Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.2.0
• GENE/GENE PANEL: VHL
• Condition: Von Hippel-Lindau Syndrome
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• VHL ⇔ 193300 (von hippel-lindau syndrome; vhl): Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Gene Condition Pairs: VHL ⇔ (OMIM:193300)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Pheochromocytoma / Surveillance	2	3C	2B	3	10CB
Renal cell carcinoma / Surveillance	2	3C	3C	3	11CC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

VHL has a prevalence of 1/39,000-1/53,000 and is estimated to account for approximately a third of patients with a CNS hemangioblastoma, >50% of patients with a retinal angioma, 1% of patients with renal cell carcinoma, 50% of patients with apparently isolated familial pheochromocytoma, and 11% of patients with an apparently sporadic pheochromocytoma. [1]

Clinical Features

VHL is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal carcinoma; pheochromocytomas; pancreatic tumors including simple cysts, serous cystadenomas, and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. [1, 2, 3, 4, 5]

Natural History

Retinal angiomas are the most common presenting feature of VHL, have an average age of diagnosis of 25, and are multiple and bilateral in ~50% of cases with 35% experiencing visual loss. CNS hemangioblastomas are the prototypic lesions of VHL, are the presenting feature in ~40% of cases, and have an average age of diagnosis of 29-34 years. Multiple renal cysts are common and lead to renal cell carcinoma in 70% of cases by age 60. Renal cell carcinoma has an average age of diagnosis of 40-45 years and is a leading cause of mortality. Pancreatic lesions are found in ~60% of patients with 5-10% developing pancreatic tumors. Overall, the median age of tumor diagnosis is 22-26 years, significantly younger than sporadic cases of the associated tumors, and the median life expectancy is ~50 years. There is no sex or ethnicity bias. [1, 2, 3, 4, 5]

2. How effective are interventions for preventing harm?

Patient Management

No patient management recommendations have been provided for the Adult context.

Surveillance

Patients should undergo screening for pheochromocytomas. (Tier 2) [6]

Patients should undergo annual neurologic, vision, ophthalmology, and hearing evaluation; annual blood pressure monitoring; annual blood or urinary normetanephrine levels; thin-slice MRI with contrast of the internal auditory canal in those with repeated ear infections; annual abdominal ultrasound and every other year MRI scan of the abdomen; and MRI of the brain and total spine every 1-3 years. (Tier 4) [1, 2, 5]

Women should undergo intensified surveillance for cerebellar hemangioblastoma and pheochromocytoma during preconception and pregnancy, including MRI without contrast of the cerebellum at four months' gestation. (Tier 4) [2]

Circumstances to Avoid

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) [2]

Computed tomography should only be applied in particular situations given the high cumulative radiation load. (Tier 4) [1, 5]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

VHL mutations have the same prevalence as VHL, which is estimated as 1/39,000-1/53,000. (Tier 3) [1]

Penetrance

VHL mutations are highly penetrant, with almost all individuals expressing a disease-related symptom by age 65. The frequencies of specific features among cases are: CNS hemangioblastomas=60-80%, retinal angiomas=70%, renal cell carcinoma=70%, epididymal cystadenomas in males=60%, endolymphatic sac tumors=10-11%, and head and neck paragangliomas=0.5%. (Tier 3) 60% of cases have pancreatic lesions. Neuroendocrine tumors are found in 15% of patients with 2% found to be malignant. (Tier 1) [1, 2, 3]

Information on the penetrance of variants was not available for the Adult context.

The frequencies of specific features among cases are: CNS hemangioblastomas=60-80%, retinal angiomas=70%, renal cell carcinoma=70%, epididymal cystadenomas in males=60%, endolymphatic sac tumors=10-11%, and head and neck paragangliomas=0.5%. (Tier 3) [1, 2]

Relative Risk

Information on relative risk was unavailable.

Expressivity

VHL manifestations and their severity are highly variable both within and between families, even among those with the same mutation. (Tier 4) [1, 2, 4]

4. What is the Nature of the Intervention?

Nature of Intervention

The interventions identified in this report involve extensive clinical surveillance.

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

The clinical management of VHL is highly complex, extends beyond routine clinical surveillance, and involves referral to medical specialists and centers. The majority of patients are diagnosed after the discovery of CNS tumors. Thus tumor development and progression is likely to escape detection in the setting of general clinical care. (Tier 4) [1, 3]

Date of Search: 02.28.2014

Reference List

1. Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. (2011) 19(6):617-23.

2. Von Hippel-Lindau Disease. Gene Reviews. (2012) Website: http://www.ncbi.nlm.nih.gov/books/NBK1463/

3. Charlesworth M, Verbeke CS, Falk GA, Walsh M, Smith AM, Morris-Stiff G. Pancreatic lesions in von Hippel-Lindau disease? A systematic review and meta-synthesis of the literature. J Gastrointest Surg. (2012) 16(7):1422-8.

4. Von Hippel-Lindau Disease. Orphanet. (2012) Website: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=892

5. Decker J, Neuhaus C, Macdonald F, Brauch H, Maher ER. Clinical utility gene card for: von Hippel-Lindau (VHL). Eur J Hum Genet. (2014) 22(4).

6. Hackam DG, Quinn RR, Ravani P, Rabi DM, Dasgupta K, Daskalopoulou SS, Khan NA, Herman RJ, Bacon SL, Cloutier L, Dawes M, Rabkin SW, Gilbert RE, Ruzicka M, McKay DW, Campbell TS, Grover S, Honos G, Schiffrin EL, Bolli P, Wilson TW, Feldman RD, Lindsay P, Hill MD, Gelfer M, Burns KD, Vallee M, Prasad GV, Lebel M, McLean D, Arnold JM, Moe GW, Howlett JG, Boulanger JM, Larochelle P, Leiter LA, Jones C, Ogilvie RI, Woo V, Kaczorowski J, Trudeau L, Petrella RJ, Milot A, Stone JA, Drouin D, Lavoie KL, Lamarre-Cliche M, Godwin M, Tremblay G, Hamet P, Fodor G, Carruthers SG, Pylypchuk GB, Burgess E, Lewanczuk R, Dresser GK, Penner SB, Hegele RA, McFarlane PA, Sharma M, Reid DJ, Tobe SW, Poirier L, Padwal RS. The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol. (2013) 29(5):528-42.