129: von Hippel-Lindau Syndrome

Key Points

• Disease summary:

  • Manifestations of von Hippel-Lindau (VHL) disease were first observed in the early 20th century by Drs. von Hippel (retinal angiomas) and Lindau (cerebellar hemangioblastomas).

  • The disease is characterized by the development of multiple tumors including retinal angiomas, central nervous system (CNS) hemangioblastomas, pancreatic cysts and neuroendocrine tumors, renal cell carcinomas (RCC), pheochromocytomas, and epididymal cystadenomas.

  • Prior to comprehensive screening and early intervention, median survival of those with VHL was less than 50 years due to complications of RCC and hemangioblastomas.

  • VHL has an incidence of 1:35,000 and the majority of affected individuals have a family history of the disease.

  • Patients can have a germline missense, nonsense, or partial/complete deletion of the VHL gene. Most tumors generally have a second hit in the wild-type allele, which results from loss of heterozygosity, hypermethylation, and occasionally a second mutation.

• Hereditary basis:

  • VHL is a highly penetrant autosomal dominant disease due to a germline mutation in the VHL gene. Children of affected individuals have a 50% chance of inheriting the affected allele. In kindreds with VHL, up to a quarter have no family history and have been considered as founder mutations. However in cases of apparently de novo mutations, these actually may represent a nontraditional transmission of the VHL mutation. Detailed testing of parents of affected individuals can demonstrate genetic mosaicism in VHL.

• Differential diagnosis:

  • It is important to distinguish VHL from other multiorgan syndromes that have overlapping tumor types. Syndromes that feature pheochromocytomas include multiple endocrine neoplasia (MEN2a/b), neurofibromatosis type 1, and succinate dehydrogenase deficiency (SDH). Other kidney cancer syndromes associated with multiple tumor types include Birt-Hogg-Dubé (BHD), hereditary leiomyomatosis and renal cell carcinoma (HLRCC), SDH B and C deficiency, and Cowden syndrome.

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria

The presence of two or more characteristic tumors associated with VHL should raise clinical suspicion for this syndrome. Over 75% of VHL individuals are diagnosed in kindreds with a prior family history of the disorder. These patients generally are asymptomatic when genetic testing is performed and routine screening can find manageable disease in one or more affected organ systems. Up to 25% of individuals with VHL have a de novo mutation. Many of these patients present with symptomatic, advanced disease due to a delay in diagnosis. The presence of two or more characteristic tumors associated with VHL should raise clinical suspicion for this syndrome.

Clinical Characteristics

VHL-associated tumors generally present after the second decade of life with mean age presentation between 20 and 40 years of age. One exception is retinal angiomas; these tumors can occur as early as 1 year of age. See Table 129-1.