VHL 101 & VHL Genetics | UTSW | Family Weekend 2024

VHL 101
Qian Qin MD
Summary:
VHL Syndrome Overview:
Prevalence: Affects 1 in 36,000 individuals.
Inheritance: Typically passed from parents to children.
Everyone has two copies of the VHL gene.
A mutation in just one copy is enough to cause VHL syndrome.
Each person with VHL syndrome has a 50% chance of passing the mutated gene to their children.
VHL gene mutation drives the symptoms of VHL syndrome.
VHL Protein and Oxygen Sensing:
HIFα Protein: Essential for sensing oxygen in cells.
Under normal oxygen conditions, the body degrades HIFα through the VHL protein.
In low oxygen conditions, HIFα is not degraded by VHL, allowing it to bind with HIFβ.
This interaction stimulates blood vessel growth to supply oxygen to vital organs, to protect the cells in the organ from dying.
When the VHL protein is lost, HIFα builds up, leading to abnormal blood vessel growth, prolonged cell survival, and the potential spread of cells to other parts of the body.
Manifestations of VHL:
Eye Tumors (Retinal Capillary Hemangioblastomas):
Tumors form on the retina.
Can cause vision changes or loss.
Detectable during a routine eye exam.
Brain/Spine Tumors (CNS Hemangioblastomas):
Can occur in the brainstem, cerebellum, or spinal cord.
Typically small tumors, but often appear in multiple areas.
Some tumors may contain cystic (fluid-filled) components.
Can affect balance, sensation, motor function, and strength.
Inner Ear Tumors (Endolymphatic Sac Tumors):
Rare tumors, affecting 5-15% of VHL patients.
Can develop in one or both ears.
Symptoms include fullness in the ear, pain, ringing (tinnitus), dizziness (vertigo), hearing loss, and facial muscle weakness.
Adrenal Gland Tumors (Pheochromocytomas):
Develop in the adrenal glands located on top of each kidney.
Tumors produce adrenaline.
Symptoms include headaches, sweating, fast heartbeat, and high blood pressure.
Kidney Tumors (Renal Cysts and Clear Cell Renal Carcinoma [ccRCC]):
Two forms: non-cancerous cysts or cancerous tumors (ccRCC).
Cysts:
Can be simple (one pocket) or complex (many small pockets).
Complex cysts may become clear cell renal carcinoma, so must be closely monitored.
Tumors:
Usually multiple and slow-growing, with a low risk of spreading.
However, they tend to recur.
Symptoms include blood in urine, pain, and decreased kidney function.
Pancreatic Tumors (Pancreatic Cysts and Pancreatic Neuroendocrine Tumors):
The pancreas is located between the stomach and spine.
The pancreas' normal role is to secrete digestive enzymes and regulate blood sugar.
Manifestations include non-cancerous simple cysts, non-cancerous complex cysts (serous cystadenomas), or cancerous pancreatic neuroendocrine tumors.
Tumors are usually slow-growing but must be closely monitored to prevent them from spreading to other parts of the body.
Symptoms include upper abdomen pain, hormone imbalances, and digestive issues.
Broad Ligament and Epididymal Tumors (Papillary Cystadenomas):
Females: Tumors start in the broad ligament, which is near the fallopian tubes/ovaries.
Males: Tumors develop in the epididymis, a structure in the testis that stores sperm.
Can cause fertility challenges.
VHL Genetics
Remington Fenter MS
Summary:
Genetic Information and Cancer:
Our genetic information is stored in chromosomes.
Genes are contained in small sections of each chromosome.
Cancer is caused by multiple mutations in our genetic information.
Mutations can occur from exposure to harmful chemicals or radiation.
People with hereditary (genetic) cancer predisposition syndromes, such as VHL, are born with one mutation, increasing their overall risk of developing cancer.
VHL Gene Specifics:
Location: The VHL gene is located on the short arm of Chromosome 3.
Functions: The VHL gene plays a critical role in:
Sensing oxygen levels in the body.
Producing red blood cells.
Preventing uncontrolled cell growth and division.
VHL Gene Mutation Effects:
When the VHL gene malfunctions, cells divide rapidly, new blood vessels grow excessively, and too many red blood cells are produced.
Mutations in the VHL gene are detectable in approximately 95% of patients.
Research is still ongoing to identify which mutations are most likely to cause different VHL symptoms/manifestations.
Around 20% of VHL cases result from new (de novo) mutations that are not inherited.
Even individuals with de novo VHL mutations have a 50% chance of passing it on to their children.
VHL Screening and Treatment:
Screening Guidelines: VHL screening guidelines were developed by the VHL Alliance and are regularly updated based on the latest research findings. Following them helps improve surgical outcomes and belzutifan treatment success while minimizing risks.
Chuvash Polycythemia: Not all VHL gene mutations cause VHL syndrome. At least 10 mutations in the VHL gene are associated with another condition called Familial Erythrocytosis-2 (also known as Chuvash polycythemia).
This condition leads to the overproduction of red blood cells.

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