eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

von Hippel-Lindau Disease

Author: Germaine L Defendi, MD, MS, FAAP, Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center
Contributor Information and Disclosures

Updated: Apr 20, 2009

Introduction

Background

von Hippel-Lindau (VHL) disease, von Hippel-Lindau syndrome, is a rare genetic disorder characterized by visceral cysts, benign masses, and the potential for malignant transformation in multiple organ systems. Clinical hallmarks of von Hippel-Lindau disease are the development of retinal and CNS hemangioblastomas, pheochromocytomas, multiple cysts in the pancreas and kidneys, and an increased risk for malignant transformation of renal cysts into carcinoma. Because of the wide age range and pleiotropic manner in which von Hippel-Lindau disease presents, the diagnosis and the treatment for affected individuals, as well as their at-risk relatives, can be challenging.

Pathophysiology

The von Hippel-Lindau gene is located on the short arm of chromosome 3 (3p26-p25) and encodes an ubiquitously expressed 4.7-kilobase (kb) messenger RNA (mRNA) that encodes 3 alternately spliced exons. The resultant 2 von Hippel-Lindau proteins (pVHL) shuttle between the nucleus and the cytoplasm, where they form a complex with several proteins. At present, this gene is the only gene known to cause von Hippel-Lindau disease.

The functions of pVHL are as follows:

• Polyubiquitination: pVHL forms a complex with several proteins (elongins B and C, Cullin2, Rbx1). This multiprotein complex ubiquitinates different substrates, thus marking them for degradation. Ubiquitinated substrates are normally degraded; thus, defective pVHL leads to the accumulation of undegraded products. pVHL gives the complex its target specificity, recruiting specific proteins to the complex for degradation. Two of the key targets that are recruited to the complex under normal oxygen conditions are the transcription factors HIF1a and HIF2a.
• Regulation of hypoxia-inducible factors (HIF1a, HIF2a): Cells lacking pVHL fail to degrade HIF in the presence of oxygen, thus permitting accumulation of high levels of stable protein and activating transcription of a large cohort of hypoxia responsive genes constitutively. Although many tumors have high levels of HIF genes in hypoxic regions of the tumor, tumors resulting from von Hippel-Lindau inactivation express high levels of HIF genes in all of the tumor cells.
• Regulation of other hypoxia-inducible genes: Cells without pVHL activity overproduce other hypoxia-induced mRNAs such as erythropoietin (EPO), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and enzymes involved in glycolysis through HIF-mediated transcription. Tumors associated with von Hippel-Lindau disease are often highly vascular, possibly because of overproduction of these mRNAs. Paraneoplastic polycythemia is frequently observed as a result of erythropoietin production.
• Interaction with the extracellular matrix: pVHL also binds to microtubules and to fibronectin, a glycoprotein that interacts with structural proteins of the cell. Cells with defective pVHL have increased proliferation and decreased differentiation.
• Cell cycle control: This is likely a multifactorial activity; pVHL can interact with cyclin D1 and affects the exit from the cell cycle.

The mechanism by which the loss of pVHL function causes tumorigenesis is not yet fully understood. The von Hippel-Lindau gene may act as a classic tumor suppressor gene, as originally described by Knudson in his 2-hit theory of carcinogenesis.¹ When an individual inherits a germline mutation that renders one von Hippel-Lindau allele inactive, an acquired "second hit" in the other von Hippel-Lindau allele in a somatic cell leaves that cell without tumor suppressor activity. Application of Knudson's theory leads to a selective growth advantage and an increased risk of malignant progression. The ubiquitous expression of pVHL explains, to some extent, the pleiotropic manifestations of this disorder.

Frequency

United States

von Hippel-Lindau disease is inherited in an autosomal dominant Mendelian pattern with a frequency of approximately 1 case per 36,000 newborns.

Mortality/Morbidity

Due largely to the high incidence of renal cell carcinoma (approximately 40% of affected individuals will develop this complication), the average life expectancy of individuals with von Hippel-Lindau disease is 49 years. However, diligent surveillance may increase life expectancy. The current surveillance strategies outlined in Further Outpatient Care will hopefully improve this statistic.

The morbidity of von Hippel-Lindau disease varies, depending on the particular organ system involved.

The primary cause of morbidity and mortality as well as the most serious sequela of von Hippel-Lindau disease involves the malignant degeneration of renal cysts. Renal cysts are seldom clinically significant; however, in von Hippel-Lindau disease they have an appreciable rate of malignant transformation. Renal cell carcinoma is the leading cause of death in patients with von Hippel-Lindau disease, with a prevalence as high as 75% reported in one autopsy series. The average age at which patients with von Hippel-Lindau disease develop renal cell carcinoma is 44 years. These facts reinforce the importance of obtaining renal imaging studies on a regular basis.

The second most common cause of morbidity and mortality in patients with von Hippel-Lindau disease is CNS hemangioblastomas. Approximately 70% of affected individuals develop these tumors. The mean age of diagnosis is 25 years. They typically occur below the tentorium with 80% of the lesions in the cerebellum and 20% of the lesions in the spine. Although hemangioblastomas are usually benign, enlargement of these tumors within the confines of the CNS can cause neurologic compromise and death.

Retinal hemangioblastomas are diagnosed at an average age of 29 years. These benign ocular tumors can lead to considerable morbidity through retinal detachment or visual loss from an enlarging lesion.

Endolymphatic sac tumors (ELSTs) of the middle ear are vascular lesions growing within the posterior temporal bone.²  They often occur bilaterally and are diagnosed in about 10% of patients. Presenting clinical signs include hearing loss, tinnitus, vertigo, and facial weakness. Deafness of varying severity is the major complication, if appropriate surgical intervention does not occur.

Pheochromocytomas may be asymptomatic or cause episodic or sustained hypertension in patients with von Hippel-Lindau disease. Often seen in younger patients (median age of 30 y), these tumors are often multiple or extra-adrenal and only about one-third of patients have increased catecholamine production.  

Pancreatic involvement is common in patients with von Hippel-Lindau disease. Most pancreatic lesions are simple cysts (70%) and rarely cause symptoms or develop into malignant tumors.  Neuroendocrine tumors of the pancreas are less common and have malignant potential with risk of metastasis to the liver.

Epididymal papillary cystadenomas are present in about 50% of patients with von Hippel-Lindau disease. Single papillary cystadenomas occur in the general population; therefore, they do not pose concern if other von Hippel-Lindau disease clinical findings are absent. However, bilateral epididymal cysts are considered pathognomonic for von Hippel-Lindau disease. These benign cysts are usually asymptomatic and do not require treatment. In women, the equivalent benign lesion is a papillary cystadenoma of the ovarian broad ligament. Symptoms may include pain, dyspareunia, and menorrhagia. Symptomatic treatment is indicated for these patients.

Race

von Hippel-Lindau disease affects all races and ethnic groups. No differences in incidence have been reported.

Sex

No sex predilection is noted.

Age

Age at diagnosis varies from infancy to age 60-70 years. The average age of clinical diagnosis in patients is 26 years.

Clinical

History

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.

Physical

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.

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    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.

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