Neurological Implications of von-Hippel Lindau disease

1. Neurological Implications
of von Hippel–Lindau Disease
Ade Wijaya, MD – December 2021

2. von Hippel–Lindau (VHL) disease
 Neoplasia
 Autosomal dominant
 Germline mutation of the VHL tumor
suppressor gene (NC_000003.12)
located on the short arm of
chromosome 3
 1 in 36.000 births
 Highly penetrant > 90 % by age 65
years
Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993;260(5112):1317-1320.
Wait SD, Vortmeyer AO, Lonser RR, et al. Somatic mutations in VHL germline deletion kindred correlate with mild phenotype. Ann Neurol. 2004; 55(2):236-240.
Maher ER, Iselius L, Yates JR, et al. Von Hippel-Lindau disease: a genetic study.J Med Genet. 1991;28(7):443-447.
Neumann HP, Wiestler OD. Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. Lancet. 1991;337(8749): 1052-1054.

3. Clinical Presentation
• renal cell carcinomas or cysts,
pheochromocytomas, pancreatic
neuroendocrine tumors or cysts,
and benign cystadenomas of the
adnexal organs.
Viscera
• Hemangioblastomas of the retina
and craniospinal axis as well as
endolymphatic sac tumors
(ELSTs).
CNS
The most frequent cause of VHL disease– associated morbidity and mortality is
craniospinal hemangioblas toma development and progression
Neumann HP, Wiestler OD. Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. Lancet. 1991;337(8749): 1052-1054.
Lonser RR, Glenn GM, Walther M, et al. von Hippel-Lindau disease. Lancet. 2003;361 (9374):2059-2067.
Richard S, Campello C, Taillandier L, Parker F, Resche F; French VHL Study Group. Haemangioblastoma of the central nervous system in von Hippel–Lindau disease. J
Intern Med. 1998; 243(6):547-553.

4. Dornbos, D., Kim, H. J., Butman, J. A., & Lonser, R. R. (2018). Review of the neurological implications of von Hippel–Lindau disease. JAMA neurology, 75(5), 620-627.

5. Diagnosis
 Clinical criteria
 Genetic testing
 Imaging
 Opthalmologic screening
 24-hour urinary catecholamines.
Dornbos, D., Kim, H. J., Butman, J. A., & Lonser, R. R. (2018). Review of the neurological implications of von Hippel–Lindau disease. JAMA neurology, 75(5), 620-627.
Maher ER, Iselius L, Yates JR, et al. Von Hippel-Lindau disease: a genetic study.J Med Genet. 1991;28(7):443-447

6. Clinical Criteria
Family history (+)
• Single tumor
Family history (-)
• 2 CNS hemangioblastomas or
• 1 CNS hemangioblastoma and a
VHL-associated visceral tumor
Lonser RR, Glenn GM, Walther M, et al. von Hippel-Lindau disease. Lancet. 2003;361 (9374):2059-2067.
Lamiell JM, Salazar FG, Hsia YE. Von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore). 1989;68(1): 1-29.
Melmon KL, Rosen SW. Lindau’s disease: review of the literature and study of a large kindred. Am J Med. 1964;36:595-617.

7. Hemangioblastoma
 Most common tumor associated with VHL
disease
 > 80% of VHL patients develop a craniospinal
hemangioblastoma during their lifetime (with
a mean (SD) age of presentation of 33 (10.2)
years)
 > 90 % hemangioblastomas are multiple
 Cerebellum (45-50%), brainstem (5-10%),
spinal cord (40-45%)
 Patients with solitary CNS hemangioblastoma
should undergo craniospinal imaging,
systemic screening, and genetic testing.
Butman JA, Linehan WM, Lonser RR. Neurologic manifestations of von Hippel-Lindau disease.JAMA. 008;300(11):1334-1342.
Wanebo JE, Lonser RR, Glenn GM, Oldfield EH. The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease.J
Neurosurg. 03;98(1):82-94.
Feletti A, Anglani M, Scarpa B, et al.Von Hippel-Lindau disease: an evaluation of natural history and functional disability. Neuro Oncol. 2016;18(7):1011-1020.

8. Tumor Burden, Progression, and Development
 Symptomatic tumors grow up to 10 times
faster than asymptomatic tumors.
 Younger age is associated with new
tumor development in patients with VHL
disease.
 Peritumoral cysts  proggresive, grow
faster
 Cyst growth rate was associated with
younger age, symptom development,
and anatomical location (cerebellar cysts
enlarged fastest)
Dornbos, D., Kim, H. J., Butman, J. A., & Lonser, R. R. (2018). Review of the neurological implications of von Hippel–Lindau disease. JAMA neurology, 75(5), 620-627.

9. Prognosis
 Primary cause of mortality in VHL
 Neurological disability ismost likely to
occur in the fourth to fifth decades
withmean life expectancies of 67
years for men and 60 years for women
Binderup ML, Jensen AM, Budtz-Jørgensen EBisgaard ML. Survival and causes of death in patients with von Hippel-Lindau disease.J Med Genet. 2017;54(1):11-18.
Feletti A, Anglani M, Scarpa B, et al. Von Hippel-Lindau disease: an evaluation of natural history and functional disability. Neuro Oncol. 2016;18(7):1011-1020

10. Endolymphatic Sac Tumors
 3-15 % in VHL
 30 % bilateral  typical in VHL
 VHL germline mutation in 39%
 Initial manifestation of VHL disease for
32% of patients.
 Location: vestibular aqueduct
 Prognosis: good, once hearing loss
occurs, ELST resection is unlikely to
improve hearing
Dornbos, D., Kim, H. J., Butman, J. A., & Lonser, R. R. (2018). Review of the neurological implications of von Hippel–Lindau disease. JAMA neurology, 75(5), 620-627.

11. Radiology
Butman JA, Linehan WM, Lonser RR Neurologic manifestations of von Hippel-Lindau disease.JAMA. 2008;300(11):1334-1342.
Chittiboina P, Lonser RR. Von Hippel–Lindau disease. Handb Clin Neurol. 2015;132:139-156.

12. Chittiboina P, Lonser RR. Von Hippel–Lindau disease. Handb Clin Neurol. 2015;132:139-156.
Butman JA, Linehan WM, Lonser RR Neurologic manifestations of von Hippel-Lindau disease.JAMA. 2008;300(11):1334-1342.

13. Butman JA, Linehan WM, Lonser RR Neurologic manifestations of von Hippel-Lindau disease.JAMA. 2008;300(11):1334-1342.

14. Treatment
Dornbos, D., Kim, H. J., Butman, J. A., & Lonser, R. R. (2018). Review of the neurological implications of von Hippel–Lindau disease. JAMA neurology, 75(5), 620-627.

15. Summary
 Benign pathological origin
 However, most frequent sources of
morbidity in patients with VHL disease
due to these tumors’ anatomical
location and/or mass effect
 Proper surveillance and management
of this disease mitigate potential
neurological deficits and substantially
improve patient quality of life

16. THANK YOU