In the two decades since Stacy Lloyd was diagnosed with Von Hippel-Lindau, much has changed in genetic research, treatment, and counseling methods. Despite a complicated healthcare system, new methods are evolving constantly to treat, diagnose, and maybe even prevent this rare and often debilitating genetic disorder.
The morning of June 28, 1996, Stacy Lloyd – 10 years old at the time — was at home and started to feel light-headed and dizzy – then collapsed and had a seizure. She was air-lifted to Children’s Hospital of Pittsburgh with a blood pressure of 240/120, and the emergency room physicians didn’t know what was wrong with her. They thought she hit her head when she fell.
It wasn’t until Lloyd’s grandfather spoke up that they knew: he told the doctors that Lloyd’s aunt had a tumor removed from her adrenal gland at age 16. “It was like a lightbulb moment in the room,” Lloyd says.
Lloyd was diagnosed with a pheochromocytoma and spent the next month at the hospital being stabilized, followed by a 12-hour surgery to remove the pheochromocytoma from her right adrenal gland and a paraganglioma between her aorta and vena cava. Lloyd had another surgery three years later after another tumor was spotted on a routine ultrasound, and her physicians diagnosed her with metastases to the bone. “We were quickly referred to the National Institutes of Health,” she says, “where I would officially be diagnosed with Von Hippel-Lindau (VHL) [a rare genetic disease that causes tumors to grow in up to ten different areas of the body]. Since then, I continue to be followed regularly and have annual imaging and lab tests. I have been fortunate to have remained fairly stable over the last 20 years but continue to monitor the metastatic pheochromocytoma in the bone and watch for new tumors.”
Lloyd now lives in Chicago, and as an adult, she has had to take responsibility for and make decisions about her health on her own – like deciding where to seek follow-up and treatment. She is active in the VHL Alliance, a non-profit dedicated to education, awareness, and research for VHL. They have a list of designated clinical care centers, which pointed her to Northwestern Medicine in 2011. It’s there that she started under the care of Peter Kopp, MD, a professor of medicine in the Division of Endocrinology, Metabolism, and Molecular Medicine at Northwestern, who has a particular interest in genetic endocrinopathies.
“For those already diagnosed, I feel it’s very important to review results in-person (or at the very least over the phone). I’ve had a letter sent to me with imaging results prior to any conversation with the physician and it was scary to read and I wasn’t sure what everything meant, which can lead to anxiety and fear.” – Stacy Lloyd, patient with Von Hippel-Lindau
Genetics, and how they apply to endocrine disorders, is a rapidly developing field, but it’s an area that has fundamentally changed in the last 20 years because physicians and researchers have been able to identify the majority of the genes underlying these inherited disorders. This is good news, but the fact that gene mutations and carriers can be identified opens up a slew of other questions and potential concerns for the involved patients and their doctors.
Examining the Phenotype’s Pedigree
It took three years from the time of Lloyd’s first pheochromocytoma diagnosis to her diagnosis of VHL through genetic testing. The average time between the onset of symptoms and formal diagnosis is nine years. “That means we still have some work to do in raising awareness and education around symptoms for both patients and physicians,” she says.
The problem is that VHL is such a rare disease that many physicians may not ever see a case. VHL is also a disease that has a huge spectrum of phenotypic manifestations, ranging from very mild to very problematic, according to Kopp. “In Stacy’s particular case, she has this unusual finding of widely metastatic pheochromocytoma, which is an endocrine tumor, at a very young age” he says.
Kopp stresses the importance of describing the phenotype in any of these inherited conditions as accurately as possible as the first step to get to a definitive diagnosis. For example, there are various genetic forms of diabetes mellitus. And pheochromocytomas can be part of several familial syndromes caused by mutations in distinct genes. Describing the phenotype accurately requires looking at the pedigree, i.e. the family tree as a whole. “Importantly, for many disorders, mutational analysis can facilitate a definitive diagnosis,” Kopp says. Of course, a definitive diagnosis is just the first step. Once a patient tests positive for a genetic endocrinopathy, or any inherited disease, there are many other potential implications.
Lloyd says that a significant percentage of living relatives on her mother’s side also tested positive for VHL. Her grandfather passed away in 1996 – the same year as her first surgery to remove the two tumors – from his second heart attack. “We know he carried the gene as my grandmother tested negative,” she says. “He likely had a pheochromocytoma (based on what we now know to be common systems) when he passed. I think my grandmother deals with some guilt and it’s just hard for her to watch her children and grandchildren have to deal with something so awful and unpredictable and to be powerless to change or fix it.”
These feelings of guilt among family members are not uncommon in these settings, even among family members who test negative for a disease for which their siblings tested positive. “I think they feel it is unfair that my sibling suffers” Kopp says. “They may not be unhappy that they don’t have to suffer, but they have this feeling that it’s unfair that a sibling or another family member has to suffer.”
Lloyd says her mother deals with guilt too. Lloyd’s mother also tested positive for VHL and has had a pheochromocytoma removed, but she did not know she had VHL when she was expecting her daughter. “I think it’s just been hard for her to watch me go through so much, especially at a young age,” Lloyd says. “And she just wishes she could take it all away or switch places with me. I think that’s natural for any parent with a child facing any health-related issue.”
The diagnosis of an inherited disorder often requires involving the whole family, but so does addressing disease-related feelings, and keeping up on treatments once the diagnosis is made. It can be complicated to deliver a diagnosis of a disease like VHL to patients and their family. Kopp says it should be done with empathy and a thorough explanation of the condition, treatments, implications, and prognosis, but clinicians often lack the time for a thorough discussion. “This is a situation where genetic counselors can be very helpful because they have a good understanding of the phenotype, the mode of inheritance, genetic testing, and the implications of being a carrier. They can often commit the necessary time to cover all aspects, and sometimes are better communicators than physicians who are not specialized in this area,” he says.
A Family Mission
But getting the family together isn’t always easy. Kopp says there can be two extremes. One extreme is the family who gets very interested and involved and united, attending clinical visits and educational events together and rallying each other to keep up with their screenings. “It becomes a family mission, if you will,” he says.
The other extreme is a family in total denial. “They know that they have a genetic disorder running in their family, and that certain individuals are at risk, and they simply don’t want to address the issue and they walk away and get lost to follow-up,” Kopp says.
And this isn’t even including potential family members. Lloyd says that her generation is largely more equipped than previous generations with specific knowledge of VHL, its manifestations, and the odds of passing it on, which means they more often will know whether they have VHL before marriage, and that can be a difficult conversation to have with a potential partner. VHL patients never know what to expect – when tumors might appear, when they’ll need surgery. And there’s a 50% chance they will pass VHL to their offspring.
“So, what do you tell them?” Lloyd says. “At what point in a relationship do you have that conversation? When do you discuss children and the potential to pass it on if having kids is something you want? These are all very personal decisions that each individual patient has to make, but it’s certainly not an easy conversation to have. And you have to be prepared for that person to potentially walk away, too.”
And now that genetic testing is more available, and patients know the risks of passing their conditions on to their children, some ask about the possibility of editing genes. Kopp says genetic editing is in very early stages, and it has been done successfully in only a few instances. However, there is the possibility of pre-implantation testing. “You have an embryo, you test whether the embryo has the mutation or not, and you only take the embryo that doesn’t have the mutation,” he says. “This can permit a patient to make a selection. And while this is very acceptable for some, it will unacceptable for others due to ethical concerns.”
Indeed, these are very difficult questions, which are influenced by ethical considerations, religious beliefs, and even political views. Kopp says it’s important to not view these questions in black and white, but rather to consider that there are a lot of “grays.” “I think it certainly will become possible to do gene editing for some of these disorders,” he says. “And I think on a positive side note it can alleviate a lot of suffering. It can reduce the frequency of negative genes in certain populations.”
“From the other side you could argue, we are making a selection,” Kopp continues, “and we are, if you will, breeding the human species to eliminate certain genes. Whether this is acceptable, is a challenging ethical question. Where are the limits? Who defines them? The examples of eugenics also illustrate that such approaches could potentially be abused “
A Fragmented Healthcare System
Lloyd says she is fortunate to have a supportive family and friends and knowledgeable physicians whom she trusts. She also works in the healthcare industry, which she says has given her access to the best care and the tools to navigate the health system as a patient. But she still sees barriers to quality care for VHL patients, even among her own family members – cost of care, what insurance will cover or whether they will cover VHL care at all, or access to care depending on location. “Those living in rural areas often don’t have access to physicians that are knowledgeable about the disease close to home, so they may not be followed regularly or have to travel far distances to be seen,” she says.
What’s worse, the U.S. healthcare system remains very fragmented, making it difficult to share medical records and coordinate care. “For patients that require care across multiple specialties — like VHL patients — navigating the system and coordinating their care can be extremely frustrating, time-consuming, and stressful,” Lloyd says.
Delivering a diagnosis of VHL, or other genetic diseases, can also be daunting. Some physicians who aren’t trained in this specialty or don’t have access to the patient’s record may deliver the diagnosis and subsequent information poorly. Lloyd was initially told she would never be able to drive or walk at prom. But, she points out this was 20 years ago and there have been many developments in subsequent decades. Her personal awareness, education, knowledge of surveillance guidelines, and resources have greatly expanded.
“From the other side you could argue, we are making a selection and we are, if you will, breeding the human species to eliminate certain genes. Whether this is acceptable, is a challenging ethical question. Where are the limits? Who defines them?” – Peter Kopp, MD, professor of medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University, Chicago
Based on her own experiences, Lloyd’s advice is: At the time of diagnosis, healthcare providers should be direct in telling patients what VHL is, all the ways it may manifest, and inform the patient about the different options related to treatment (i.e. surgery, clinical trials, etc.). “Knowledge is power for patients and enables them to take care of themselves appropriately,” she says. “Physicians should also go over the plan of care, what’s next, and the necessary surveillance with the patient (and caregiver/family as appropriate) and allow them to ask questions. Patience is really important at this time, in my opinion.
“For those already diagnosed, I feel it’s very important to review results in-person (or at the very least over the phone). I’ve had a letter sent to me with imaging results prior to any conversation with the physician and it was scary to read and I wasn’t sure what everything meant, which can lead to anxiety and fear.”
“This ‘advice’ might sound silly or ridiculous because this should be the norm in healthcare,” Lloyd says, “but in a time where we are seeing many healthcare organizations looking to cut costs and physicians having to see more and more patients with fewer resources, patient-physician interactions can suffer.”
— Bagley is the senior editor of Endocrine News. He wrote about the link between essential oils and endocrine disruption in pre-pubescent boys in the July issue.