Review of the Neurological Implications of von Hippel–Lindau Disease

Abstract

on Hippel-Lindau (VHL) disease is an autosomal dominant neoplasia syndrome caused by a germline mutation of the VHL tumor suppressor gene (NC_000003.12) located on the short arm of chromosome 3. [1][2][3] This disease carries a prevalence of 1 in 36 000 births 4 and is highly penetrant (>90% penetrance by age 65 years). 3 Patients with VHL disease can develop lesions of the viscera and central nervous system (CNS). Visceral lesions include renal cell carcinomas or cysts, pheochromocytomas, pancreatic neuroendocrine tumors or cysts, and benign cystadenomas of the adnexal organs. The CNS-associated lesions include hemangioblastomas of the retina and craniospinal axis as well as endolymphatic sac tumors (ELSTs). [4][5][6] The most frequent cause of VHL diseaseassociated morbidity and mortality is craniospinal hemangioblastoma development and progression. 7 IMPORTANCE von Hippel-Lindau (VHL) disease-associated central nervous system (CNS) lesions include hemangioblastomas and endolymphatic sac tumors (ELSTs), which are associated with significant neurological morbidity and mortality. Recent studies provide critical new biological, diagnostic, and management insights into these tumors.OBSERVATIONS Biological features, natural history, clinical findings, and management strategies of VHL disease-associated CNS tumors are reviewed. The VHL disease results from a germline mutation of the VHL gene (located on the short arm of chromosome 3), a tumor suppressor that encodes for the VHL protein. Whereas VHL disease is associated with visceral manifestations, CNS lesions are the most common source of morbidity and mortality. Craniospinal hemangioblastomas are almost entirely (99%) found in the cerebellum, brainstem, and spinal cord. These tumors arise from multipotent hemangioblasts. Peritumoral cysts frequently underlie the clinical findings associated with hemangioblastomas (>90% of symptomatic tumors). Prospective natural history studies demonstrate that CNS hemangioblastomas typically grow in a saltatory pattern. Due to this unpredictable growth pattern, surgical resection is reserved for symptomatic lesions, as many tumors do not become symptomatic. Recent studies indicate that VHL disease-associated ELSTs cause audiovestibular morbidity (hearing loss, tinnitus, and vertigo) via 3 mechanisms-otic capsule invasion, intralabyrinthine hemorrhage, and endolymphatic hydrops. Specialized magnetic resonance imaging techniques have been defined to elucidate each of these mechanisms, even when a tumor mass is not identified on imaging. Endolymphatic sac tumors cause audiovestibular morbidity unrelated to size or progression, and resection is now recommended at initial discovery of a tumor mass or a tumor-associated mechanism of morbidity.CONCLUSIONS AND RELEVANCE New insights into the development, pathobiological origin, natural history, and long-term outcomes of VHL disease-associated CNS tumors have redefined their management and treatment indications and potentially provide new targeted therapeutic strategies. Resection is rese...

Intronic mutation of the VHL gene associated with central nervous system hemangioblastomas in two Chinese families with Von Hippel–Lindau disease: case report

“…According to the American College of Medical Genetics and Genomics standards and guidelines, we found that both variants were pathogenic [16]. According to previous research, there is increasing evidence that CNS HGBs are the most frequent cause of mortality in patients with VHL disease [17,18]. However, some studies reported that approximately 20% of patients have VHL disease resulting from a de novo mutation and have no family history [19].…”

Teaching NeuroImages: CNS hemangioblastomas in von Hippel-Lindau disease with exon 3 deletion

“…1 Our patient had truncating mutation, correlating to a higher rate of hemangioblastoma, but a lower risk for pheochromocytoma. …”

Anorexia as the first clinical manifestation of von Hippel‑Lindau syndrome

“…VHLs is caused by germline mutations of the VHL gene, which is located on chromosome 3 (3p25-26) (11). Mutations in this gene have been reported in all three of its exons and may affect several organs, including the retina, kidneys, adrenal glands, nervous system and pancreas (12,13). Haploinsufficiency of this gene may promote the development of benign cystic lesions, but tumor development depends on allele wild-type inactivation.…”