Life With von Hippel-Lindau Disease

At first, Camron King’s sixth- grade teacher thought he was nervous. King had just started at a new school when he told the teacher he couldn’t read aloud from his textbook. The problem, however, was more complicated than childhood stage fright.

He couldn’t see the words on the page. King’s parents took him to a doctor, who diagnosed him with a rare type of tumor called pheochromocytoma, a type of tumor located on the adrenal gland that can produce excessive adrenaline and lead to blurred vision and other side effects. After a month of tests and exploratory procedures, King underwent surgery to remove the tumor and his adrenal gland. He and his family thought it was a once-in-a-lifetime event.

“At that point in time, we thought that the ‘pheo’ was just a rare, fluke occurrence,” says King, now 46.

His endocrinologists, however, recommended ongoing tests to monitor adrenal tissue or growth over the course of King's life. As long as he got the tests, his care team said, he should be fine. “Well, I was, for about another 10 years,” King explains.

In his early 20s, he started having migraines and began seeing floaters that interrupted his vision. He opened the phone book and made an appointment with a retinologist.

“It was divine intervention at that point,” says King, who now owns a public relations consultancy and a management company that serves nonprofit organizations.

The retinologist determined that King had new blood vessel tumors called hemangiomas on his right retina. King was referred to genetic testing, and not long after, he received a diagnosis of von Hippel-Lindau (VHL) disease, a rare genetic disease that causes patients to develop tumors, some malignant and some benign, repeatedly over the course of their lifetime. According to the VHL Alliance, cases are diagnosed in every 36,000 people, and 97% of patients with the disease will experience manifestations in the form of cysts, tumors and/or abnormal blood vessels by age 60.

CAUSE, SYMPTOMS AND DIAGNOSIS

Everyone is born with two copies of the VHL gene, which plays a role in cellular functions like regulation of cellular metabolism and/or oxygenation. VHL, however, follows what is called an autosomal dominant inheritance pattern, which means that one mutated copy is inherited. A single acquired mutation in a cell will disrupt the usual cellular process.

“If you have VHL disease, one of the (VHL) genes you were born with was already mutated,” says Dr. Nicholas Cost, director of the VHL Clinical Care Center Program at the University of Colorado Cancer Center, associate professor of surgery-urology at the University of Colorado School of Medicine and the co-director of the Surgical Oncology Program at Children’s Hospital Colorado. However, about 20% of affected individuals will have a new (or “de novo”) mutation, not from their parents, but one they can still pass on to their children.

The body’s cells are constantly engaged in what Cost describes as “housekeeping,” with the VHL protein helping to carefully balance cellular activities by responding to surrounding oxygen levels for the cells and determining how to use nutrients. If the gene is mutated, the VHL protein and its associated proteins cannot do their job, making the cell feel as though it is oxygen deprived. This leads to an unchecked accumulation of various “pro-growth” proteins, particularly hypoxia inducible factor 1-alpha (HIF-1-alpha).

“If you have (a functional VHL gene), this particular protein is kept at bay,” says Dr. Othon Iliopoulos, an associate professor of medicine at Harvard Medical School and director of the VHL program at Massachusetts General Hospital in Boston. “If you don’t, you start accumulating this protein in the cell, and then this protein ... turns on genes that make the cell cancerous.”

The most common manifestations of VHL disease are clear cell renal cell carcinoma (kidney cancer), pancreatic neuroendocrine tumors — not to be confused with the more typical pancreatic cancer of the ductal cells — and hemangiomas of the retina, cerebellum, brainstem and spinal cord, as well as epididymal cystadenomas (benign para-testicular tumors) in men, broad ligament cystadenomas (benign para-uterine tumors) in women and pheochromocytomas (a type of adrenal tumor) or paragangliomas (similar to pheochromocytomas but not in the adrenal gland).

VHL may be diagnosed with genetic testing after a patient presents with one or several of these tumors, but about 80% of VHL cases are inherited. Children of patients with VHL have a 50% chance of inheriting it. The VHL Alliance and the American Society of Clinical Oncology both recommend genetic counseling for patients with VHL who are considering having children.

Genetic testing has revealed that both of King’s children have VHL, although only his son has developed tumors. His daughter has yet to experience any manifestations of the disease. “As we had our children, it was like, ‘We already know what we’re dealing with,’” says King.

Dr. Samira Sadowski, an investigator at the National Cancer Institute in Bethesda, Maryland, says the more information patients can gather about VHL disease in their families, the better. “It’s an important question whether families or parents want to reproduce," she says. "These are very anxious and justified questions."

With advances in less invasive surgery, King says his son’s experience of VHL has been a little easier than his own.

King describes his surgical scars as a “road map.” So far, he’s undergone surgery for the removal of kidney, spinal and adrenal tumors, as well as liver cysts. He’s also undergone gamma knife radiation therapy, during which beams of radiation are aimed at a target — in King’s case, a brain tumor — to precisely destroy a tumor without harming surrounding tissue. His son, on the other hand, has had a series of minimally invasive procedures that left behind much smaller scars.

LIFE WITH VHL

Kwame Garrett-Price, 34, of Dallas, says he got lucky by having a father and a brother who are both physicians. After Garrett-Price received a diagnosis of VHL disease in 2019, he found that many general physicians weren’t as familiar with the disease. With the help of his brother, he set out to assemble a care team.

“I’d been having migraines my whole life, and sometimes they were debilitating,” says Garrett-Price, a fashion designer who owns a company that sells luxury leather goods.

One morning, after a particularly brutal headache, he passed out. His mother took him to an emergency room, where he learned that his blood pressure was at stroke level. After some tests, a doctor gave him terrifying news: He had a tumor on his cerebellum. A visit to Baylor Scott & White Health in Dallas for more imaging revealed that Garret-Price had VHL.

He’d had surgeries before for injuries he sustained running track and playing soccer, “but this was quite different,” Garrett-Price explains. “You instantly question your mortality and your impact on the world.”

A neurosurgeon successfully removed the brain tumor that February, but shortly afterward, his care team found tumors on his pancreas, as well as kidney cancer. That October, his doctors found hemangioblastomas on his spine. Garrett-Price underwent a partial adrenalectomy for the pheochromocytomas in November 2019 and a surgery to remove two of the spinal tumors
in February of this year. The kidney tumor remains under surveillance.

Care for VHL-associated cancers is different from other cancers because VHL care teams — knowing that a patient will likely develop many tumors and cysts over a lifetime — try to monitor tumors until they reach a size at which surgery is necessary, rather than operating immediately. Surgeons operating on patients with VHL will also usually try to conserve as much of the organ as possible, particularly in kidney cancers.

“What we’ve realized is that we could manage (patients with VHL) by waiting until they had a tumor that reached a size at which we would be worried about it spreading — that’s at about 3 centimeters. And then at that point, (we) go into that kidney and take out all the possible
tumors we can, (all while) leaving as much of that kidney as (we) can,” Cost explains. “The reason ... we do that is because we’re balancing controlling the cancer with not putting them into renal failure and on dialysis.”

Fortunately, says Cost, VHL-associated renal cell carcinomas tend to be low-grade tumors, so these surgeries can “reset the clock,” and with any luck, the patient won’t need another surgery for years. However, Cost notes, “it’s so variable, and it speaks to why patients really need to be seen in a VHL center.”

At the University of Colorado Cancer Center, Cost says that patients with VHL disease have urology and ophthalmology appointments every year and a visit with a neurosurgeon and an ear, nose and throat specialist every other year. Patients also meet with specialists as needed
to conduct surveillance on tumors and form treatment plans if necessary. Cost says it’s best to conduct MRIs rather than CT scans because they do not use ionizing radiation (a radiation consisting of particles, X-rays or gamma rays with sufficient energy to cause ionization), an important consideration for a screening that a patient will undergo many times.

“Essentially, (VHL) involves an annual follow-up with someone who is kind of a quarterback, who really under- stands the care of (the disease),” Cost notes.

Both Garrett-Price and King assembled their own care teams of neurosurgeons, oncologists, endocrinologists, ophthalmologists and audiologists. Garrett-Price obtained referrals from his primary care physicians once he figured out which specialists he needed to see, a process he

describes as “like walking in the dark” because of how few doctors are familiar with VHL.

BREAKTHROUGH THERAPY

One of the most promising pieces of news for patients with VHL comes in the form of an experimental drug from Merck called belzutifan, which was granted priority review by the Food and Drug Administration in March.

Belzutifan is a HIF2A inhibitor, which means it blocks certain proteins that would otherwise promote blood vessel and tumor growth. This means that it can stop tumors from growing and even shrink them.

In a recent midstage clinical trial of patients with VHL disease, the drug demonstrated
a response rate of 36.1% (22 of 61 patients enrolled in the study). Although this midstage trial was focused on patients with clear cell renal carcinoma, patients enrolled in the study also demonstrated shrinkage of pancreatic neuroendocrine tumors, hemangioblastomas of the central nervous system and retinal hemangioblastoma — showing promise for patients with VHL dealing with other types of cancer. In nonrenal cancers, researchers reported an 80% overall response rate to belzutifan.

“It has a widespread effect, and this is because the mechanism of these cancers is the same,” explains Iliopoulos, who co-authored the study.

Sadowski, who hopes that belzutifan will offer patients a new treatment option, also is optimistic that research will lead to the development of better biomarkers to help care teams make treatment decisions.

As patients with VHL await these future therapies, Garrett- Price says he’s faced VHL by taking charge of his physical and mental health by maintaining a healthy diet, exercising and managing anxiety. He and his brother are also working on starting a nonprofit to promote health care in under- served communities.

“These things are paying rent to me,” he says of the malignancies, cysts and tumors. “I reversed it and said, ‘I control you’ because I control what I put in my body, I control my wellness and I control what I choose to feed these diseases. If I take care of myself mentally, to not be defeated by these diagnoses, it makes the landing a bit softer.”