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  Disease summary:

  
  
  
  
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    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).

    
    
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    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.

    
    
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    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.

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

    
    
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    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.

  
  
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  Hereditary basis:

  
  
  
  
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    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.

  
  
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  Differential diagnosis:

  
  
  
  
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    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

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.

Retinal Angiomas

These tumors occur in the periphery of the retina and optic nerve and frequently are bilateral and multifocal. Initially they are asymptomatic but as these tumors grow they can cause permanent loss of vision from bleeding, development of macular exudate, and retinal detachment.

Cerebellar, Brainstem, and Spinal Hemangio-Blastomas

These highly vascular tumors can occur in the brain stem, cerebellum, and anywhere in the spinal cord. Symptoms are dependent on the location, size, and compressive effects of the lesion. If lesions become compressive to the surrounding tissue, common side effects include headaches, numbness, weakness, dizziness, worsening coordination, weakness, and back pain.

Endolymphatic Sac Tumors

The endolymphatic sac runs from the inner ear to the dura and controls balance and equilibrium. In patients with VHL, endolymphatic sac tumor (ELST) arises from this structure. When tumors are small they generally do not cause symptoms, however as tumors grow larger, patients can experience either gradual or sudden hearing loss, vertigo, tinnitus, and problems with balance. Large tumors can cause facial paralysis by damaging the seventh cranial nerve and can also erode into the temporal bone.

Renal Cell Carcinoma and Renal Cysts

Renal cysts generally are asymptomatic. However, while rare, cyst rupture can cause flank pain. Clear cell renal tumors when small cause no symptoms, but when larger they can cause hematuria, flank pain, and abdominal mass. Prior to the current screening methods in VHL patients, approximately 20% to 50% of patients would develop metastasis and die from kidney cancer.

Pheochromocytoma

Pheochromocytomas are adrenaline-producing chromaffin tumors located in the adrenal gland and may cause hypertension, anxiety, palpitations, diaphoresis, and rage. Prompt diagnosis, proper management, and treatment of pheochromocytoma is important to prevent complications related to catecholamine-induced cardiovascular morbidity such as malignant hypertension, stroke, heart failure, and fatal arrhythmias. While rare in patients with VHL, malignant pheochromocytoma can occur and patients frequently succumb to their disease.

Pancreatic Cysts and Neuroendocrine Tumors

Pancreatic cysts are the most common VHL manifestation of pancreatic disease. Cysts are generally asymptomatic but extensive replacement of the pancreas can cause exocrine dysfunction (steatorrhea) and endocrine dysfunction (diabetes mellitus). Pancreatic neuroendocrine tumors (PNETs) are the most common pancreatic tumor in VHL. When small, PNETs are generally asymptomatic. However, when larger they can obstruct the biliary tract and patients can present with jaundice and pruritus from elevations in bilirubin. Additionally these tumors tend to metastasize to the liver.

Papillary Cystadenomas of the Epididymis (Men) and Broad Ligament (Women)

Epididymal cystadenomas are palpable tumors of the head of the epididymis and are common in young men with VHL. They do not generally cause symptoms, but may be tender to palpation on examination. Cystadenomas of the broad ligament are generally incidentally detected on abdominal imaging and rarely cause symptoms.

Screening

Routine ophthalmologic, CNS, and visceral screening are strongly encouraged in those affected with VHL and nongermline-tested individuals who may be asymptomatic carriers (Table 129-2). Close screening and early intervention greatly reduces the risk of permanent morbidity and mortality from VHL-related tumors. Aside from retinal angiomas, most VHL manifestations do not present until the second and third decade of life. Age-stratified screening has been developed to minimize unnecessary anxiety and radiation exposure in children who are less likely to have these manifestations. Clinicians should be aware that outliers can occur and additional testing should be obtained when indicated.