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'Truly a Remarkable Person'
NICHD's Winer Hailed as Healing Hero by Grateful Patients

On the Front Page...
How would you like to wake up one day to find yourself hailed as "the best specialist in the world," and to have grateful parents shouting from the rooftops that you've saved their child?

How would you like whole newsletters and international Internet campaigns devoted not only to singing your praises, but also calling NIH "the greatest place on Earth?"

Continued...
All of this has happened to Dr. Karen Winer, a quiet, low-key physician from New York who works in NICHD's Developmental Endocrinology Branch. She has just published a paper in the Journal of the American Medical Association on a new treatment for hypoparathyroidism, a potentially life-threatening hormonal disorder affecting an estimated 1 million people worldwide that has long lacked a cure. You could read that paper -- "Synthetic Human Parathyroid Hormone 1-34 vs. Calcitriol and Calcium in the Treatment of Hypoparathyroidism, Results of a Short-term Randomized Crossover Trial" (JAMA, Aug. 28, Vol. 276, No.8) -- and come away impressed that its findings will almost certainly be applied in major medical centers worldwide.

Or you could read Hypoparathyroidism Newsletter for June 1996 (Vol. 3, No. 2), published by James Sanders of Idaho Falls, Idaho, and read the front page article headlined, "Halla Ruth's Story." Both Sanders and Halla Ruth Halldorsdottir are NIH patients who are beneficiaries of a new treatment Winer common-sensically applied at the inspiration of her boss and mentor Dr. Gordon Cutler. In a sense, the JAMA article is the sheet music, and HN is the actual "Hallelujah Chorus" being sung.

A fellow at NICHD for the past 6 years, Winer is too seasoned to wear a halo. Like a lot of clinicians around here, she is busier than is probably healthy, constantly shifts between a cluttered lab (with an appended "office" that makes a coffin seem capacious) and patient care units, and can only be conjured if her pager is working. Once captured, however, she is wholly unpretentious, patient, soft-spoken, nice to the people around her -- in short, the kind of doc a mom can trust her kid with.

Halla Ruth's family is all smiles during a recent visit to NIH.

Halla Ruth's mom, Gudrun Vidarsdottir, needed all the reassurance she could gather when she finally found NIH and Karen Winer after years of desperate searching for the cause of her daughter's chronic illness. Let Gudrun's words begin the story:

"Halla Ruth and her nonidentical twin sister, Silja Bjorg, were born on Nov. 9, 1987, in Iceland. They were delivered by C-section after I had been pregnant for 36 weeks. At birth, Silja Bjorg was small and weak and had to stay in the intensive care unit for premature babies. Halla Ruth, however, was bigger and stronger and was able to stay with me.

"Two days after they were born, I noticed Silja Bjorg was getting stronger, but Halla Ruth was weak and tired. It was difficult to feed her. It was as if she was having problems swallowing. That day she suddenly turned blue in the face, and I noticed that she had stopped breathing..."

The succeeding 2 years were hellish for both Halla Ruth and her mother. Despite visits to the most prominent pediatricians in Iceland and Sweden, the little girl's health problems worsened. They included episodes of spasms, a grand mal seizure, difficulty eating and drinking, pneumonia and asthma.

Gudrun herself ended up making a diagnosis of hypoparathyroidism as the cause of all these symptoms on Mar. 31, 1989, when she read about the illness in a home medical book. She found a doctor who would listen to her and who immediately put Halla Ruth on the standard treatment of the day -- intravenous calcium and vitamin D.

This treatment, which mercifully erased many of Halla Ruth's symptoms, nevertheless had side effects, including the development of kidney stones.

Gudrun continued to query every specialist she could find. She was wise enough at this point to know that Halla Ruth needed therapy with synthetic human parathyroid hormone (hPTH). After reading hundreds of articles in Medline and corresponding with world authorities on hypoparathyroidism, she was given the name of Dr. Karen Winer.

"I am grateful to the people who helped me to get in touch with her," says Gudrun. "On Oct. 1, 1993, Dr. Winer told me that Halla Ruth was welcome to take part in her protocol. That was the best news we had heard since she was born. On Jan. 5, 1994, she started on the hPTH and has been on it ever since. She was the first child in the world to be treated with hPTH."

Winer's recitation of how this treatment evolved is almost staggeringly logical. Since hypoparathyroidism is, at root, a hormonal disorder, the trick is to replace the missing hormone.

As the locus of so much potential metabolic trouble, the parathyroid glands themselves are relatively puny; there are four of them located in the lower central portion of the neck. "They are very small glands," notes Winer. "Most people don't pay any attention to them."

But if they are damaged by neck surgery, or by a congenital or autoimmune disorder, they can disrupt the metabolism of calcium. Doctors are clued to the condition when they notice abnormal levels of calcium, phosphorus and magnesium in patients' blood. Another clue is excess calcium in urine. Parathyroid hormone absorbs the calcium out of urine; the lack of PTH leads to excess urine calcium, which can lead to kidney stones.

The conventional therapy for hypoparathyroidism is vitamin D, which can normalize a patient's serum calcium. "But it also may lead to excess calcium in the urine," said Winer, "so it's a palliative treatment at best."

Classic symptoms of hypoparathyroidism are cramping of hands and feet, seizures, and difficulty swallowing. "Halla Ruth had all these symptoms," Winer said.

Shift locales for a moment from Scandinavia to America's mountain west, where a young man named James Sanders was growing up both torturedly and tortuously. He began displaying symptoms of hypoparathyroidism at age 8, but, as he says, "the doctors didn't know what was going on. They told me it was psychosomatic -- all in my head. They told me to take two aspirin and go to bed."

Sanders' illness became so severe that he was "basically bent into a pretzel. My father had to carry me into the emergency room."

He had learned to cope with undiagnosed hypoparathyroidism through various means: "I learned to deal with difficulty breathing when my vocal cords went into spasm," he recalls. "I had all the classic symptoms but seizures."

By the time he was set to start classes at New Mexico State University, Las Cruces, at age 18, he was tired all the time. A pre-college physical exam, however, revealed astonishingly low levels of serum calcium. For the next 3 years, he spent a total of several months in the hospital as physicians finally concluded that what had been vexing him for the past decade was not hysterics or mental illness but hypoparathyroidism. In 1992, he became one of the patients in Karen Winer's first pilot study of synthetic PTH as a cure for hypoparathyroidism.

This 20-week study compared vitamin D with hPTH, and was successful enough to yield longer-term studies, with more patients, to determine optimum dose levels and possible side effects on bone and kidney function. Today, Halla Ruth, Sanders, and the four of Sanders' five sons who have a familial form of hypoparathyroidism are all enrolled in Winer's long-term study of hPTH as a new therapy for hypothyroidism. All are doing remarkably well.

"This is an extremely important breakthrough, in my opinion," said Winer, who also cautions that it is "very important to determine the long-term effects of PTH" in the body as many years of exposure to hPTH pass.

Parathyroid hormone was first synthesized in 1974 by John Potts at Massachusetts General Hospital, relates Winer, but was never applied as a treatment for hypoparathyroidism.

It was successfully used in the late 1970's as an experimental treatment for osteoporosis because it has a direct effect on bone, she continued. "Despite good results, PTH never emerged as a conventional therapy for osteoporosis."

During her first year as a fellow on rounds at NIH in 1991, Winer met Jennifer, a long-time patient with autoimmune hypoparathyroidism who had been followed since her early childhood and was now age 14 and suffering renal insufficiency.

"We discussed the case during pediatric endocrinology rounds with my mentor Gordon Cutler and he said that what this patient needs is PTH," Winer remembers. "I went to the library to see if it had ever been used, and saw the literature on osteoporosis. I also found a case report, written in German, that had just appeared involving two children from Vienna. PTH had actually worked for these children -- their calcium normalized and their symptoms disappeared. But the researchers did not have enough of the drug to continue their treatment long-term.

"I said, 'Gee, this would be a wonderful project -- it's something that needs to be done,'" Winer recalls. And because "patients were being adversely affected by the conventional therapy," she resolved to begin the experiment.

"I found out where to get the drug, and worked with the pharmaceutical development service (PDS, part of the Clinical Center pharmacy department) to turn the raw material into something we could use."

A company called Bachem in Torrance, Calif., supplied the makings of hPTH to George Grimes of the CC pharmacy, who tested and formulated a product fit for human use.

"The pharmacy here did an excellent job," said Winer. "The PDS here is phenomenal. They took the basic material, the PTH peptide, and made it into something we could treat patients with."

Winer says the German case report was very brief and included little data, so that the earlier study of hPTH for osteoporosis was actually more valuable to her research. The JAMA paper, she expects, will lead to more clinical trials across the country.

Obviously pleased that Halla Ruth is doing well, Winer recounts meeting her for the first time in January 1994. "Her mom tracked me down. She was very desperate for help. Halla's calcium metabolism was not well controlled. Her mom was trying the best she could to manage it, but vitamin D was not a good therapy for her."

Kidney problems were cropping up, her serum calcium fluctuated enormously and Halla Ruth basically saw herself as a permanently sick child. "Her problems were consuming the whole family's energy," Winer said.

She began treating the girl with hPTH. "At the molecular level, we now understand her rare form of hypoparathyroidism. It involves a sporadic mutation of her calcium-sensing receptor. Understanding the underlying cause of her disorder helped us in managing her appropriately.

Twins Halla Ruth (l) and Silja Bjorg Halldorsdottir of Iceland pose during a recent NIH visit. Halla Ruth has been successfully treated for hypothyroidism; her sister played a key role in her battle to cope with illness.

"She's quite stable now," Winer reports. "She's more energetic, she's doing well in school. She's told her mom, 'I'm not sick anymore, I just have to take medicine.'

"It's a nice thing," smiles Winer, understatedly. "Her whole self image has changed."

Halla Ruth now takes two shots a day, 12 hours apart, and every other day takes a tablespoon of magnesium before bed.

Winer monitors the progress of her far-flung patients by testing in her laboratory the urine and blood specimens they mail her periodically from their homes.

Halla Ruth's twin sister Silja Bjorg also played an important role in her restoration, Winer notes. "They really have a remarkable relationship." Normally, parents sleep over with pediatric patients when they must stay overnight in the hospital, and siblings stay at the Children's Inn. "But it was very, very hard for Halla Ruth to be separated from her sister, even for one night," said Winer. Nurses set aside standard practice to accommodate the girls and let them sleep together in the CC.

Winer credits the inn environment, too, with bolstering Halla Ruth's emerging sense of normalcy. "Every time she's here she meets other people with hypoparathyroidism. They all seem normal to her, and this helps Halla Ruth. She realizes that she is going to have a normal life, and that things probably will be okay for her to live a long, healthy life."

So far, no patient with hypoparathyroidism has failed to respond to Winer's treatment.

"Halla Ruth, out of all my children, was the most difficult to treat," she says. There are 30 patients -- 9 kids and the rest adults -- in the current study. "All the children seem to be responding well."

The dose study so far seems to indicate that patients do much better on a twice-a-day regimen than just once.

Winer expects to see Halla Ruth and the Sanders family during twice-yearly clinic visits, now planned through 2002.

Concludes Sanders, "Karen Winer is the best in the world. I can't say enough about her. She follows everything real close. She's just a top-notch physician. She really cares about her patients. I can't imagine what my life would be like if my family weren't participating in her protocol."

Echoes Gudrun Vidarsdottir, "My dreams finally came true! Halla Ruth is in the hands of the best specialist in the world and is getting the best treatment available for her disorder. We are very grateful to Dr. Karen Winer for giving Halla Ruth the possibility of a new life."

Birth of a Newsletter

James Sanders is determined that no other child on earth should have to go through the misery he suffered before he was diagnosed with hypoparathyroidism. Hence he launched, in August 1994, Hypoparathyroidism Newsletter, a friendly 12-page publication produced on a desktop computer and mailed quarterly to more than 100 subscribers free of charge. It consists almost wholly of letters sent in by patients from around the world who share Sanders' conviction that no one with hypoparathyroidism should feel alone, helpless or despairing.

A health physics technician at the Idaho National Engineering Laboratory, a Naval reactor facility, Sanders spent years 8 through 18 in a misery of misdiagnoses as physicians took his complaints of cramps, trouble swallowing, and problems breathing as hysteria or mental illness. Not one had thought to check his serum calcium.

Finally, just before entering New Mexico State University at Las Cruces, Sanders was seen by an Air Force doctor who made the correct diagnosis. Sanders went on to major in journalism and graduate from college, and now lives in Idaho Falls, Idaho, with his wife and five sons, four of whom have hypoparathyroidism. Like their dad, these boys are grateful participants in Dr. Karen Winer's NICHD protocol using synthetic human parathyroid hormone.

Not until he entered Winer's protocol did Sanders meet a fellow sufferer from hypoparathyroidism. "It was an opportunity to hug and cry together," he recalls. "It made a big difference in my life. My newsletter expands that, makes it a little bit easier" to endure the loneliness of having a rare disease. "There's a lady up in Montana who says it saved her life, gave her a 100 percent turnaround in the way she felt. To me, that's important."

A number of physicians from major U.S. medical centers are also subscribers, as are various NIH doctors and nurses.

Twenty-five years after gaining a degree in journalism, Sanders is finally getting to write the story of his life. And his audience is hungry for every word.

Reluctant to hone in on the accounts he publishes from others, Sanders does allow himself the last word -- in prose ringing with the modesty and clarity of high desert -- in the June 1996 issue: "The least we could say is that we were a part of a great moment in medicine, at least as far as patients with hypopara-thyroidism are concerned."