Genetics of von Hippel-Lindau Disease 

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.

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.