Von Hippel-Lindau Disease

Von Hippel-Lindau (VHL) disease is an autosomal dominant tumour predisposition syndrome with an incidence of about 1 in 27,000 to 36,000, caused by loss of function of the VHL tumour suppressor gene (3p25.3). Inactivation of both alleles (germline mutation plus somatic second hit) stabilises hypoxia inducible factors (HIF-1 alpha and HIF-2 alpha), driving VEGF, PDGF and erythropoietin expression and angiogenic tumours. Penetrance is above 90% by age 65. About 20% are de novo.

VHL is divided clinically into:

• Type 1: low risk of pheochromocytoma (deletions and truncating variants)
• Type 2A: pheochromocytoma, haemangioblastoma, low risk of renal cell carcinoma
• Type 2B: pheochromocytoma, haemangioblastoma and renal cell carcinoma
• Type 2C: isolated pheochromocytoma

• Retinal haemangioblastomas (about 50 to 60%; from age 1 year or in teens, can cause retinal detachment, exudates and vision loss)
• Central nervous system haemangioblastomas (60 to 80%; cerebellum, brainstem, spinal cord; headache, ataxia, vomiting, hydrocephalus, myelopathy, syringomyelia)
• Renal cell carcinoma, clear cell type (24 to 45%; multifocal, bilateral, onset at about 37 years), and renal cysts
• Pheochromocytoma and paraganglioma (10 to 20%; hypertension, headaches, palpitations, sweating)
• Pancreatic lesions: serous cystadenomas, simple cysts, and pancreatic neuroendocrine tumours (about 10 to 15%)
• Endolymphatic sac tumours (about 10 to 15%; sudden or progressive sensorineural hearing loss, tinnitus, and vertigo)
• Epididymal and broad ligament cystadenomas, erythrocytosis from tumour erythropoietin (haemangioblastoma)

Clinical diagnosis if there is a family history plus one haemangioblastoma (retinal, cerebellar or spinal), renal cell carcinoma, or pheochromocytoma; in patients without a family history, two or more haemangioblastomas, or one haemangioblastoma plus a visceral tumour. Confirm by VHL gene sequencing and deletion or duplication analysis. Genetic testing of children at risk is advised by age 1 to 2 years. Surveillance protocol:

• From age 1 year: annual ophthalmoscopy (dilated)
• From age 5 years: annual plasma free metanephrines or 24-hour urinary fractionated metanephrines
• From age 11 to 15 years: audiology every 2 to 3 years, MRI brain and spine with contrast every 2 years
• From age 15 years (or 16 to 18 years): annual abdominal ultrasound and MRI of the abdomen every 1 to 2 years for renal, adrenal and pancreatic lesions

• Belzutifan (oral HIF-2 alpha inhibitor), 120 mg once daily: approved for VHL-associated renal cell carcinoma, CNS haemangioblastoma and pancreatic neuroendocrine tumours not requiring immediate surgery; objective response about 49% in renal cell carcinoma, 63% in CNS haemangioblastomas. Adverse effects: anaemia (frequent; monitor haemoglobin), hypoxia, and teratogenicity (contraception is mandatory, and it reduces efficacy of hormonal contraceptives).
• Renal cell carcinoma: nephron sparing surgery or ablation (radiofrequency, cryotherapy) when the largest tumour reaches 3 cm, to reduce metastatic risk and preserve renal function; avoid radical nephrectomy where possible; dialysis and transplantation for end stage disease.
• Haemangioblastomas: surgical resection or stereotactic radiosurgery for symptomatic or growing lesions; spinal tumours may need surgery with expert neurosurgery; vigilance for peritumoural cysts; avoid unnecessary operations on asymptomatic lesions.
• Retinal haemangioblastomas: laser photocoagulation or cryotherapy for peripheral lesions, photodynamic therapy, vitreoretinal surgery for tractional detachment, and anti-VEGF therapy has limited benefit.
• Pheochromocytoma: pre-operative alpha blockade (phenoxybenzamine 10 mg twice daily, increasing to 20 to 40 mg/day, or doxazosin) for 10 to 14 days, then beta blockade after alpha blockade, followed by adrenalectomy (cortical sparing in bilateral disease to avoid lifelong steroid dependence).
• Endolymphatic sac tumours: surgical resection to preserve hearing and prevent progression; cochlear implant for deafness.
• Pancreatic neuroendocrine tumours: resect when above 3 cm, growing quickly, or in exon 3 deletion patients.
• Genetic counselling and cascade testing of family members.