Von Hippel-Lindau Syndrome

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: VHL (HGNC:12687)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 01/04/2022
• Curation Status: Released (2.0.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
VHL	von Hippel-Lindau disease (0008667)	193300	Strong Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion of strong according to the rubric. Note that effectiveness impact is highest in patients with truncating variants.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality from VHL-related tumors / Evaluation by specialist with imaging and biochemical testing to detect tumors (or precursors) and guide treatment	2	3A	3B	2	10AB

Severity of Outcome

Prevalence of the Genetic Condition

The incidence of von Hippel-Lindau syndrome (VHL) is estimated to be between 1/43,000-1/27,000 live births in the general population. It has an internationally reported prevalence between 1/93,000-1/31,000. VHL is estimated to account for approximately a third of patients with a central nervous system (CNS) hemangioblastoma, >50% of patients with a retinal angioma, 1% of patients with renal cell carcinoma, 50% of patients with apparently isolated familial pheochromocytoma (PHEO), and 11% of patients with an apparently sporadic PHEO.

Clinical Features (Signs / symptoms)

VHL is characterized by CNS and retinal hemangioblastomas; renal cysts that are typically multifocal and bilateral, and clear cell renal carcinoma; PHEOs and paragangliomas; pancreatic neuroendocrine tumors (pNETs), cysts, and serous cystadenomas; endolymphatic sac tumors (ELSTs); and cysts and papillary cystadenomas of the broad ligament and epididymis. VHL-related tumors of the brain, spinal cord, and retina are benign, while tumors in the kidneys and pancreas may become malignant. Cerebellar hemangioblastomas may be associated with headache, vomiting, gait disturbances, and limb or truncal ataxia. Spinal hemangioblastomas are usually associated with pain. Sensory and motor loss may develop with cord compression. Retinal hemangioblastomas can cause retinal detachment, macular edema, glaucoma, and vision loss. Pheochromocytomas can be asymptomatic but may cause sustained or episodic hypertension, headaches, irregular or rapid heartrate, heavy sweating, hot and/or cold flashes, abdominal pain, weight loss or what feels like a panic attack, fear, anxiety, or rage. Pancreatic lesions often remain asymptomatic and rarely cause endocrine or exocrine insufficiency. ELSTs can cause hearing loss of varying severity, tinnitus, dizziness, aural fullness, or facial paresis; and symptoms often occur suddenly. Cystadenomas of the epididymis, which are virtually pathognomonic for VHL when bilateral, rarely cause problems, but may cause infertility.

Natural History (Important subgroups & survival / recovery)

Retinal hemangioblastomas are the most common presenting feature of VHL (up to 80%), have an average age of diagnosis of 25-37 years but may present as young as 1 year, and are multiple and bilateral in ~50% of cases with 35% experiencing visual loss and 8% developing blindness. CNS hemangioblastomas, the prototypic lesions of VHL, are the presenting feature in ~40% of cases, have an average age of diagnosis of 25-38 years but have been reported as young as 8 years, and are often multifocal. Renal cysts have an average age of diagnosis of 34-39 years, and lead to renal cell carcinoma in 70% of cases by age 60. Renal cell carcinoma has an average age of diagnosis of 37-45 years (diagnosed as early as 13 years) and is one of the leading causes of mortality, along with CNS hemangioblastomas. Pancreatic lesions are found in ~60% of patients with 5-29% developing pNETs, have a median age of onset between 32-38 years but have been described as early as 5 years, and are often multifocal and bilateral. Metastatic pNETs have been reported as young as 11 years. ELSTs have an average age of diagnosis of 22-40 years. PHEOs and paragangliomas have an average age of diagnosis of 20-29 years but have been reported as young as 4 years. Overall, the median age of tumor diagnosis is 22-31 years, significantly younger than sporadic cases of the associated tumors, and an overall penetrance of 87% at 60 years of age. Historically, patients with VHL had poor survival (median life expectancy <50 years). However, with improved medical management, recent studies have demonstrated median survival rates of 60-67 years. VHL-associated pancreatic lesions are slightly more common in women than men. But overall, males have been reported to have more manifestations, increased tumor burden, and faster CNS hemangioblastoma tumor growth than females.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

< 1-2 in 100000

The estimated point prevalence of heterozygotes is between 1/53,000-1/85,000.

Tier 3

Unknown

Pathogenic VHL germline variants can be detected in nearly 100% of patients fulfilling the

clinical criteria for VHL.

Tier 3

Unknown

Up to 25% of individuals have VHL due to a de novo pathogenic variant.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

VHL pathogenic variants are highly penetrant, with >90% of all individuals expressing a disease-related symptom by age 65, and nearly 100% by age 75.

Tier 3

Unknown

A meta-analysis of 45 studies including 4263 patients with a clinical and/or molecular diagnosis of VHL reported the frequencies of the following phenotypic manifestations:

• CNS hemangioblastoma = 63%

• Retinal angiomas = 51%

• Pancreatic cyst or cystadenoma = 38%

• Renal cell carcinoma = 33%

• PHEO and/or paraganglioma = 19.4%, with 59.5% of patients having bilateral PHEOs

• ELST = 3%.

Tier 1

Unknown

In the VHL population, the malignancy rate of PHEO is extremely low (<5%).

Tier 3

Unknown

A systematic review including 1442 patients with a clinical diagnosis of VHL (genetic status unknown) from 10 studies reported that pNETs were found in 15% (211/1442) of patients and 2% of those (27/211) were malignant.

Tier 1

Unknown

A recent registry study that included 273 patients with VHL-associated pNETs, found pNETs and metastatic pNETs to be more frequent in patients with VHL exon 3 pathogenic variants compared to those with variants in exons 1 and 2 (pNETs, 107/521 vs 84/728; p < 0.001 and metastatic pNETs, 30/521 vs 13/728; p < 0.001).

Tier 3

Unknown

Two recent retrospective studies of 143 and 340 patients with VHL (100% and 72% genetically confirmed, respectively) reported that CNS hemangioblastomas account for 51-67.7% of deaths and renal cell carcinoma account for 27.8-36% of deaths.

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

No information on relative risk was identified.

Expressivity

VHL manifestations and their severity are highly variable both within and between families, even among those with the same pathogenic variant. Age of onset can also vary considerably from family to family and from individual to individual.

Tier 4

A retrospective analysis of 52 VHL pathogenic variant carriers, spanning 799 person-years, found that the rate of new tumor development varied significantly with age and was highest at 30-34 years. The risk of retinal tumors was highest in subjects during the teenage years but was highest for cerebellar tumors in subjects during their 30s. Thus, the rate of new manifestation development is not constant throughout the life span of VHL patients.

Tier 3

Carriers of truncating VHL pathogenic variants have a significantly higher manifestation rate compared with missense variant carriers (hazard ratio = 1.85, p = 0.031).

Tier 3

Genotype-phenotype correlation studies have been published primarily on the presence/absence of PHEOs for the general VHL phenotypes (Types 1, 1B, 2A, 2B, 2C) and classes of variants (e.g., truncating, missense) and/or specific missense variants, but further investigation is needed. Patterns are not clear-cut, significant overlap exists, and genotype-phenotype correlations have no current diagnostic or therapeutic value.

Tier 3

Intervention Effectiveness

Patient Management

Patients with VHL should be followed in a VHL clinical care center whenever feasible. A coordinated multidisciplinary care approach should be led by a provider with experience with VHL. Specialists involved in the care of patients with VHL include clinical genetics providers, neurosurgeons, urologists, radiologists, oncologists, ophthalmologists, audiologists, gastroenterology, and endocrinologists.

Tier 2

Initial work-up of an individual suspected of having VHL includes:

• Interviewing about VHL-associated symptoms and neurological examination

• Ophthalmoscopy with dilation

• Hearing examination in a department of audiology

• Plasma-metanephrines and plasma-normetanephrine (if age 5 or older) and plasma-chromogranin A (if age 18 or older)

• Magnetic resonance imaging (MRI) of the entire CNS (the craniospinal axis), kidneys, pancreas, and liver.

Tier 2

Management of VHL is organ-specific, with the aim of intervening at a time point of maximal benefit to the patient to either resolve symptoms or limit the chance of development of metastatic disease while considering the recurrent and multiple interventions many patients will have over the course of their lifetime. Generally, for benign lesions (e.g., CNS hemangioblastomas, pancreatic cysts), intervention should be done upon development of symptoms, and for those whose malignant potential cannot be discerned. For VHL-associated tumors with the potential to become metastatic (renal masses, pNETs), the decision to operate versus observe depends primarily on tumor size, but may also include rate of tumor growth, germline VHL pathogenic variant, tumor location, and comorbidities.

Tier 2

Belzutifan, a hypoxia-inducible factor inhibitor, may be used as a treatment option for adults with VHL-associated CNS hemangioblastomas and progressive pNETs, not requiring immediate surgery; and is a preferred treatment for RCC.

Tier 2

Belzutifan is not approved for pediatric patients for any indication. Guidelines did not specifically discuss the use of Belzutifan for retinal hemangioblastomas. In a phase II trial including 61 adult patients with a germline VHL alteration and VHL-associated RCC, there were 12 evaluable participants (16 eyes) with retinal hemangioblastomas at baseline, all of which were graded as showing improvement. Objective responses were also observed in patients with RCC (49%), pancreatic lesions (77%) and CNS hemangioblastomas (30%).

Tier 5

Pheochromocytomas should be surgically removed, and preoperative treatment with alpha-adrenergic blockade and optional additional beta-adrenergic blockade is recommended.

Tier 4

Surveillance

Presymptomatic individuals should undergo the following evaluations:

• History and physical examination (yearly from birth)

• Blood pressure and pulse for PHEOs and paragangliomas (yearly from age 2)

• Measurement of blood or urinary metanephrines and possibly catecholamines for PHEOs and paragangliomas (yearly from age 2-5). If not already being performed, begin measurement of plasma chromogranin A levels by age 15 (yearly)

• Additional laboratory evaluations may include serum creatinine, liver enzymes, hemoglobin, leukocyte and platelet counts, lymphocyte-to-neutrophil ratio, lactate dehydrogenase, and serum-corrected calcium for screening of renal masses

• Neurological assessments for ELSTs (yearly from age 5)

• Ophthalmoscopy with dilation (yearly from birth)

• Hearing evaluation (every 1-2 years from age 5)

• MRI of the inner ear (every 2 years from age 8-15)

• MRI of the brain (with or without contrast) and spine (every 2 years from age 8-16). Consider annually from mid- to late-adolescence

• MRI (with or without contrast) of the abdomen to evaluate kidneys, adrenal glands, pancreas, liver (every 1-2 years from age 10-16). Consider computed tomography (CT) with and without contrast and/or ultrasound in some scenarios.

Tier 2

MRI with gadolinium is the most sensitive and specific imaging modality for detecting and monitoring changes in CNS hemangioblastomas in patients with VHL and can reliably detect small hemangioblastomas (≥2 mm in diameter). When patients with VHL undergo routine MRI of multiple organ systems for surveillance, the rate of intercurrent CNS manifestations was 7% when MRI of the craniospinal axis was performed biennially and 3% when performed annually.

Tier 2

Four meta-analyses (N=286-6741 renal masses in non-VHL patients) reported that in well-selected patients with small renal masses, the risk of metastatic progression while on active surveillance is <2% beyond the first 3 years of follow-up. In addition, the incidence and mortality of metastatic RCC have significantly decreased among patients with VHL since the implementation of routine abdominal imaging screening guidelines.

Tier 2

A meta-analysis including 3 comparative studies (ranging from 20-40 histopathologically diagnosed patients per imaging group) found that the sensitivity for detecting pNETs in patients with VHL ranged from 82-96% for CT versus 54-82% for MRI. Two of the studies reported genetic status, with 60-93% of patients being genetically confirmed.

Tier 1

A registry study of 2330 patients with VHL (85% of whom were genetically confirmed), 273 (12%) of which had pNETs, reported survival estimates based on tumor size and operation status. All 273 patients had an MRI (71%) and/or CT (51%) as initial imaging study, and then either MRI or ultrasonography for follow-up monitoring at intervals of ≥12 months. Overall, 91% of pNets were detected by screening in asymptomatic patients, and metastatic pNETs were diagnosed in 55 patients (20%). In the 117 patients who underwent surgery, survival was significantly longer for patients with smaller (1.5–2.7 cm) versus larger (≥2.8 cm) tumors (94% vs 80%; p=0.03, median follow-up 7 years). Ten-year survival was significantly longer in operated vs non-operated patients, regardless of tumor size (88% vs 74%; p=0.04).

Tier 5

MRI and CT scans have excellent performance characteristics for the detection of PHEOs with a sensitivity of greater than 90%.

Tier 3

Longitudinal surveillance in VHL limits morbidity and mortality. One retrospective study of 143 carriers of pathogenic variants in VHL found no significant differences in risk of VHL-related death or overall survival based on whether they underwent surveillance for CNS and abdominal lesions for 3 or more consecutive years. However, in a sub-analysis of 62 VHL missense variant carriers and 70 carriers of VHL truncating variants, truncating variant carriers who underwent surveillance had significantly lower death rates than those who did not (hazard ratio [HR]=0.22, 95% confidence interval 0.07-0.69, p=0.0095). There were no significant differences in risk of VHL-related death for missense variant carriers based on their surveillance status (HR=1.63, 95% CI 0.52-5.15, p=0.41).

Tier 2

Once an organ becomes affected, a specific follow-up program for this organ should be composed. Symptoms that occur between routine surveillance examinations will lead to new targeted examinations. Any positive findings should lead to referral to a relevant specialist. Imaging frequency should be increased once lesions are detected based on growth rate and size of lesion.

Tier 2

A meta-analysis including 2 cohort studies of 108 and 111 VHL patients with pNETs reported rapid doubling time in patients with metastatic disease (median 11-22 months for metastatic versus 87-126 months for non-metastatic), warranting frequent surveillance until tumor size stabilizes.

Tier 1

Neuraxial and abdominal MRI should be performed prior to a planned pregnancy, if possible. If a patient becomes symptomatic while pregnant, MRI can be obtained without contrast if the clinician suspects a developing mass. Previous anecdotal reports, case reports, and small studies have described the effect of pregnancy on hemangioblastoma development and progression with conflicting results. Anecdotal case reports have described occasional dramatic increases in the cysts or edema associated with hemangioblastomas during pregnancy, but these have often occurred in the aftermath of missed surveillance imaging.

Tier 2

Women should also undergo all recommended presymptomatic (non-imaging) evaluations just prior to planned conception. After the preconception dilated eye exam, eye exams should be performed every 6-12 months. It is extremely important to test for and manage PHEOs before childbirth to ensure the safety of the patient and unborn child. Approximately 2–3 months post-partum, a thorough check-up to evaluate any changes may be warranted, as new symptoms or complications of CNS lesions have been reported in one study to occur postpartum. However, there is no clear evidence as to whether pregnancy impacts tumor growth or leads to an increase in complications.

Tier 4

Prior to any surgical procedure, patients with VHL should have blood and/or urine screening for PHEOs due to increased risk of these tumors.

Tier 2

Clinicians can cease additional routine asymptomatic imaging for pNETs and CNS hemangioblastomas in patients beyond the age of 65 years if they have not developed a lesion previously.

Tier 2

Circumstances to Avoid

Due to the unknown, but possible, risks of long-term low exposure to radiation, CT scans should be avoided for children and pre-symptomatic individuals and should be reserved for when truly needed.

Tier 4

Tobacco products should be avoided since they are considered a risk factor for kidney cancer; chemicals and industrial toxins known to affect VHL-involved organs should be avoided; and contact sports should be avoided if adrenal or pancreatic lesions are present.

Tier 4

Nature of Intervention

Nature of Intervention

The clinical management of VHL is highly complex, extends beyond routine clinical surveillance, and involves referral to medical specialists and centers. The interventions identified in this report involve extensive clinical lifelong surveillance. Tumor surveillance is time consuming and may incur substantial financial and psychosocial burdens. This may lead to noncompliance, particularly in children. Due to the frequency and extent of imaging required, routine use of CT is of concern with regards to radiation exposure. Anesthesia may be required for eye exams and MRI scans for young children. Laboratory tests to screen for PHEO can be difficult to perform on a child.

Context: Adult Pediatric

Chance to Escape Clinical Detection

Most patients are diagnosed after the discovery of CNS tumors. Thus, tumor development and progression are likely to escape detection in the setting of general clinical care. Due to the complex nature and rarity of VHL, physicians often fail to recognize the underlying disease for many years, impeding the implementation of a prophylactic screening program. ELSTs, which can be missed on standard MRI, are often misdiagnosed as Meniere’s disease. PHEO symptoms in pregnant VHL patients can be overlooked and undiagnosed, assuming high blood pressure due to possible preeclampsia.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			VHL			193300	0008667

References List

(VHLA) VA. The VHL Handbook. 6th ed. 2020 (2020) URL: https://www.vhl.org/wp-content/uploads/2020/10/Handbook_2020_final.pdf?cf_id=4409&eType=ActivityDefinitionInstance&eId=1a0048a9-6697-48fb-b79d-9d74f8aca982.

Ahmad S, Naber MR, Giles RH, Valk GD, van Leeuwaarde RS. (2021) Diagnostic and management strategies for pNETs in Von Hippel-Lindau: a systematic review. Endocrine-related cancer. 28(1479-6821):151-160.

Binderup ML, Bisgaard ML, Harbud V, Møller HU, Gimsing S, Friis-Hansen L, Hansen Tv, Bagi P, Knigge U, Kosteljanetz M, Bøgeskov L, Thomsen C, Gerdes AM, Ousager LB, Sunde L, Danish vHL Coordination Group. (2013) Von Hippel-Lindau disease (vHL). National clinical guideline for diagnosis and surveillance in Denmark. 3rd edition. Danish medical journal. 60(2245-1919):B4763.

Castro-Teles J, Sousa-Pinto B, Rebelo S, Pignatelli D. (2021) Pheochromocytomas and paragangliomas in von Hippel-Lindau disease: not a needle in a haystack. Endocrine connections. 10(2049-3614):R293-R304.

Chahoud J, McGettigan M, Parikh N, Boris RS, Iliopoulos O, Rathmell WK, Daniels AB, Jonasch E, Spiess PE, International VHL Surveillance Guidelines Consortium-Renal Committee. (2021) Evaluation, diagnosis and surveillance of renal masses in the setting of VHL disease. World journal of urology. 39(1433-8726):2409-2415.

Charlesworth M, Verbeke CS, Falk GA, Walsh M, Smith AM, Morris-Stiff G. (2012) Pancreatic lesions in von Hippel-Lindau disease? A systematic review and meta-synthesis of the literature. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 16(7):1422-8.

Decker J, Neuhaus C, Macdonald F, Brauch H, Maher ER. (2014) Clinical utility gene card for: von Hippel-Lindau (VHL). European journal of human genetics : EJHG. 22(4).

Food and Drug Administration. FDA label for WELIREG (belzutifan).. (2021) Accessed: 2022-01-19. URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215383s000lbl.pdf

Howe JR, Merchant NB, Conrad C, Keutgen XM, Hallet J, Drebin JA, Minter RM, Lairmore TC, Tseng JF, Zeh HJ, Libutti SK, Singh G, Lee JE, Hope TA, Kim MK, Menda Y, Halfdanarson TR, Chan JA, Pommier RF. (2020) The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors. Pancreas. 49(1536-4828):1-33.

Huntoon K, Shepard MJ, Lukas RV, McCutcheon IE, Daniels AB, Asthagiri AR. (2021) Hemangioblastoma diagnosis and surveillance in von Hippel-Lindau disease: a consensus statement. Journal of neurosurgery. 1-6.

Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, Oudard S, Else T, Maranchie JK, Welsh SJ, Thamake S, Park EK, Perini RF, Linehan WM, Srinivasan R, MK-6482-004 Investigators. (2021) Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. The New England journal of medicine. 385(1533-4406):2036-2046.

Keutgen XM, Hammel P, Choyke PL, Libutti SK, Jonasch E, Kebebew E. (2016) Evaluation and management of pancreatic lesions in patients with von Hippel-Lindau disease. Nature reviews. Clinical oncology. 13(1759-4782):537-49.

Krauss T, Ferrara AM, Links TP, Wellner U, Bancos I, Kvachenyuk A, Villar Gómez de Las Heras K, Yukina MY, Petrov R, Bullivant G, von Duecker L, Jadhav S, Ploeckinger U, Welin S, Schalin-Jäntti C, Gimm O, Pfeifer M, Ngeow J, Hasse-Lazar K, Sansó G, Qi X, Ugurlu MU, Diaz RE, Wohllk N, Peczkowska M, Aberle J, Lourenço DM, Pereira MAA, Fragoso MCBV, Hoff AO, Almeida MQ, Violante AHD, Quidute ARP, Zhang Z, Recasens M, Díaz LR, Kunavisarut T, Wannachalee T, Sirinvaravong S, Jonasch E, Grozinsky-Glasberg S, Fraenkel M, Beltsevich D, Egorov VI, Bausch D, Schott M, Tiling N, Pennelli G, Zschiedrich S, Därr R, Ruf J, Denecke T, Link KH, Zovato S, von Dobschuetz E, Yaremchuk S, Amthauer H, Makay Ö, Patocs A, Walz MK, Huber TB, Seufert J, Hellman P, Kim RH, Kuchinskaya E, Schiavi F, Malinoc A, Reisch N, Jarzab B, Barontini M, Januszewicz A, Shah N, Young WF, Opocher G, Eng C, Neumann HPH, Bausch B. (2018) Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors. Endocrine-related cancer. 25(1479-6821):783-793.

Laks S, van Leeuwaarde R, Patel D, Keutgen XM, Hammel P, Nilubol N, Links TP, Halfdanarson TR, Daniels AB, Tirosh A, Pancreatic Manifestations Recommendations Development Subcommittee of the VHL Alliance. (2021) Management recommendations for pancreatic manifestations of von Hippel-Lindau disease. Cancer.

National Cancer Institute. Von Hippel-Lindau Disease (PDQ(R)): Health Professional Version. PDQ Cancer Information Summaries (2021) URL: https://pubmed.ncbi.nlm.nih.gov/33724751/#_586

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Kidney Cancer. Version 4.2022 — Dec. 21, 2021.. (2021) URL: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Neuroendocrine and Adrenal Tumors. Version 4.2021 — Dec.14, 2021.. (2021) URL: https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf

National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Central Nervous System Cancers. Version 2.2021 — September 8, 2021.. (2021) Accessed: 2022-01-20. URL: https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf

Rabi DM, McBrien KA, Sapir-Pichhadze R, Nakhla M, Ahmed SB, Dumanski SM, Butalia S, Leung AA, Harris KC, Cloutier L, Zarnke KB, Ruzicka M, Hiremath S, Feldman RD, Tobe SW, Campbell TS, Bacon SL, Nerenberg KA, Dresser GK, Fournier A, Burgess E, Lindsay P, Rabkin SW, Prebtani APH, Grover S, Honos G, Alfonsi JE, Arcand J, Audibert F, Benoit G, Bittman J, Bolli P, Côté AM, Dionne J, Don-Wauchope A, Edwards C, Firoz T, Gabor JY, Gilbert RE, Grégoire JC, Gryn SE, Gupta M, Hannah-Shmouni F, Hegele RA, Herman RJ, Hill MD, Howlett JG, Hundemer GL, Jones C, Kaczorowski J, Khan NA, Kuyper LM, Lamarre-Cliche M, Lavoie KL, Leiter LA, Lewanczuk R, Logan AG, Magee LA, Mangat BK, McFarlane PA, McLean D, Michaud A, Milot A, Moe GW, Penner SB, Pipe A, Poppe AY, Rey E, Roerecke M, Schiffrin EL, Selby P, Sharma M, Shoamanesh A, Sivapalan P, Townsend RR, Tran K, Trudeau L, Tsuyuki RT, Vallée M, Woo V, Bell AD, Daskalopoulou SS. (2020) Hypertension Canada's 2020 Comprehensive Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension in Adults and Children. The Canadian journal of cardiology. 36(1916-7075):596-624.

Rednam SP, Erez A, Druker H, Janeway KA, Kamihara J, Kohlmann WK, Nathanson KL, States LJ, Tomlinson GE, Villani A, Voss SD, Schiffman JD, Wasserman JD. (2017) Von Hippel-Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clinical cancer research : an official journal of the American Association for Cancer Research. 23(1557-3265):e68-e75.

van Leeuwaarde RS, Ahmad S, Links TP, Giles RH.. Von Hippel-Lindau Syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, et al., editors. GeneReviews((R)) (2018) URL: https://www.ncbi.nlm.nih.gov/pubmed/20301636

Von Hippel-Lindau disease. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=892

VON HIPPEL-LINDAU SYNDROME; VHLS. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 193300, (2020) World Wide Web URL: http://omim.org/