John and I were married at 18 and 20 — wedding my French-Irish heritage to an athletic Scot. He completed a Ph.D. in chemistry, I finished my nursing degree, and we launched two careers and six children over the next twenty years. We were a healthy lot. One of our few complaints was our constant "battle of the thermostat" — John was very intolerant of heat, and would break out in sweats when I thought the temperature was approaching normal. I attributed it to his chilly upbringing in Scotland, which had left him intolerant of civilized central heating. Beginning about age 40 he was treated for high blood pressure, like so many men his age.

In 1987, John was driving home when he noticed one eye was tearing — but what he wiped from his cheek was blood! He went to an ophthalmologist who sent him to a retina specialist. They told him that he had von Hippel-Lindau disease, but that there was no treatment for it. While VHL could also cause brain tumors, there was no need to test for those since "the cure is worse than the disease."¹ They would make themselves known if they needed to be dealt with.

I checked in a few medical textbooks, but the descriptions were not helpful. No one in John’s family had any problems with eyes, nor any brain tumors. His mother was healthy, his father retired and died of a heart attack at 67. Perhaps the diagnosis was wrong? In any event, the bleeding episode ended, there was no change in John’s vision, and the ophthalmologist didn’t give us anything to do, so we promptly put VHL out of our minds and settled back into our happy, hectic daily life.

Two years later, our son Matthew, age 13, began experiencing headaches, restlessness and cold sweats. He would call in a panic from school, declaring himself to be deathly ill. I would go get him, bring him home, and within fifteen minutes he was miraculously cured. I wondered if he were simply "allergic to school" and making up a good excuse to get home. Dramatically, Matthew declared he "was dying," and nobody would believe him. Routine blood work revealed bouncing blood sugars. He was diagnosed as glucose intolerant. His blood pressure and heart rate were normal. But the episodes of panicky calls from school continued.

Meanwhile, John had a heart attack. I was careful to tell the doctors that he had a diagnosis of VHL in the eye, worrying that the blood thinners they were using to dissolve the clot might cause a hemorrhage in the eye. His doctors did not consider that information relevant to his heart condition.

After nine months and no improvement from diet therapy, Matt developed a rapid heart rate. The cardiologist we consulted found a blood pressure of 260/140 — dangerously high! — and Matt was admitted to the hospital. We never suspected that there might be a connection among Matt’s blood sugar, his father’s heart attack, and the mysterious eye disease mentioned by John’s retinal specialist. As part of the comprehensive family history, we mentioned VHL in passing, and the pediatric endocrinologist began to put the puzzle together.

Matt had an abdominal ultrasound and urine tests which revealed pheochromocytomas, or pheos (pronounced FEE-ohs), a kind of tumor on both adrenal glands. Surgeons subsequently removed both his adrenal glands and put him on hormone therapy to balance the cortisone and mineral levels normally regulated by these glands. His condition quickly stabilized and he was out of the woods.

Now that the VHL connection was established, the doctors recommended that the entire family be screened as well — 24-hour urine collections, blood tests, and ultrasounds of the abdomen. John’s and most of the children's tests came back normal, but son Jeff (25) was found to have elevated levels of urine catecholamines, adrenal by-products, indicating a malfunction of the adrenal gland.

Jeff had pheos on both adrenal glands, and the doctors felt they had been there for a very long time. He had always been the frail child, but he did not have particularly dramatic symptoms. Looking back, I realize now that he had episodes of symptoms twice before: a period of severe headaches when he was 3, and symptoms which had been diagnosed as hypoglycemia when he was 14-15. This latter problem was attributed to the rapid growth spurt he was going through at the time, and it normalized after several months of watching his diet.

John’s own blood and urine tests were normal. For fifteen years he had been treated for high blood pressure, which had seemed to be under control. His heart attack in 1989 was followed by two more in 1990. Clearly something was wrong, but what could it be? If these tests were coming back normal, his adrenal glands must be OK, right? Little by little we began to learn about pheochromocytomas.

Pheochromocytomas are one of the abdominal manifestations of VHL. These tumors of the adrenal gland emit varying amounts of unnecessary adrenalin into the bloodstream in an unpredictable manner. While rarely malignant in the VHL population, they are nonetheless potentially deadly because of the effects of excess adrenalin on the cardiovascular system. The symptoms of pheos are variable but may include elevated blood pressure, sweating, anxiety, rapid pulse, facial flushing, frequent urination, and elevated blood sugar levels. With such a variety of effects, pheos are easily misdiagnosed. They mimic symptoms of more common disorders such as essential hypertension (high blood pressure), and glucose intolerance, disruptions in the body’s ability to metabolize sugar.

In the past, traditional testing has included abdominal scans, such as ultra-sound, a 24-hour urine collection to test for adrenalin by-products, and blood testing. While abdominal scans discovered many of these tumors, others were missed due to size or location. The tumor does not always produce excess hormones in a steady stream; they may be given off in surges, or "attacks". Unless the blood or urine testing happens to be conducted during an attack, the results can look quite normal.

In the early 1980’s a specific test for pheo was developed at the University of Michigan. Called an MIBG, this test involves injection into the bloodstream of a specialized radioactive tracing material (Meta-Iodo-Benzyl-Guanidine) which is absorbed by the pheochromocytoma. This, like other nuclear medicine tests, is a kind of reverse X-ray. Instead of passing radioactive beams through the body onto the film, as in an X-ray, a much lower dosage of radioactive material is injected into the body, to be absorbed by the particular part of the body to be studied. Computerized photographs are then taken which record the location of the radioactive dye. The resulting pictures tend to be much clearer and more precise, and the total exposure to radiation by the patient is much lower, than in traditional X-ray.

On the imaging study, the pheo literally "lights up" and can be readily seen. A few other endocrine tumors can also be identified by this test. A series of pictures are taken over a period of three days, as some tumors are slower than others to absorb the tracer. Since the MIBG tracer material is cleared from the body by the kidneys, patients with impaired kidney function are given smaller doses.

The MIBG test is highly accurate for pheochromocytoma. With MIBG, pheos were finally identified in Jeff, and John, and also in our daughter Lisa, and appropriate treatment plans were worked out for each of them. Unfortunately, John had already sustained permanent heart damage, but our children’s conditions were identified early enough to avoid permanent damage.

In 1986, during an ultrasound check for cysts on her ovaries, our daughter Lisa was found to have a tumor on her right adrenal gland. Her urine and blood tests were normal, however, so it was declared a cyst or benign tumor, and was left alone. Following this new MIBG testing, Lisa had one pheo removed.

Episodes of sweating, "hot flashes" or inability to tolerate heat, facial flushing, and the racing pulse that Matthew experienced are typical symptoms of pheo. However, they may not always be present. John and Jeff both seem to have adapted to the pheo surges. Instead of characterizing the surge as a "hot flash," John was more generally intolerant of heat.

In the largest study of pheochromocytomas every undertaken,² Dr. Neumann and his team at the University of Freiburg demonstrated that traditional blood and urine testing for pheos found only about 40% of the tumors. CT was more useful (72%), but the most reliable tests were MIBG and MRI (95%). While these tests are more expensive, they are so much more accurate that the additional expense is well worth the potential saving in cardiovascular damage.

Moreover, the Neumann study showed that among people with seemingly random pheochromocytoma, 20% proved to have VHL — four times the number they would have expected. Conversely, of the 79 VHL subjects studied who did not have symptoms of pheos, 46% proved to have pheos, nearly four times the expected rate. There are familial variations -- some families tend to have more pheos than others. But everyone with VHL should be screened for pheo, especially before any kind of surgery or childbirth. The stresses of surgery or childbirth can cause a pheo attack and complications.

We are hopeful that increased awareness of the more accurate tests documented in the Neumann study will lead to earlier and more accurate diagnosis of pheochromocytoma, and of VHL.

Both Matt and Jeff have had both adrenal glands removed and are on replacement therapy. Matt's body handles it quite well, but Jeff's cortisone level is very unstable. Whenever he has a cold, or is under a lot of stress, or on some medication, he must increase his cortisone dosage to avoid trouble.

For this reason, Dr. Neumann and Dr. John Libertino³ at the Lahey Clinic, Burlington, Massachusetts, now recommend whenever possible removing the pheo only, and leaving as much remaining adrenal tissue as possible, to minimize the need for replacement therapy.

Now that we know that we have VHL to deal with in our own family, and now that we understand its many features, we all go regularly for checkups and work actively with our medical team to determine the action plan for dealing with issues as they arise.

1. This is certainly not true today. It is very important to get regular checkups for the leading features of VHL, especially eye, adrenal, and kidney, in order to deal with problems before they become critical. See the VHL Handbook for details.

2. Hartmut P. H. Neumann et al, "Pheochromocytomas, Multiple Endocrine Neoplasia Type 2, and von Hippel-Lindau Disease," New England Journal of Medicine, 329:21, Nov. 18, 1993, pp. 1531-1538.

3. Malone, Libertino, et al, "Preoperative and Surgical Management of Pheochromocytoma," pp. 567-582 in Adrenal Surgery, ed. Libertino and Novick, The Urologic Clinics of North America, 16:3 (1989).

Our thanks to Dr. Brahm Shapiro, Dept of Nuclear Medicine, Univ. of Michigan, for his assistance in the preparation of this article. q

As published in the VHL Family Forum 1:4, December 1993. For permission to reprint, please contact the VHL Family Alliance at editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.