Von Hippel-Lindau disease: gene to bedside

Curr Opin Neurol 14:695-703

Correspondence to Katherine B. Sims MD, Neurology Department, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA NS R2

Introduction
hereditary tumor syndrome associated with inactivation of a gatekeeper tumor suppressor gene and its encoded protein (pVHL) - multiple hemangioblastomas of the brain, spinal cord and retina - renal cysts or clear cell carcinoma - cyst adenomas of epididymis, broad ligament, pancreas, or liver - pheochromocytoma

Molecular genetics
VHL gene (vhl) - three exons encoding a 25 kD, 213 amino acid Germ-line mutation in the VHL gene is associated with an increased genetic risk of hemangioblastoma, renal carcinoma, and other tumor formation Appropriate delineation of those family members carrying genetic risk then allows for appropriate clinical monitoring and intervention isolated VHL-associated tumors -> negative molecular vhl mutational screening may significantly lower genetic VHL risk in any one patient (esp. familial pheochromcytoma or in sporadic cases under the age of 20 years, and in isolated hemangioblastomas)

Von Hippel-Lindau protein function

1. In normoxic conditions - The pVHL/elongin complex (VCBC) targets HIF-alpha subunits - ubiquination and degradation 2. In hypoxic conditions - pVHL becomes inactivated and HIF is dysregulated - secondary overexpression of HIF targets including VEGF, erythropoietin, TGF-beta and TGFalpha exception: type 2c VHL

Clinical syndrome
Incidence - 1:3136 000 live births

Clinical syndrome: Hemangioblastomas

highly vascular, non-metastatic, non-invading tumors CNS hemangioblastomas - most common, earliest and most characteristic lesions (6080%) - Amlostly, cystic lesions with mural nodules - regional predilection to the cerebellar hemispheres (with less frequent appearance in the spinal cord and brainstem and rarely in other CNS sites) - 35%~58% of CNS hemangioblastomas are part of the VHL syndrome - no significant difference between VHL-associated hemangioblastomas and sporadic forms Spinal cord hemangioblastomas - Clinical presentation : pain, posterior column proprioceptive disturbances, motor weakness and bowel and bladder dysfunction - small superficial intramedullary, well demarcated, strongly enhancing tumors with relatively large syrinx formation (64%) - 38% in cervical, 51% in thoracic region

Clinical syndrome: Endolymphatic sac tumors

non-metastatic papillary adenocarcinomas that arise from the membranous labyrinth ectoderm Subacute onset of hearing loss, tinnitus, vertigo, and risk progression to facial nerve and vocal cord paralysis all cases of ELST should be screened for VHL (rare incidence in the general population)

Clinical management
Molecular DNA mutational screening: the standard of care for assessment of at-risk family members Specific genotype information, coupled with clinical history in family members tailored routine monitoring or symptom evaluation Clinical monitoring - Current National Institutes of Health recommendations . ophthalmologic screening as young as possible and at least by age 5 years . annual imaging of CNS and other organs by computed tomography scan or magnetic resonance imaging with inclusion of the spinal cord . blood pressure monitoring and catecholamine metabolite screening, especially for those with type 2 associated phenotypes Therapeutic management - selective use of preoperative angiography/embolization for hemangioblastomas - microvascular surgery, stereotaxic radiosurgery, including gamma knife, fractionated XRT - radiofrequency ablation of renal lesions, - Photo- or cryo-coagulation of retinal hemangioblastomas

Clinical management: Hemangioblastomas

frequent recurrence, unpredictable growth characteristics, risk of spontaneous hemorrhage and often surgically inaccessible localization Associated with significant morbidity and mortality

microvascular techniques and radiotherapy options - minimally invasive stereotaxic radiosurgery - subtotal surgical resection augmented with XRT

Clinical management: Endolymphatic sac tumors

Current screening recommendations - pure tone and speech discrimination thresholds, otoacoustic emission studies, brainstem auditory evoked response testing and MRI of the petrous bone with special attention to the region of the external aperture of the vestibular aquaduct Therapeutic intervention is surgical Subtotal resection and radiotherapy have been associated with recurrence

Future therapy
small molecules to inhibit HIF-alpha transcription antiangiogenic agents which block VEGF, TGF-beta, TGF-alpha or histone deacetylase Gene therapy based replacement of vhl and pVHL function