"It was like a bowling ball hitting us in the face," said Vicki. She was referring to the moment when she and her sisters learned that they may all have inherited a gene that could give them VHL, the disease that had killed their oldest sister Lydia. Lydia had been sickly throughout her childhood. Vicki, Mary, and Charlotte had been fine as kids. But in their thirties and shortly after they discovered that their sister's disease was hereditary, each sister developed some sign of the disease. VHL is rare in the general population--probably seven thousand people in the United States have it. But, in this one family, the four sisters inherited the VHL gene as did three of their eight kids, and the sisters' mother Nellie has it as well. Nellie is sure that her mother died of VHL, even though that diagnosis was never attached to her illness. And Nellie's mother's father had died of a kind of cancer that is associated with the disease. So, even though VHL is not a common disease, for Nellie's family and for other "affected" families, the disease is as common as the "common cold." Family tree showing Nellie and her relatives. This tree or "pedigree" shows which individuals in the family inherited the altered VHL gene. All the individuals who inherited the VHL gene are shown in white. Nellie thinks that her mother and her mother's father both had VHL, but they were never tested for the gene; this is indicated by the question marks on those two figures. Nellie says she first heard of VHL when she was in her twenties. She was chasing one of her tiny daughters at a swimming pool, slipped, fell, hit her head, and was instantly and permanently blind in one eye. One doctor said the blindness was caused by the fall; another said it was caused by a rare condition called VHL. Nellie says she heard no more about VHL for about thirty years. Then, when Lydia was hospitalized, the doctor said Lydia had VHL. Every person inherits two copies of the VHL gene, one from each parent. Each copy is called an "allele." Nellie has one normal allele and one mutated allele of the VHL gene. The mutation is shown in red. Her husband has two normal alleles. This illustration, called a Punnet Square, shows how the two alleles from each parent could sort in any one of the daughters. Each daughter had a 50% chance of inheriting her mother's normal gene and a 50% chance of inheriting the mutated VHL gene. Each daughter would always inherit a normal allele from her father. Thus each daughter's chance of inheriting VHL was 50%. Nellie recalls how hard it was to return home from the hospital that day and tell her other daughters that Lydia had a genetic disease and that they might all have it too. "Mama, please tell me I'm adopted," said one of the daughters who was hoping against hope that her genes had come from someone else. The chance for each daughter to inherit the VHL gene was just 50:50, but, as they learned several years later, the gene had found its way into all of them. VHL can be a mild disease or severe, an inconvenience to those who have it or a killer. Tumors and cysts can develop in several areas of the body--the eyes, brain, spinal cord, kidneys, and a few other sites (1)--and patients' symptoms reflect where the tumors and cysts are growing. Some patients have headaches and a range of motor problems and pain because they have tumors in their brains; some experience vision problems or blindness as a result of eye tumors; some have kidney failure when tumors overtake that organ. Tumors associated with VHL arise in certain parts of the body. Most often they develop in the brain, the eyes, the spinal cord, the kidneys, and the adrenal glands (glands that lie above the kidneys). Two turn-of-the-century eye doctors--von Hippel in Germany and Lindau in Sweden--were the first to publish descriptions of the VHL tumors in patients' eyes and brains; in the 1960s the disease was named VHL, von Hippel-Lindau, to recognize their contributions in characterizing the disease (2). Von Hippel and Lindau observed that these tumors ran in families (3), but it was not until 1993 that scientists actually identified and isolated the disease-causing gene (4). The search took six years and involved studies of genes from hundreds of people in 120 affected families. Nellie, her daughters, and many of their relatives were among those who donated blood samples for this research. Dr. Berton Zbar, one of the discoverers of the gene, first met with Nellie and her family in 1988. Together they made a family tree that went back as far as the family could remember. It listed each relative's illnesses and any symptoms that might suggest VHL. Zbar then collected 40 milliliters of blood from each of the 25 members of the family who had come together. These blood samples and samples from hundreds of other people in affected families were key to the identification of the VHL gene, which was tracked to the short arm of chromosome 3. Humans have 23 pairs of chromosomes. The gene for VHL is located on chromosome 3. In this "karyotype," the pairs of chromosomes were tagged such that each pair has a unique colorful appearance (described in Science1996, 273:494). Courtesy of T. Ried and E. Schrock, National Center for Human Genome Research, NIH. Associating a gene with a disease is just the first step in a long and often slow process whose goal is to do something useful--find either a treatment, a prevention, or a cure--for those who have the disease. Yet, shortly after the VHL gene was discovered, scientists developed a simple test for the gene that has proved extremely valuable for people in families where VHL is prevalent. Through the test, individuals can determine if they have or have not inherited the gene. Those without the gene are off the hook. Those with it know that they must be examined regularly for tumors and cysts. And, although annual screening can be upsetting--"I always get anxious two months before the test," says Mary, "it's like a burr under the saddle, like waiting for the other shoe to drop"--people fare far better in the long run, because surgeons can remove tumors that are detected at early stages before the tumors can cause serious problems. Zbar says that patients can make rational plans for their futures once they have genetic information. He tells the story of one woman who, like many people with VHL, had had numerous tumors in her kidney and was left with only one kidney that could function. "It is not uncommon," said Zbar, "for someone to develop 30-60 kidney tumors during the first three decades of life." The patient told Zbar that, should her other kidney fail, she could not accept a transplant from her older son, because "he needs to save his kidney to give to his brother." Many of the woman's relatives had been tested for the VHL gene, which is how she knew that one son had inherited the VHL gene and the other had not. The woman's niece learned that she had not inherited the VHL gene, and the woman reported to Zbar with relief that "my niece says she'll give me one." "A person can live without one kidney," says Zbar, "and even with just a part of one. People have an appreciation for what VHL does and doesn't do to them." The VHL gene is a tumor suppressor gene (3). Normally, this gene does just what its name suggests: it stops or suppresses cells from forming tumors. When a person has VHL, the tumor suppressor gene is damaged and cannot fulfill its normal function. Cells multiply out of control and tumors develop. Cells of people who inherit VHL contain one altered copy of the VHL tumor suppressor gene and one normal copy of that gene. Each copy is called an "allele." As long as the normal allele of the tumor suppressor gene remains normal and works correctly and can produce its product--a tumor suppressor protein--tumors will not grow, and the person will remain healthy and have no signs of the disease. But, if the second allele is altered, tumor suppression ends in that cell and the disease begins. It takes two "hits" to turn a cell into a tumor cell, one hit on each allele. Family members who inherit the VHL gene are born with the first hit (red); later in life, the second allele may be hit as well (yellow). All known tumor suppressor genes seem to work on the "two-hit" principle, which holds that tumors develop only after both copies of the VHL gene in a cell are damaged (5). In families where VHL is inherited, the mutation or "hit" on the inherited VHL gene occurred some time in the past, and this nonworking VHL gene is what is handed down from generation to generation. So far, scientists have identified more than 140 different mutations in the VHL genes of people who have VHL. The "hit" on the second allele can occur at any time, and the timing and form of the hit will vary from person to person and from cell to cell. Not only do the hits to the VHL genes differ from individual to individual, but so do the signs and symptoms of the disease. The situation is quite complicated. On the one hand, there is evidence that specific mutations are associated with the development of distinctive signs and symptoms. On the other hand, within a family, where all members have the same VHL mutation, the nature of the disease and its severity can vary enormously. Joyce Graff, co-founder of the VHL Family Alliance, says that at the Alliance they "see families every day, in fact most families with VHL, where one member may have one small tumor and that's it and another member may have 6-10 of everything. Yet they have the same genetic (change). . . Genes are risk factors, not determinants." "Virtually all diseases, except maybe trauma, have a genetic component," says Dr. Francis Collins, Director of the National Human Genome Research Institute. Those caused by a single gene have been the first to be identified and analyzed; but with time and technologic advances, scientists expect to be able to explain the genetic roots--simple and complex--of many other diseases. All people with serious diseases share some experiences and concerns, whether their disease has a simple genetic origin, has complex or poorly understood genetic components, or has not yet been linked to specific genes. Please Karen Koenig Please Don't make me feel worse. Don't blame me for being ill. Don't shame me For my genetic defect. Please. One issue that currently is uniquely troubling for those with VHL and other "simple" genetic illnesses is a worry about health insurance. "None of us pick our genes," says Collins, "so our genes should not be used against us." But insurance companies have been known to deny coverage to people on the basis of their genes (see 6). New legislation is moving in the direction of ensuring the privacy of patients' medical records, so that genetic information cannot be used in discriminatory ways. The more that people fear discrimination and reprisals--by insurance companies, by employers, by people they meet--the less willing they are to participate in the research that is vital for finding treatments and cures for their diseases. "I never thought," writes Dr. James Lamiell in the VHL Family Forum newsletter, "that if the test was developed and it was possible to diagnose with certainty that a person had VHL early on--at birth or early chidhood, or even in utero, before birth--I never imagined that someone would not want that test done for fear of losing insurance. . ." But this has become a serious issue, he writes, because "technological advances in medicine (have) outpace(d) our social and ethical abilities to deal with them (6)." Another troubling issue for people with genetic diseases is concern about passing the disease gene along to their children: "You know," says Mary, "how parents say that they would give up their life for their child? The killer of this disease is the pain of knowing that my child will face multiple surgeries and that she maybe should not have children. The feeling is not guilt. It is the deepest, regrettable sadness, sadness from deep in the soul." I Feel Like a Wild-Eyed Doe Karen Koenig I feel like a wild-eyed doe. All deer know That there are wolves out there, But life goes on. We do our best To be alert, To be careful, To use all of our wit and instinct And when danger swwops in close, to fight, fight! Use all of our strength and resources, And hopefully fend off the peril. When we're young, agile and strong, And when we're only needing to protect ourselves, Evading the threat is a relatively simple thing. But now I have a fawn-no, two-in danger! And the wolves are close, menacing. I hear their stealthy moves toward us now. The tiniest crackle and rustle tell me they approach. My heart pounds. I strain to be ready To protect not just myself, but now my babies. I see glowing eyes, Their gleaming fangs! I rear up on hind legs And find a roar in my throat Which I never before knew to exist. My precious young, huddled in the thicket, Get up on shaky legs to run/resist. The predators bound toward us, leaping. I rear up, eyes bulging, Hoofs flashing, thundering. Can we survive? Will all we have to fight with be enough? How much will we have Of ourselves or each other When this onslaught Is over? Graff points out, however, that VHL has become an increasingly manageable disease. People can learn about their risks and then take actions to minimize them. "Knowing what things are likely to occur," she says, "you can watch out, catch and treat tumors early . . . in other words, change the potential outcome." They can stop smoking (cigarettes are known to cause cancer), choose a diet that is associated with cancer prevention, be monitored regularly, and so on. Because VHL is not a widespread disease, a person with it may not automatically meet someone else with VHL outside the family, and a doctor may have experience treating only one person or one family with the disease. Graff's husband had VHL, and she says she went for 30 years without meeting anyone else with it. Then she met another woman whose husband also had the disease. "In one hour we were telling each other our life stories. In that one discussion, what I knew about VHL went from the size of a softball to the size of a basketball." The two women realized that there was much to learn from each other, from other patients and their families, and from a broader exchange of information. In 1993, they formed the VHL Family Alliance and began providing information to and connecting with family members, doctors, and researchers. As a result, isolation of people with VHL is decreasing. Says Graff: "The most important thing we can give one another is the knowledge that we are not alone." Poetry is Born of Pain Karen Koenig Sometimes I think My poetry well Has run dry. Several weeks (months) go by; No poems come. Then something happens Which moves me, Prods me, Brings my awareness back To my real-life drama, And- Lo and behold! The poems flow again. Memories are stirred, My heart is touched. My emotions come to the surface. I am taken And shaken Again. My poetry, Very often, Is born of pain. Karen Koenig was an artist and poet. She learned that she had VHL in 1966. In the early 1990s, she stopped painting and concentrated on writing poetry. Her poems are reprinted here courtesy of Steven Koenig, M.D. They are from Karen Koenig's collection Sacred Process, Krelek Press, 800 West End Avenue #14C, New York 10025. No one would choose to have a genetic disease like VHL, but Nellie and her daughters are philosophical about the hand that fate has dealt them. "Everyone is going to get something," says Charlotte, "it's just a matter of where and when. In a way, it's a blessing to have a disease that is being studied so much." Nellie, her husband, and their daughters Vicki, Mary, and Charlotte. Picture courtesy John Shaw Photography, Natchitoches, Louisiana. Self portrait of Karen Koenig. Karen Koenig was an artist and poet. She learned that she had VHL in 1966. In the early 1990s, she stopped painting and concentrated on writing poetry. Her poems are reprinted here courtesy of Steven Koenig, M.D. They are from Karen Koenig's collection Sacred Process, Krelek Press, 800 West End Avenue #14C, New York 10025. References: Cancer Surveys 1995, 25:219-232. American Journal of Medicine 1964, 36:595-617. Radiology 1995, 194:629-642. Science 1993, 260:1317-1320. Proceedings of the National Academy of Sciences 1993, 90:10914-10921 VHL Family Forum 1996, 4(3):1-3. Principles of Medical Genetics, TD Gelehrter, FS Collins, Williams and Wilkins, Baltimore, 1990, p. 2. VHL Family Forum 1993, 1(2):1-2. Proceedings of the National Academy of Sciences 1996, 93:10595-10599. Human Genetics 1995, 95(5):551-556.