BASICS
DESCRIPTION
Von Hippel-Lindau (VHL) disease is a hereditary syndrome with known gene mutations of the VHL gene, which manifests as benign (renal cysts, inner ear, temporal bone) and malignant tumors (renal cell carcinoma [RCC], hemangioblastomas, testicular cancer, others). ‚
EPIDEMIOLOGY
- Median life expectancy: 49 years
- Most common cause of death is RCC; is secondary to neurologic complications of hemangioblastomas and metastatic clear RCC
- 95% penetrance by age 65 years; by age 25 years, most affected individuals have a detectable lesion (1,2)
- All individuals who inherit VHL gene mutations or deletions will have some degree of phenotypic expression.
- Asymptomatic VHL gene carriers: 4%
- 40% of patients with VHL have renal lesions, which manifest as multifocal and bilateral with cystic and partially cystic areas (3).
Incidence
1:31,000 to 1:39,000 live births ‚
ETIOLOGY AND PATHOPHYSIOLOGY
- VHL disease results from variations on the VHL gene located on the short arm of chromosome 3 and the 2-hit hypothesis. The VHL gene represents 3 exons that code for the VHL protein, which is thought to regulate the hypoxia-inducible factor (HIF). The cellular response to hypoxia is regulated by HIF.
- When HIF is produced, it increases the proteins that act to reverse hypoxia, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and erythropoietin. The malfunction of the VHL protein leads to an unregulated increase in HIF. This causes an increase in VEGF, PDGF, and erythropoietin, with the end results being angiogenesis, cell growth, and division, eventually contributing to tumor formation.
- Type I VHL disease is associated with large deletions of the VHL gene, whereas type II VHL disease is associated with missense substitutions of the VHL gene.
ETIOLOGY
- Autosomal dominant hereditary syndrome caused by mutations or deletions of the VHL gene
- About 20% of people with VHL do not have a family history of the disease and have mutations that occur de novo.
Genetics
Autosomal dominant transmission of VHL gene variations ‚
RISK FACTORS
Familial ‚
GENERAL PREVENTION
- Although VHL is not a preventable disease, early detection will reduce the burden of morbidity and mortality.
- Screening of asymptomatic family members of those with VHL should be done to look for the family-specific variation in the VHL gene.
- First-line screening for a patient with family history includes genetic testing for VHL gene mutation, then pedigree analysis; a complete history and physical exam, 24-hour urine catecholamines and metanephrines to assess for pheochromocytoma, ophthalmic exam, CT or MRI of abdomen, MRI of neuraxis and skull base, and/or audiogram
COMMONLY ASSOCIATED CONDITIONS
- CNS hemangioblastomas: may present in any part of the CNS, most commonly in the cerebellum, spinal cord, brainstem, supratentorial region, and lumbosacral nerve roots (in decreasing order); patients with this manifestation may also present with paroxysmal hypertension without pheochromocytoma, as well as polycythemia, which may require occasional phlebotomy (4).
- Ocular hemangioblastomas
- Endolymphatic sac tumors of the ear
- Clear RCC
- Renal cysts
- Pheochromocytoma
- Pancreatic neuroendocrine tumor and cyst
- Epididymal cyst of the testes in men and of the broad ligament in women
- Retinal angioma
- Hypercholesterolemia (due to hypoxic activation of HIF-2α) (5)
- Upper GI bleed, duodenal stenosis, cholangitis (2)
DIAGNOSIS
HISTORY
- Ascertain a proper family history of anyone presenting with previously described symptoms/lesions.
- VHL may manifest in various organs, so it is important to do a complete review of systems to pinpoint symptoms that may be secondary to lesions.
- 11 " “16% of patients with VHL develop lesions in the endolymphatic sac or duct within the temporal bone; these benign lesions can be locally invasive, causing significant morbidity such as hearing loss, tinnitus, vertigo, and facial nerve weakness.
PHYSICAL EXAM
A complete physical exam should be done to look specifically for any abnormalities that may manifest secondary to tumors, such as neurologic deficits. ‚
DIAGNOSTIC TESTS & INTERPRETATION
- Initial diagnosis is made based on clinical criteria, with confirmation by identifying VHL gene variations.
- CNS hemangioblastomas are the most common and usually the first manifestation of VHL.
- Clinical diagnosis based on the Melmon and Rosen diagnostic criteria (6)
- If with family history, presence of 1 retinal or CNS hemangioblastoma or 1 visceral lesion
- With no family history, ≥2 CNS hemangioblastomas or 1 CNS hemangioblastoma and 1 visceral lesion (excluding unilateral papillary cystadenoma of the epididymis, renal cyst, and papillary cystadenoma of the broad ligament).
- Types of VHL (based on phenotypic expression) (1)
- Type I usually do not develop pheochromocytoma but are more susceptible to other tumors.
- Type II are at increased risk of pheochromocytoma
- Type IIa hemangiomas: low risk for RCC
- Type IIb hemangiomas: high risk for RCC
- Type IIc hemangiomas: solely pheochromocytoma
- It is currently unknown how the subtypes of type II VHL correlate to variations in the VHL gene.
- Imaging modalities of patients with suspected VHL disease will depend on the clinical manifestations as well as the family history.
TREATMENT
MEDICATION
- Treatment of VHL disease depends on the lesion or tumor identified.
- There is no systemic treatment for hemangioblastomas; however, there are some data that antiangiogenic agents, such as pazopanib [fibroblast growth factor receptor (FGFR) inhibitors], may provide some benefit in CNS hemangioblastomas (7).
SURGERY/OTHER PROCEDURES
- Once RCC is diagnosed and the lesion is >3 cm, nephron-sparing surgery is recommended (1)[B].
- Given that VHL is a disease of increased risk of tumor formations, there are multiple procedures. With the improvement of technology, some of these procedures can be done with minimally invasive techniques, such as laparoscopy, robotic partial nephrectomy, and percutaneous ablation (8).
INPATIENT CONSIDERATIONS
Patients with VHL who are undergoing surgery should have adrenal studies done to rule out pheochromocytoma. ‚
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
The following are recommended for those found to have VHL gene variations ‚
- 1 to 4 years old
- Annual ophthalmologic, endocrine (24-hour urine catecholamines and metanephrines), neurologic exam
- 5 to 15 years old
- Annual ophthalmologic, endocrine, neurologic exam
- Every 2 to 3 years: audiology assessment
- >8 years old
- Annual abdominal ultrasound
- >16 years old
- Annual ophthalmologic exam
- MRI of abdomen at least every other year (to assess pancreas, kidneys, adrenals), excluding during pregnancy
- Every 2 years: MRI with contrast: brain plus cervical spine (thin cuts through posterior fossa, attention to inner ear and petrous temporal bone)
- Preserve kidney function and limiting interventions needed in a patient until solid tumors are >3 cm in diameter.
- Patients with VHL should have annual functional adrenal studies for pheochromocytoma; if positive, they should have metaiodobenzylguanidine studies to look for extra-adrenal paragangliomas.
- Pregnancy (8,9)
- There are conflicting data whether pregnancy increases the progression of cerebellar hemangioblastomas (10).
- There is an increased VHL disease " “related complication rate; therefore, intensified surveillance is recommended especially if they have a prior history of pheochromocytomas, CNS lesions, or retinal lesions (11).
PATIENT EDUCATION
- Patients should be counseled about genetic transmission of this disease as well as its associated conditions. They should also be aware of the variable penetrance of the disease.
- There is information available for patients and their families on http://www.vhl.org/ as well as through the VHL Family Alliance.
PROGNOSIS
- Depends on the type and location of tumors
- Most complications that cause increased mortality are secondary to CNS tumors and RCC. The mortality of patients with RCC associated with VHL has decreased secondary to advances in early detection and treatment.
COMPLICATIONS
- Depends on tumor lesion location and type
- During pregnancy, there can be an increase in the rate of growth of hemangioblastomas secondary to hormonal and hemodynamic changes that occur.
REFERENCES
11 Beitner ‚ MM, Winship ‚ I, Drummond ‚ KJ. Neurosurgical considerations in von Hippel-Lindau disease. J Clin Neurosci. 2011;18(2):171 " “180.22 Cassol ‚ C, Mete ‚ O. Endocrine manifestations of von Hippel " “Lindau disease. Arch Pathol Lab Med. 2015;139(2):263 " “268.33 Coleman ‚ JA. Familial and hereditary renal cancer syndromes. Urol Clin North Am. 2008;35(4):563 " “572.44 Farrell ‚ CJ, Plotkin ‚ SR. Genetic causes of brain tumors: neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and other syndromes. Neurol Clin. 2007;25(4):925 " “946.55 Ramakrishnan ‚ SK, Taylor ‚ M, Qu ‚ A, et al. Loss of von Hippel-Lindau protein (VHL) increases systemic cholesterol levels through targeting hypoxia-inducible factor 2α and regulation of bile acid homeostasis. Mol Cell Biol. 2014;34(7):1208 " “1220.66 Tang ‚ PA, Vickers ‚ MM, Heng ‚ DY. Clinical and molecular prognostic factors in renal cell carcinoma: what we know so far. Hematol Oncol Clin North Am. 2011;25(4):871 " “891.77 Kim ‚ BYS, Jonasch ‚ E, McCutcheon ‚ IE. Pazopanib therapy for cerebellar hemangioblastomas in von Hippel-Lindau disease. Target Oncol. 2012;7(2):145 " “149.88 Smaldone ‚ MC, Fung ‚ C, Uzzo ‚ RG, et al. Adjuvant and neoadjuvant therapies in high-risk renal cell carcinoma. Hematol Oncol Clin North Am. 2011;25(4):765 " “791.99 Ye ‚ DY, Bakhtian ‚ KD, Asthagiri ‚ AR, et al. Effect of pregnancy on hemangioblastoma development and progression in von Hippel-Lindau disease. J Neurosurg. 2012;117(5):818 " “824.1010 Frantzen ‚ C, Kruizinga ‚ RC, van Asselt ‚ SJ, et al. Pregnancy-related hemangioblastoma progression and complications in von Hippel-Lindau disease. Neurology. 2012;79(8):793 " “796.1111 Hayden ‚ MG, Gephart ‚ R, Kalanithi ‚ P, et al. Von Hippel-Lindau disease in pregnancy: a brief review. J Clin Neurosci. 2009;16(5):611 " “613.
ADDITIONAL READING
VHL Alliance. http://vhl.org/ ‚
CODES
ICD10
Q85.8 Other phakomatoses, not elsewhere classified ‚
ICD9
759.6 Other hamartoses, not elsewhere classified ‚
SNOMED
von Hippel-Lindau syndrome (disorder) ‚
CLINICAL PEARLS
- Patients diagnosed with any of the associated conditions (CNS or ocular hemangioblastomas, endolymphatic sac tumors of the ear, conventional clear RCC, pheochromocytoma, pancreatic neuroendocrine tumor and cyst, and epididymal cyst of the testes in men or of the broad ligament in women) should be considered for further screening for VHL gene variation through an extensive history and physical and, if necessary, genetic testing.
- CNS hemangioblastomas are the most common and usually the first manifestation of VHL.
- Most complications that cause increased mortality are secondary to CNS tumors and RCC. The mortality of patients with RCC associated with VHL has decreased secondary to advances in early detection and treatment.