Genetics of von Hippel-Lindau Disease Clinical Presentation

The unexpected finding of a retinal or CNS hemangioblastoma or the diagnosis of a pheochromocytoma should prompt a search for other von Hippel-Lindau (VHL) disease–associated stigmata because many of these individuals meet the criteria for diagnosis. Identification is important because of the increased risk of serious complications (eg, renal cell carcinoma) that are readily treated with early intervention.

Because von Hippel-Lindau disease, or von Hippel-Lindau syndrome, is a multiorgan disease that widely varies in clinical presentation, various manifestations may lead to diagnosis.

• More than one hemangioblastoma in the CNS or retina is acceptable for the diagnosis of von Hippel-Lindau disease.

  • A single hemangioblastoma of the CNS or retina plus a visceral manifestation (multiple renal, pancreatic, or hepatic cysts; pheochromocytoma; renal cancer)
  • Definite family history plus any one of the above manifestations
  • Elucidation of a deleterious mutation in the von Hippel-Lindau gene
• Because von Hippel-Lindau disease is a genetic disorder, making the diagnosis is important in family members. Interpreting pedigree information and understanding the results of mutational analysis is complicated. The assistance of personnel trained in medical genetics (geneticists, genetic counselors) is needed to give guidance to patients and their family members.
• Even if von Hippel-Lindau disease manifestations are not discovered upon first evaluating an at-risk relative, these individuals should have periodic surveillance for von Hippel-Lindau disease–associated lesions until age 60-70 years.
• Genetic testing is indicated for identifying individuals in a family who have inherited a von Hippel-Lindau mutation. Those who test positive for a mutation require life-long surveillance, whereas at-risk family members who test negative for a known familial mutation do not need further diagnostic examination or surveillance.
• Because von Hippel-Lindau disease is inherited in an autosomal dominant fashion, children of affected patients have a 50% risk of inheriting the disorder. However, the degree of clinical severity cannot be predicted. Siblings, parents, and relatives who are more distant are at risk for von Hippel-Lindau disease as well. Thus, the diagnosis in an individual mandates a careful family history and diagnostic studies of appropriate relatives to detect serious complications while they are still in the early, hopefully treatable, stages. Regular surveillance is strongly suggested for these at-risk individuals as outlined above, at least until age 60 years or until genetic testing excludes the presence of the familial mutation in an individual. New or de novo mutations (ie, no mutation identified in either parent) occur in approximately 20% of patients.

Manifestations are pleiotropic. In the early stages, most aspects of von Hippel-Lindau disease can be detected only with detailed imaging studies, biochemical analyses, or both.

• Retinal hemangioblastomas

  • Approximately one half of individuals with von Hippel-Lindau disease have retinal hemangioblastomas. These lesions are revealed during direct ophthalmoscopic evaluation. They appear as a dilated artery leading from the disc to a peripheral tumor with an engorged vein.
  • Patients usually present with retinal hemangioblastomas in the third decade of life.
  • Although patients with retinal hemangioblastomas are usually asymptomatic, enlargement or a central location of these tumors can result in significant visual loss. Moreover, the presence of retinal hemangioblastomas can predispose patients to retinal detachment, macular edema, and glaucoma. Early detection and treatment with diathermy, laser, cryocoagulation can prevent significant visual loss.
• CNS hemangioblastomas

  • CNS hemangioblastomas are histologically identical to retinal hemangioblastomas and are almost exclusively subtentorial. The mean age at diagnosis is 25 years. Most often, CNS hemangioblastomas are located in the cerebellum, but they also can be found in the brainstem and spinal cord.T1-weighted transaxial gadolinium-enhanced MRIs show a well-defined hypervascular enhancing mass.
  • CNS hemangioblastomas are histologically benign. However, these tumors may cause diverse neurologic symptoms, as determined by their location within the CNS. Hemorrhage into these lesions is unusual. CNS hemangioblastomas are best detected using gadolinium-enhanced MRI, and are often surgically resected.
• Renal involvement

  • As many as 76% of patients have multiple renal cysts. Although these lesions themselves are not problematic, they are associated with a significant risk for malignant change to clear cell renal cell carcinoma, which is the major cause of patient mortality.
  • Renal cell carcinoma is the presenting feature in approximately 10% of patients; however, the risk of developing renal cell carcinoma by age 60 years is approximately 70%.
  • Renal cell carcinoma develops in patients at an average age of 44 years, about 20 years earlier than when sporadic renal cell carcinoma occurs in the general population.
  • In addition to simple cysts and renal cell carcinoma, numerous other renal lesions are seen, such as hemangiomas and benign adenomas.
  • Periodic imaging of the kidneys (via ultrasonography, CT scanning, MRI) is mandatory in patients and at-risk relatives. Type of renal imaging should be determined by local expertise in various imaging modalities.
  • A nephron-sparing approach for treatment of patients with renal cell carcinoma, such as tumor excision or partial nephrectomy, is often used in an attempt to preserve renal function. However, because of the high incidence of subsequent tumors, many patients ultimately progress to bilateral nephrectomy, necessitating dialysis or transplantation.
• Pheochromocytoma

  • Patients are at increased risk for developing pheochromocytomas. The risk of developing such tumors (which are usually histologically benign) appears to hinge on the precise nature of the mutation responsible for von Hippel-Lindau disease in a specific family. In kindreds with von Hippel-Lindau disease who demonstrate a deletion or protein-truncating mutation of the von Hippel-Lindau gene (type 1 VHL), the risk for pheochromocytoma is less than 10%. However, the risk for developing this tumor increases to approximately 50% in kindreds with a missense mutation (type 2 VHL).
  • Type 2 von Hippel-Lindau disease can be further divided into types 2A, 2B and 2C, depending on the relative risk for the development of renal cell carcinoma in patients with pheochromocytoma. Patients with type 2A have a low risk of developing RCC, whereas those with 2B have a high risk. Patients with type 2C have risk for pheochromocytoma and not for renal cell carcinoma.
  • Screen patients and at-risk family members for the presence of pheochromocytomas with standard biochemical means. When detected, treatment is identical to that in patients with sporadic pheochromocytomas.
• Other lesions

  • Various other lesions are observed, including epididymal cysts, epididymal cystadenomas, and multiple pancreatic cysts. Most pancreatic lesions are asymptomatic and benign. Occasionally, a malignant islet cell tumor, a functioning islet cell tumor, or a frank pancreatic carcinoma occurs in patients with von Hippel-Lindau disease. Thus, abdominal imaging should be performed regularly, keeping in mind the potential for pancreatic malignancy.
  • Endolymphatic sac tumors (ELSTs) have been described as part of the von Hippel-Lindau disease spectrum. Searching for these tumors in at-risk individuals who present with otologic symptoms such as deafness and tinnitus is important.