Von Hippel Lindau syndrome

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Status

Done

General

Rare, AD disorder

20% familiar

Benign and malignant tumors (about 40 different lesions in 14 different organs)

Tumor suppression gene chromosome 3p25-26

2ⁿᵈ-3ʳᵈ decades of life

5 Von Hippel-Lindau disease rare, AD disorder 20% familiar benign and malignant tumors (about 40 different lesions in 14 different organs) Tumor suppression gene chromosome 3p25-26 2nd-3rd decades of life Rethal ErOIymghatc hem a r -VAS u ult* Pancreatic &labral papillary Of epa%lymis Epi$:lymal cysts Raul cel arcimrna Bihral Of 1. more than one CNS hemangioblastoma 2. one CNS hemangioblastoma and VHL visceral manifestations 3. any manifestation and a known family history of VHL disease

Definition

An autosomal dominant disorder

characterized by the development of

Clear cell renal cell carcinoma (RCC)
Capillary haemangioblastoma of the CNS and retina,
Pheochromocytoma
Pancreatic tumours
Inner ear tumours

Number

1/36-45k

Diagnostic criteria (Melmon-Rosen Dx Criteria)

At least two CNS hemangioblastomas (including retinal)

At least one CNS hemangioblastoma and one other manifestation described above

At least one of the manifestations described above, and a pathogenic mutation in VHL gene (heterozygous germline pathogenic variant of the VHL gene on chromosome 3p25–26) or a first-degree relative with VHL.

Genetic

VHL gene

3p25-26

Function

Tumour suppressor protein

Cell cycle exit ( G2-->G0 phase)
Invasion

Plays a key role in cellular oxygen sensing.

Two subunits

Beta subunit

VHL beta subunit binds to HIF-alpha for degradation
When VHL is not around HIF is not degregated
HIF-alpha can activate transcription for VEGFA, DGFB, TGFA, and EP

Alpha subunit

Binds protein to form complexes that target cellular protein for ubiquitination and proteasome-mediated degradation

Types of mutation

Missense-most
Nonsense mutations
Microdeletions/insertions
Splice-site mutations
Large deletions

Elongin B c HIF« HIFO( HlFa Rbxl 02 02 VEGF t Fig. 16.18 VHL is a classic tumour suppressor gene. The VHL gene product (pVHL) has many different functions. The beta domain foms a complex with elongin and other proteins that regulate the function of hypoxia-inducible factors, including hypoxia-inducible factor protein (HIF) and VEGF. Under normoxic conditions, HIF degrades. Under hypoxic conditions, HIF accumulates. If pVHL is inactivated, there is no degradation of HIF, leading to an accumulation of VEGF, which explains why tumours associated with von Hippel-Lindau disease are highly vascularized. — VHL is a classic tumour suppressor gene. The VHL gene product (pVHL) has many different functions. The beta domain forms a complex with elongin and other proteins that regulate the function of hypoxia-inducible factors, including hypoxia-inducible factor protein (HIF) and VEGF. Under normoxic conditions, HIF degrades. Under hypoxic conditions, HIF accumulates. If pVHL is inactivated, there is no degradation of HIF, leading to an accumulation of VEGF, which explains why tumours associated with von Hippel-Lindau disease are highly vascularised.

Difference between sporadic and familial (VHL) haemangioblastoma

Criterion	Sporadic	VHL-associated
Female	41%	56%
Patient age	44 years (7–82)	23 years (7–64)
Intracranial	79%	73%
Spinal	11%	75%
Multiple	5%	65%

Evaluations

Full spine MRI (spinal haemangioblastomas)

Staging CT (renal cell carcinoma or pancreatic lesions)

Bloods: Polycythemia

Blood pressure and urine catecholamine/vanillyl mandelic acid monitoring (phaeochromocytoma)

Ophthalmology review (retinal angiomatosis)

System	Evaluation	Comment
Eyes	Ophthalmologic evaluation	Check for retinal hemangioblastomas.
Neurologic	Neurologic history & physical exam	- Examine for evidence of CNS or peripheral nerve hemangioblastomas - Baseline brain & spine MRI is considered standard procedure.
ENT/Mouth	Audiologic evaluation	Check for hearing loss associated w/endolymphatic sac tumors.
Renal	Abdominal ultrasound examination after age 16 yrs	Evaluate suspicious lesions in kidney, adrenal gland, or pancreas by more sophisticated techniques (e.g., CT, MRI).
Endocrine	- Blood pressure measurement - Measurement of 24-hr urine fractionated metanephrines & catecholamine metabolites or plasma free fractionated metanephrines after age 5 yrs	To evaluate for pheochromocytoma
Miscellaneous/ Other	Consultation w/clinical geneticist &/or genetic counsellor

Retinal haemangioblastoma

Site involved

CNS Haemangioblastoma

25-40% of cases of haemangioblastoma are associated with VHL
80% develop in the brain
20% in the spinal cord

25-40% of VHL pt will have spinal haemangioblastoma

Extra CNS

Renal cyst
RCC
Retinal haemangioblastoma
Pheochromocytoma (10-20% of VHL pt)

Summary of mean age of onset and frequency of CNS and visceral lesions in VHL

CNS, central nervous system; VHL, Von Hippel–Lindau disease.
Source: Data from Chittiboina and Lonser 2015.

ㅤ	Mean Age of Onset (years)	Frequency (%)
CNS lesions	ㅤ	ㅤ
Retinal hemangioblastoma	25–37	15–73
Endolymphatic sac tumor	22–40	3–16
Cerebellar hemangioblastoma	29–30	35–79
Brainstem hemangioblastoma	25–38	4–22
Spinal hemangioblastoma	33–34	7–53
Supratentorial hemangioblastoma	20–29	1–7
Visceral lesions	ㅤ	ㅤ
Renal cell carcinoma	40–45	30–70
Renal cyst	34–39	60
Pheochromocytoma	20–29	16
Pancreatic neuroendocrine tumor	32–38	15–56
Pancreatic cyst	29–37	21–72
Epididymal cyst adenoma	24	25

Counselling

Periodic screening of patients with VHL is mandatory, beginning with

Retinoscopy at 5 years of age and
MRI of the CNS and abdomen at 10 years of age.

VHL pathogenic variants are highly penetrant (almost 100%). Almost all individuals who have a pathogenic variant in VHL are symptomatic by age 65 years

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