Von Hippel Lindau Syndrome


Article Author:
Magui Mikhail


Article Editor:
Achint Singh


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
1/26/2019 9:56:04 PM

Introduction

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 grow 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.[1][2][3][4]

VHL can be classified as follows:

  • Type 1 (without pheochromocytoma)
  • Type 2 (with pheochromocytoma). Type 2 is further classified as:
  1. Type 2A: Pheochromocytoma is present along with CNS hemangioblastomas but no RCC.
  2. Type 2B: Pheochromocytoma is present along with both CNS hemangioblastomas and RCC.
  3. Type 2C: Pheochromocytoma is present without hemangioblastomas or RCC.

Etiology

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.

Epidemiology

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%.[5]

Pathophysiology

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.

History and Physical

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.

Evaluation

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 visceral manifestation of VHL, or any manifestation with a family history of VHL.[5][6][7][8]

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 / Management

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.[9][10]

Pearls and Other Issues

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.

Enhancing Healthcare Team Outcomes

The management of patients with VHL is multidisciplinary. 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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Von Hippel Lindau Syndrome - Questions

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Which of the following syndromes is associated with a high risk of renal cell cancer?



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A young man is seen with hypertension. He also is found to have hemangioblastomas of the brain and spinal cord, retinal angiomas. Work up reveals that he has a pheochromocytoma. He most likely has which of the following?



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A young child is seen with hypertension. He also is found to have large hemangiomas on his face, eyes, and trunk. Work up reveals a pheochromocytoma. What is the greatest risk to the patient?



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A computerized tomography (CT) is performed on a 30-year-old man for headaches who is known to have von Hippel-Lindau syndrome. The results show a cyst and two small masses in the right cerebellar hemisphere. Which statement is most accurate?



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Examination of a 30-year-old woman complaining of gait imbalance reveals an hematocrit of 55%, increased protein and RBCs in the urine, and an enlarged liver and spleen. What is the most likely diagnosis?



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Which of the following metastatic carcinomas are most commonly associated with Von Hippel-Lindau?



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Which is NOT a common finding in a patient with von Hippel-Lindau syndrome?



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A 24-year-old female with von Hippel-Lindau syndrome has a CT showing a right cerebellar cyst. Select the best management.



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A 28-year-old male presents with progressive gait problems and dysmetria. The laboratories show normal CBC but proteinuria and microscopic hematuria. Hepatosplenomegaly and cerebellar dysfunction are noted on the exam. What other exam findings are expected?



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Which of the following malignancies is more common in patients with von Hippel-Lindau syndrome?



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A 13-year-old girl is found to have many angiomatous hamartomas of the retina with cysts of the pancreas and kidney. Select the brain tumor most commonly seen in patients with this condition.



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A 16-year-old male presents for changing vision. On examination, the patient has bilateral peripheral lesions with a subtle red hue no larger than a few hundred microns. Some have a more nodular appearance with marked dilated and engorged afferent and efferent blood vessels. Retinal edema and hard exudates are noted with some macular involvement. Which of the following is the most likely underlying etiology of the patient's condition?



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Which of the following is not typically associated with von Hippel-Lindau disease?



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Which of the following is associated with von Hippel-Lindau disease?



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What are the two most common locations of cysts in patients with Von Hippel Lindau disease?



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What is TRUE about pheochromocytomas and von-Hippel Lindau disease?



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A young man presents with hypertension not fully controlled by multiple medications and microscopic hematuria. CT of the abdomen shows a mixed solid/cystic mass in the right kidney and a solid tumor of the left adrenal gland. There are multiple cysts in the left kidney and in the pancreas. Which of the following should be done?



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Von Hippel-Lindau is associated with all of the following tumors EXCEPT:



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A 28-year old presents with a long history of poor vision. She was prescribed eyeglasses but this did not help. Finally, she is seeing an ophthalmologist who notes that presence of a retinal capillary hemangioma. What is the most likely diagnosis?



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A 28-year old presents with a long history of poor vision. She was prescribed eyeglasses but this did not help. Finally, she is seeing an ophthalmologist who notes that presence of retinal capillary hemangioma. The patient states that her sister has the same problem. The primary cause of death in these patients is which one of the following?



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A young female presents with gross hematuria and weight loss. Work up reveals that she has a genetic disorder that makes her susceptible to several malignancies. Which of the following syndromes is associated with a high-risk of renal cell cancer?



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A 21-year-old male presents with hearing loss and vertigo. A CT scan of the head was performed, and a large destructive lesion in the region of right endolymphatic sac was found. Which of the following disease can be associated with this lesion?



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A 24-year-old patient presents with ataxia. A contrast-enhanced MRI was performed, and cystic cerebellar lesion with a solid enhancing nodule was found. A few pancreatic cysts are also noted in this patient on thoracic spine MRI. What is the most likely diagnosis?



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Von Hippel Lindau Syndrome - References

References

Chappell JC,Payne LB,Rathmell WK, Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers. The Journal of clinical investigation. 2019 Jan 7;     [PubMed]
Liu P,Li M,Guan X,Yu A,Xiao Q,Wang C,Hu Y,Zhu F,Yin H,Yi X,Liu L, Clinical Syndromes and Genetic Screening Strategies of Pheochromocytoma and Paraganglioma. Journal of kidney cancer and VHL. 2018;     [PubMed]
Tsang SH,Sharma T, Von Hippel-Lindau Disease. Advances in experimental medicine and biology. 2018;     [PubMed]
Barros FS,Marussi VHR,Amaral LLF,da Rocha AJ,Campos CMS,Freitas LF,Huisman TAGM,Soares BP, The Rare Neurocutaneous Disorders: Update on Clinical, Molecular, and Neuroimaging Features. Topics in magnetic resonance imaging : TMRI. 2018 Dec;     [PubMed]
van Leeuwaarde RS,Ahmad S,Links TP,Giles RH, Von Hippel-Lindau Syndrome 1993;     [PubMed]
Signoretti S,Flaifel A,Chen YB,Reuter VE, Renal Cell Carcinoma in the Era of Precision Medicine: From Molecular Pathology to Tissue-Based Biomarkers. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018 Oct 29;     [PubMed]
Koch CA,Petersenn S, Black swans - neuroendocrine tumors of rare locations. Reviews in endocrine     [PubMed]
Yilmaz U, [CNS manifestations of neurocutaneous syndromes]. Der Radiologe. 2018 Jul;     [PubMed]
Ganeshan D,Menias CO,Pickhardt PJ,Sandrasegaran K,Lubner MG,Ramalingam P,Bhalla S, Tumors in von Hippel-Lindau Syndrome: From Head to Toe-Comprehensive State-of-the-Art Review. Radiographics : a review publication of the Radiological Society of North America, Inc. 2018 May-Jun;     [PubMed]
Maher ER, Hereditary renal cell carcinoma syndromes: diagnosis, surveillance and management. World journal of urology. 2018 Dec;     [PubMed]

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