Doctor's efforts to understand daughter's condition open door to advances in genetics
By Lisa M. Krieger
http://www.JewishWorldReview.com | (MCT) A physician and scientist, Dr. Hugh Rienhoff has a deep appreciation for the discoveries of modern genetics.
And yet an explanation for the genetic error within his own beloved daughter Beatrice eludes him.
Born with small, weak muscles, widely spaced eyes and curled fingers, Beatrice is a medical mystery. So her father has set out to find the single bit of deviant DNA that explains her condition, hoping the knowledge will lead to better care.
His tireless search - studying journals, quizzing experts, even sequencing a piece of her DNA - has not yet revealed a certain culprit. But his effort opens a door to the next frontier of genetics, where scientists look beyond the vast populations with common ailments like heart disease and explore those rare cases with congenital defects that defy explanation.
"The human genome is still a wilderness," Rienhoff said.
Beatrice, now 4, is an extremely smart, happy and engaging child. Although she needs help getting up steps and frequently visits a physical therapist to strengthen her arms and legs, she swims, stacks Legos and tags behind her two brothers in the family's sunny farmhouse in San Carlos.
But when their daughter was a newborn with a puzzling array of conditions, Rienhoff and his wife, Lisa Hane, were advised: "Take her home and love her."
Born with floppy muscles, long feet and contracted fingers and toes, Beatrice was slow to gain weight. Over the course of her first year, she missed every motor milestone, such as holding her head up, sitting, crawling and walking. It was clear she had a syndrome affecting skeletal and muscular development.
"In play groups, everyone compares their babies," Rienhoff said. "She was different because she wasn't sitting up, and they were." Over time, she is catching up and will start kindergarten next year, but her future is uncertain. The family worries that new problems, such as vascular disease, might arise and shorten her life.
"With a diagnosis, you know what to expect," Rienhoff said. "But she had nothing recognizable, no syndrome that could account for the constellation of findings."
The mystery unsettles Rienhoff, an analytical man and dedicated father.
He was trained in math, medicine and genetics at Harvard University, Johns Hopkins and the Fred Hutchinson Cancer Research Center in Seattle. He had founded DNA Sciences, a Fremont diagnostic company focused on genetic discoveries. He now is also a venture investor and entrepreneur for life sciences companies such as WebMD.
He believed Beatrice's symptoms were related to each other - and were probably caused by a specific mutation in a gene. Yet Rienhoff, his wife and their sons are healthy.
Did she have an unusual form of a common condition? Had similar children gone undetected? Or had a new mutation cropped up?
Dad and daughter bonded over long plane trips as they sought an array of pediatricians, orthopedic surgeons, geneticists and neurologists around the country.
Only once has she questioned her condition. "She asked why her hand didn't look like mine," Hane said. "I said she was born that way and it made her unique - and that's what Poppy is trying to study."
Each doctor offered a different diagnosis. But none was a perfect fit.
Could Beatrice have a muscle-wasting disease? No. A team of experts suggested the newly identified Loeys-Dietz syndrome, a devastating vascular disease. But her aorta was normal. They marked off Marfan's disease, because her muscles were undeveloped. Beals syndrome didn't fit, because her large joints, like her knees, were not contracted.
Rienhoff has spent thousands of hours researching diseases and observing Beatrice, jotting down each new clue or theory in a black bound notebook.
"It is intellectually and emotionally exhausting to be reading about your daughter's illnesses," Rienhoff said. "It's a nightmare."
"You say: 'These three things fit - maybe she has a version of that.' Or 'Maybe I should talk to these five people,' or 'I have to call the author of that paper to get more information.' "
He worried that scientists would dismiss him as an overreactive parent. "I got to the point that I wouldn't tell doctors it was my daughter," he said. "I'd write up a description of the case and send it off."
Although Beatrice didn't have Marfan's or Beals, she clearly had something similar. So Rienhoff focused on a related hormone that regulates muscle cell size and number and he zeroed in on several stretches of DNA with genes in that pathway.
To test his hypothesis, he needed to look at his daughter's DNA.
So he bought a used PCR machine, a microcentrifuge, pipettes and gel box. Thus equipped, he picked relevant genes out of his daughter's genome, copied them and sent them off for sequencing.
At night, while the family was sleeping, he examined her chromatogram, which shows the color-coded DNA sequence.
"It was eerie examining her DNA, as though I were peering through a powerful microscope looking deep into my daughter," Rienhoff said.
Beatrice's genes looked largely unremarkable. But he did find one change - and it was in a location likely to regulate the activity of a muscle-related gene.
Finding an aberrant gene is just the beginning - he needs to find other people like Beatrice, to see if their DNA has an error as well.
In search of others, he launched a Web site in early 2007 called http://mydaughtersdna.org/, which encourages the public to publish puzzling conditions, with the hope that new cases might surface. Someday he would like to see the National Institutes of Health create a much larger version so research can be done on mystery syndromes. "If I broadcast her findings to others - doctors, patients and parents who may have seen a similar condition - I am more likely to pin down precisely what she has," he said.
Already, about a dozen other mystery cases have been posted. "I write you because there are some resemblances between my daughter and yours. I really want to find what's the cause for the state of my daughter, so I would know how can I adequately help her," wrote father Stefan Petkov.
Another father, Robert Konstanty, wrote: "I have a beautiful daughter ... She cannot sit, crawl on hands/knees, stand, walk, or talk."
Rienhoff hopes that the steady accumulation of stories will help find the needle in the haystack that afflicts Beatrice and other patients.
"Does she have something new - 'Beatrice syndrome'?" he asked. "Or are there other people walking around who have a few problems, maybe just funky little things, that nobody's put together into a diagnosis?
"To be a parent of a patient is to be continually searching," Rienhoff said.
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