vhl

VHL, or Von Hippel-Lindau disease, is a rare hereditary disorder characterized by the development of multiple tumors and cysts in various organs. The disease results from inactivating germline mutations in the VHL tumor suppressor gene on chromosome 3p25-26. The VHL gene encodes the pVHL protein, which is part of an E3 ubiquitin ligase complex that targets hypoxia-inducible factors (HIF-1α and HIF-2α) for degradation under normal oxygen conditions. Loss of pVHL function leads to constitutive HIF activity and increased expression of angiogenic and growth-promoting factors.

Clinical features commonly include retinal and CNS hemangioblastomas, clear cell renal cell carcinoma (RCC), pheochromocytoma, pancreatic neuroendocrine tumors, and less frequently endolymphatic sac tumors or epididymal cystadenomas. The manifestations are highly variable between individuals, even within the same family, and there is autosomal dominant inheritance with high penetrance and variable expressivity. De novo mutations occur in a substantial minority of cases.

Diagnosis relies on genetic testing for VHL mutations and on vigilant surveillance for tumors. Recommended monitoring typically includes regular MRI of the brain and spine beginning in childhood, annual ophthalmologic examinations for retinal lesions, abdominal imaging for RCC and pancreatic lesions, and biochemical screening for pheochromocytoma.

Management is multidisciplinary and tailored to tumor type and size. Treatments may include laser photocoagulation or cryotherapy for retinal lesions, surgical or radiosurgical approaches for CNS hemangioblastomas, nephron-sparing surgery or ablation for RCC, and adrenalectomy after appropriate preoperative management for pheochromocytoma. Prognosis has improved with systematic screening and individualized treatment, though lifelong surveillance is generally required. The condition was named after Julius von Hippel and Arvid Lindau, who described it in the early 20th century.