast of the internal auditory canal in those with repeat ear infections.
Starting at age 16 years: Annual abdominal ultrasound; MRI scan of the abdomen and MRI of the brain and total spine every two years.
Agents/circumstances to avoid: Tobacco products should be avoided since 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 during preconception and pregnancy; MRI without contrast of the cerebellum at four months' gestation.
Genetic counseling: VHL syndrome is inherited in an autosomal dominant manner. Approximately 80% of individuals with VHL syndrome have an affected parent and about 20% have VHL syndrome as the result of a de novo pathogenic variant. Parental mosaicism has been described; the incidence is not known. The offspring of an individual with VHL syndrome are at a 50% risk of inheriting the VHL pathogenic variant. Prenatal testing for a pregnancy at risk is possible if the pathogenic variant has been identified in a family member.
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