Von Hippel-Lindau (VHL) syndrome is a hereditary autosomal dominant disease affecting several organ systems. The disease is characterized by the growth of cysts and/or tumors. Tumors can either be benign or malignant. The most characteristic type of tumor in VHL is hemangioblastoma, which is a benign tumor made of newly formed blood vessels. Hemangioblastomas develop in the central nervous system (CNS) and retina and can cause complications including ataxia and loss of vision. Cysts are also a very common manifestation of VHL and occur in the kidneys, pancreas, and genital tract. Renal cell carcinoma (RCC) and pancreatic neuroendocrine tumors are also seen with VHL. Endolymphatic sac tumors, which are found in the inner ear, can be seen in patients with VHL.
The hemangiomas are found in close to 50% of patients with VHL and can occur in any part of the retina. These hemangiomas may leak serum leading to the formation of fibroglial bands that can cause retinal detachment and vitreous hemorrhage. The end result is the development of glaucoma and/or permanent vision loss.
VHL can be classified as follows:
Mutations in the VHL tumor suppressor gene located on chromosome 3 cause VHL. These mutations prevent the production or cause abnormal production of the VHL protein (pVHL). pVHL is primarily responsible for the degradation of hypoxia-inducible factor (HIF), which is a protein responsible for oxygen regulation in the cells. Abnormal or absent pVHL results in the uninhibited upregulation of HIF and multiple downstream growth factors leading to the formation of cysts and hypervascular tumors characteristic of VHL.
VHL is autosomal dominant and has a high penetrance leading to early-onset and high frequency of clinical manifestations. It is the most common hereditary renal cancer syndrome. The estimated prevalence of VHL is 1:30,000 to 1:50,000 with 6000 to 7000 patients affected in the United States. Males and females are equally affected. The average age of onset is 26 years with an age range of infancy to the seventh decade but most commonly at 18 to 30 years. Renal cysts occur in 59% to 63% of patients. RCC occurs in 25% to 45%. CNS hemangioblastomas occur in 13% to 72%. Retinal hemangioblastomas occur in 45% to 59%. Endolymphatic sac tumors occur in 2% to 11%. Pancreatic lesions occur in 17% to 56%, and pheochromocytomas occur in 0% to 60%.
Von Hippel-Lindau is caused by autosomal dominant mutation of the von Hippel–Lindau tumor suppressor gene on chromosome 3 that result in an abnormal pVHL. pVHL regulates a protein known as HIF-1-alpha, which is responsible for cellular response to hypoxia. VHL genetic mutations result in alterations to pVHL at the HIF-1-alpha binding site. As a result, pVHL does not bind effectively to HIF-1-alpha which, in turn, leads to the transcription of several genes and subsequent upregulation of growth factors including erythropoietin, vascular endothelial growth factor, platelet-derived growth factor B, and other genes involved in glucose uptake and metabolism.
Presenting history varies in patients depending on the size and location of tumors. Family history is important given the hereditary nature of VHL. Hemangioblastomas in the CNS can cause headaches, vomiting, sensory or motor deficits, and ataxia. Hemangioblastomas in the retina, also known as retinal angiomas, may cause vision loss. Pheochromocytomas, which affect the adrenal glands, may be asymptomatic, but they also may cause an array of symptoms including headaches, panic attacks, excessive sweating, and elevated blood pressures. VHL patients with endolymphatic sac tumors, which occur in the inner ear, may present with tinnitus, vertigo, or hearing loss.
Physical examination findings are usually limited since the diagnosis generally is made based on laboratory and radiographic studies. However, it may yield positive neurological findings such as muscle weakness, sensory deficits, and ataxia in the case of CNS hemangioblastomas.
Identification of a heterozygous pathogenic variant of pVHL using molecular genetic testing establishes the diagnosis of VHL even if clinical and radiographic findings are inconclusive. Various clinical criteria can be used to establish the diagnosis such as more than one CNS hemangioblastoma, one CNS hemangioblastoma and a visceral manifestation of VHL, or any manifestation with a family history of VHL.
Fundoscopy can detect retinal hemangioblastomas, as well as other associated findings such as retinal detachment, macular edema, or cataracts. Glaucoma may be detected on tonometry. An audiological evaluation should be done to evaluate for hearing loss that can be caused by endolymphatic sac tumors.
Laboratory studies include serum and urinary catecholamines that can assist in the diagnosis of pheochromocytomas.
Imaging studies play a major role in identifying VHL lesions. CNS hemangioblastomas can be detected on MR of the brain and spinal cord. Their typical appearance is that of a cystic lesion with an enhancing mural nodule. About 80% will develop in the brain and 20% in the spinal cord. Renal cysts can be detected on ultrasound, MRI, or CT and are usually bilateral, multiple, and of different sizes. CT with the renal mass protocol is the preferred imaging tool for RCC, which is usually bilateral and multiple and can be solid or cystic. Pheochromocytomas can be detected on CT or MR. Usually, pancreatic cysts and tumors are detected on CT. Pancreatic cysts can also be visualized on ultrasound. MR and CT through the middle ear can detect endolymphatic sac tumors.
Treatment of VHL syndrome depends on the location and size of the lesions as well as the extent of the disease. CNS hemangioblastomas can be excised surgically. Gamma-knife surgery may be useful for small solid tumors or ones in inoperable sites. If hemangioblastomas are extensive, preoperative embolization is performed to decrease the risk of bleeding given the high vascularity of these tumors. Retinal angiomas are usually treated to avoid vision loss. Treatment options include diathermy, xenon, laser, cryocoagulation, and external beam radiotherapy. Early nephrectomy is the best treatment option for RCC. Smaller lesions are also treated with cryoablation and radiofrequency ablation. Pheochromocytomas are removed surgically. Partial adrenalectomy is the treatment of choice for pediatric patients. Surgical removal of pancreatic neuroendocrine tumors should be considered if they pose a high risk of metastasis suggested by a tumor size greater than 3 cm, a doubling rate of fewer than 500 days, or a pathologic genetic variant. Surgical removal of endolymphatic sac tumors should be considered to avoid hearing loss.
The differential diagnosis of VHL contains all of the types of VHL-associated tumors as isolated entities including retinal hemangioblastoma, renal cell carcinoma, and CNS hemangioblastoma, pheochromocytoma, pancreatic tumors, and endolymphatic sac tumors.
Because many patients with VHL will develop renal cell cancer, their life expectancy is reduced. The morbidity depends on the number of organs involved. The presence of CNS hemangioblastomas also affects morbidity. The lesions often expand and lead to neurological compromise. Retinal disease can be associated with cataracts, glaucoma, retinal detachment, macular exudation, and vitreous hemorrhage. The endolymphatic sac tumors are often bilateral and induce tinnitus, hearing loss and facial weakness. Patients with VHL are also at risk of developing pheochromocytomas. The pancreatic cystic lesions rarely cause symptoms and do not become malignant. Overall, the quality of life of these patients is poor.
Early detection of VHL syndrome through surveillance and screening can help minimize complications including neurological deficits, hearing and vision loss, and renal impairment. For individuals with known VHL syndrome, a known VHL genetic mutation, or first-degree relatives of VHL patients, annual evaluation starting at age one for vision and hearing problems, neurological symptoms, and blood pressure monitoring is recommended. An MRI of the brain and entire spine is recommended every 2 years starting at age 16 to screen for CNS lesions. For visceral lesions, an abdominal ultrasound or MRI is recommended starting at age 16 every 1 to 2 years. Annual blood or urinary fractionated metanephrines are used to screen for pheochromocytomas starting at age 5. For endolymphatic sac tumors, an MRI with thin slices through the internal auditory canal is recommended in symptomatic patients. An audiology evaluation every 2 to 3 years starting at age five can help detect early hearing deficits.
Genetic counseling and testing should be offered to individuals at risk to help confirm the diagnosis and prevent screening tests in individuals without the pathogenic variant.
The management of patients with VHL is interprofessional. These patients need life long monitoring. Family members need surveillance and screening which can help minimize complications including neurological deficits, hearing and vision loss, and renal impairment. For individuals with known VHL syndrome, a known VHL genetic mutation, or first-degree relatives of VHL patients, annual evaluation starting at age one for vision and hearing problems, neurological symptoms, and blood pressure monitoring is recommended. An MRI of the brain and entire spine is recommended every 2 years starting at age 16 to screen for CNS lesions. For visceral lesions, an abdominal ultrasound or MRI is recommended starting at age 16 every 1 to 2 years. Annual blood or urinary fractionated metanephrines are used to screen for pheochromocytomas starting at age 5. For endolymphatic sac tumors, an MRI is recommended in symptomatic patients. An audiology evaluation every 2 to 3 years starting at age five can help detect early hearing deficits.
Genetic counseling and testing should be offered to individuals at risk to help confirm the diagnosis and prevent screening tests in individuals without the pathogenic variant. The prognosis for most patients with VHL is guarded.
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