What’s in a name? For families desperate for a diagnosis, knowing the cause of illness matters

Medicine has made strides understanding rare genetic diseases but many patients, often children like Sylvie Wallis, Harper Jamrosz and Rithvik Kottapalli, face a diagnostic odyssey to find out what is wrong.
Medicine has made strides understanding rare genetic diseases but many patients, often children like Sylvie Wallis, Harper Jamrosz and Rithvik Kottapalli, face a diagnostic odyssey to find out what is wrong.

No one can explain the infections that regularly descend on 6-year-old Harper Jamrosz.

Rithvik Kottapalli, 16, still doesn't know what genetic glitch causes his loose joints, blood clots and inability to digest food.

Sylvie Wallis' parents waited more than a decade for an explanation for her neurodevelopmental delay. Now 16, she was diagnosed with the wrong condition in the meantime.

Although medicine has made tremendous advances in understanding genetic diseases, some people, often children, still face a yearslong or never-ending diagnostic odyssey. A typical patient with a rare disease waits six to seven years before learning the cause of their condition.


The third in an occasional series exploring how scientific advances are transforming care for rare diseases.

Along the way, they are often misdiagnosed, given useless medications or treated only for their symptoms rather than their underlying disease. Some die while waiting. Others miss key opportunities to change the trajectory of their disease.

Scientific sleuthing is making progress against some of these disorders. Improvements in genetic sequencing and a drop in price are making it easier for more people to get the type of analysis that might yield answers.

But advances are coming slowly.

DNA sequencing "has tremendous potential to reduce the time to diagnosis for rare genetic diseases, (but) such methods have not yet been applied very widely," said Ed Neilan, chief scientific and medical officer for the National Organization for Rare Disorders.

And even among the toughest cases, about two-thirds remain beyond the grasp of current analysis or won't ever be solved by genetics, experts say.

Each of as many as 7,000 rare diseases may strike only a small number of people people – fewer than 200,000 in the U.S., a definition set by Congress in the Orphan Drug Act of 1983. But combined, about 1 in every 10 people worldwide suffers from a rare disease.

For every one, an accurate diagnosis matters. Their journey for transformative care can begin only once the search for a cause ends.

A correct diagnosis can lead directly to an effective treatment – either an existing or future one. It's necessary to entice a company to invest in developing a potential therapy for an ultra-rare disease.

Even knowing there's no treatment can be helpful. "At least you have a name so you can stop looking," said Dr. Cynthia Tifft, deputy clinical director for the National Human Genome Research Institute.

A properly diagnosed person can cost society less than one who isn't.

Searching for a cause, Tifft said, requires resources both from families and the medical system. Wealthy or well-educated families with rare diseases will seek out the doctors whose expertise best matches their child's symptoms, she said, traveling across the country to find a specialist if necessary.

Children whose parents struggle just to put food on the table and who don't know the language of medicine can't do that, she said. Their lack of understanding and access can be mistaken for a lack of caring. These families may never even get the chance to try to figure out what is wrong.

Without a specific diagnosis, in some states a child can't get services such as physical therapy, occupational therapy or speech therapy. Having a name also takes away parents' sense of guilt that they may have done something wrong to cause their child's disease, she said.

"There's a lot of ramifications to having a name," Tifft said.

Here are stories of a few who have been or are still on that quest and the researchers working to help them.

Struggling without a name

Lakshmi Kottapalli carefully threaded her arms under her son's and took on most of his weight as he eased himself down the three front steps of their home in Nashua, New Hampshire. Then she headed back inside to get his walker. He waited patiently, then shuffled slowly to the passenger seat of their Toyota SUV.

Unlike most teenagers, Rithvik Kottapalli doesn't seem to resent his lack of independence. He answers "fine" when people ask how he's doing.

"He's very easygoing. Never complains," Kottapalli said.

Rithvik Kottapalli, 16, walks down the stairs from his home under his mother Lakshmi Kottapalli's watchful eye. Rithvik, who is recovering from knee and ankle surgery, has a rare condition — prune-belly syndrome — that since birth has left him with no muscles in his gut region.
Rithvik Kottapalli, 16, walks down the stairs from his home under his mother Lakshmi Kottapalli's watchful eye. Rithvik, who is recovering from knee and ankle surgery, has a rare condition — prune-belly syndrome — that since birth has left him with no muscles in his gut region.

Until he was 12, the family thought Rithvik's only problem was that he was born without muscles in his abdomen.

His severe case of what's called prune-belly syndrome – because lack of musculature gives the area a shriveled look, like a prune – left him unable to eat or digest food. He's fed every night through a central line, and his stomach and bladder empty into bags.

Then came the strokes caused by inflamed blood vessels in his brain.

Rithvik's constellation of symptoms also includes weak joints. He needed a walker or wheelchair most of the summer and early fall, after his first surgery on his left ankle and the third on his left knee. He'll probably need spinal surgery in a few months.

Rithvik plays video games after returning home from school.
Rithvik plays video games after returning home from school.

At least twice a week, Kottapalli helps him into the car for the short drive to physical therapy. She packs his wheelchair for the school's long hallways. She speaks for him when the ideas get too complex. And she drives him an hour each way for his many appointments at Boston Children's Hospital, where he sees 10 specialists – "no, probably more," she says.

Although he has had the best possible medical care, no one – so far – has been able to figure out whether Rithvik's many problems are related to one another or why he has more than one rare condition. Without that knowledge, it's impossible to know how to treat him effectively.

Physical therapist Danielle O'Shea helps Rithvik exercise his leg at Northeast Rehabilitation Center in Nashua, New Hampshire.
Physical therapist Danielle O'Shea helps Rithvik exercise his leg at Northeast Rehabilitation Center in Nashua, New Hampshire.

The Undiagnosed Diseases Network, funded by the National Institutes of Health, recently took on the family's case, hoping to figure out what's causing Rithvik's ailments. He's now getting his third and most detailed round of genetic testing, which the family hopes will yield answers.

Rithvik doesn't care much about identifying the problem. He just copes with whatever comes his way.

But his mother would very much like to know the location of that – or those – genetic mistakes.

"If you can find a particular gene that's messed up, there are many targeted therapies to those genes, so I'm hoping ... one day there could be a targeted therapy."

Revealing genetic secrets

Heidi Rehm wants to expose the human genome's secrets and help find diagnoses for people like Rithvik.

A human geneticist at the Broad Institute of Harvard and MIT in Cambridge, Massachusetts, Rehm said that despite recent technological improvements, her team solves only about 35% of the genetic puzzles brought to them.

Some may not be genetic diseases at all or may be unusual variants of known diseases, due to a new disease gene, or may have more than one mutation causing their problems. Some conditions, including types of autoimmune diseases, may be a combination of genetic vulnerability and a "hit" from their environment.

Other times doctors don't realize their patient's problem is genetic, so they don't even think to ask for genetic sequencing, she said.

The biggest breakthrough over the past five years, Rehm said, hasn't been scientific but financial. Patients' bills for genetic sequencing are now capped in the hundreds of dollars and increasingly covered by insurance, rather than costing as much as $25,000 or more and rarely reimbursed.

This growing predictability and falling costs worldwide means more people are contributing genetic data to shared databases, like one Rehm and her colleagues established called matchmakerexchange.org.

Genetic misspellings are only clues to diseases: Everyone has about 100 mutations that didn't exist in their parents. To confirm a diagnosis, Rehm has to match a genetic fluke with a known disease-causing gene or other people with the same mutation and symptoms.

By including as many people as possible from her database and others, she's more likely to find matches.

"It's like playing Go Fish," Rehm said. She sends a query out to other geneticists and families around the world. "Anybody have a match for my Jack of Spades?"

Now that so many common genetic diseases have been discovered, the ones Rehm and her team are finding affect fewer and fewer people.

About 80% of people with rare disorders have one of only 150 conditions, she said. The remaining 20% are spread across the rest of the 7,000 known rare diseases. "We've found the really common things within rare diseases," Rehm said. "So now, every time we find a new gene it's like, this may only cause disease in a handful of people on the planet."

Sometimes, she said, it feels as if her team is making great progress. She and her collaborators have discovered 300 new gene-causing mutations in the past few years and are studying 600 more candidates.

"Wow. This is awesome!" she said. "But the number of patients we're impacting is so small at this point, that it's not changing the needle substantively."

What a difference a name makes

Even when no cure is possible, an accurate diagnosis makes a difference.

Doctors knew something was wrong with Sylvie Wallis even before birth. She failed to thrive in infancy, missed every developmental milestone and just one of her many early cardiology visits cost over $10,000.

The Wallises, of Malden, Massachusetts, were told she had Noonan syndrome, a rare disease that is associated with delayed development and heart defects.

But the diagnosis never quite fit, said her father, Theron Wallis. The disease carries distinctive facial features that were different from Sylvie's, and basic genetic tests kept coming back negative for Noonan. But "it was the closest thing we found to a tribe, even if it was like they're a frog and we're a toad," he said.

Sylvie Wallis, 16, was born with a genetic mutation that left her with developmental disabilities. It took more than a decade to correctly identify the genetic cause.
Sylvie Wallis, 16, was born with a genetic mutation that left her with developmental disabilities. It took more than a decade to correctly identify the genetic cause.

In 2015, Sylvie's doctor recommended a test of all her genes to see if they could better identify and treat the girl's health problems. Insurance denied coverage two or three times over three years, her mother, Paige Wallis said. "In their eyes, it wouldn't change her treatment; it would just be informational," she said.

That information, however, was crucial for the Wallises, who wanted another child but didn't know whether Sylvie's condition was a random circumstance or could happen again. Finally, in 2012, when Sylvie was 7, they decided to take the chance and have another child.

For several years, every time little Julian didn't match up to their expectations, the couple wondered if he, too, had the same genetic fluke.

In April 2018, they learned that the Undiagnosed Disease Network had agreed to take their case and would pay for the extra genetic testing.

Four months later, they got their answer. "There are others like you, but not many," the geneticist told them.

Sylvie and her brother Julian.
Sylvie and her brother Julian.

Sylvie was the eighth person in the world known to have a mutation in a gene called TRAF7. "She's the Eighth Wonder of the World," Paige said.

The condition was first described in the scientific literature in June 2018, literally while Sylvie’s genetic sequencing was being performed. So in her case, earlier testing wouldn't have provided an answer, according to Lauren Briere, a genetic counselor with the Undiagnosed Diseases Network.

Julian didn't have the mutation and wouldn't pass it on to his own children, the Wallises learned, though some families do have more than one child with TRAF7.

Around the same time, Sylvie had surgery on her spine to decompress some of her vertebrae, a problem they later learned was common among those with the mutation.

The surgery went well, but there was a complication pulling out her breathing tube. Sylvie's heart stopped beating. She ended up in intensive care for two weeks and the hospital for months with a paralyzed left side.

Now on the other side of that ordeal, Paige said she takes comfort in knowing that Sylvie's part of the "TRAF7 tribe."

The newest study found 40 people around the world who have the condition. So far, Sylvie is the oldest female, so Paige and Theron haven't been able to learn much about how her condition will progress. But Paige often offers advice to families just learning about the mutation. The couple have started a Facebook support group for "TRAF tribe" members around the world.

"We can tell them what we've gone through, whereas we were flying blind," she said. "There's comfort in that, too."

There's no specific therapy for TRAF7, and because it changes a person's developmental path, there's no way to "cure" them. Sylvie's "always going to need a lot of care," Paige said.

"We're not going to see anything in our lifetime for Sylvie," Theron added. "But we're hopeful for those maybe who are starting in our tribe with infants."

The challenge of raising such a medically complicated child has brought the couple, who met in art school, closer, both said. "I'm less of an optimist than I used to be," Paige said. "But I also know that you can come back from a lot of really bad places."

Sylvie has mostly regained movement since the stroke, though her lower left leg remains weak. She can say multi-word sentences, like "pick me up," and "time to go to bed." She likes to watch videos, particularly of Elmo and can sing along. And she loves to swim, doing dives and flips in the water, Theron said.

"That's when she comes alive."

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Modeling disease

Cathleen Lutz has spent years trying to make the diagnostic process easier – by starting with mice. A senior research scientist at The Jackson Laboratory in Bar Harbor, Maine, Lutz runs a scientific program using mice with the same genetic mutations as people to try to understand what goes wrong and test possible treatments.

But to do her work, she needs to know which gene has malfunctioned.

Modeling a rare disease in a mouse used to take two to three years and cost upwards of $250,000. Now she can do it in a matter of months for less than $25,000, tinkering with the mouse's genes while it's still an embryo.

That allows parents and disease advocacy groups to learn more about a condition and explore drugs that might be used to treat it.

Her team has made hundreds of mouse models and is systematizing the process so it can be done at a large scale, rather than one lab studying one disease year after year.

The models, funded by the National Institutes of Health are available to anyone, Lutz said. She doesn't mind if companies make a profit off of her work, as long as patients benefit, too.

She also hopes her work will make the process more equitable. With the help of a federal grant, Lutz is trying to level the playing field and better understand a wide range of diseases, not just those with parent groups that have the wherewithal to hold golf tournaments and 5k run fundraisers, she said.

"It's incredibly unfair and unfortunate that families have to fund the research for their own children," Lutz said. "That's horrifically wrong."

There's no question the models can be useful. Once families or foundations have a mouse model of their disease in hand, "the exercise is no longer academic," she said. "They can go to experts and say, 'Here are the next experiments we need to do.'"

The uncertainty of not knowing

In many ways Harper Jamrosz of Richmond, Texas, is just like any other bright, adventurous 6-year-old.

Chatty and eager to please, she used to like vanilla ice cream but now prefers chocolate. She loves posing for photos and wants to take acting, ballet and gymnastics classes. And her favorite books are those by Mo Willems, about elephants, pigs and pigeons.

By the time Harper Jamrosz was 2 she had seven different diagnoses for her autoimmune issues.
By the time Harper Jamrosz was 2 she had seven different diagnoses for her autoimmune issues.

She has also spent long parts of her short life in a hospital fighting off infections.

By the time she was 2, Harper had seven diagnoses, "a whole gamut of autoimmune diseases and no reason as to what was causing all this autoimmunity," said her mom, Chantel.

She catches every possible bug and ends up with high fevers, diarrhea and vomiting. She has had liver biopsies, colonoscopies and gastric tubes threaded into her digestive system.

Harper, 6, is part of the Undiagnosed Disease Network.
Harper, 6, is part of the Undiagnosed Disease Network.

"Anytime she shows a fever or tiredness, it's automatic freak-out for us," Chantel said. "Usually, she will end up spending days in the hospital."

Harper's a trouper about being sick. Last year, when she had a fever of 108, a doctor came in her room and asked how she was doing. "She gave him a thumbs-up and then continued throwing up," Chantel said. "It doesn't even faze her. She is just a sport about everything."

The family considered getting Harper a bone marrow transplant – wondering whether little brother Parker, who seems healthy – would be a good match. But without knowing what's causing her condition, they worry a transplant could cause more harm than good.

Harper was accepted into the Undiagnosed Disease Network back in 2017, and her genes were sequenced along with both her parents'. It turned up nothing.

In 2019, all three provided skin samples hoping that something that didn't show up in blood would turn up in tissue. But again, there was no diagnosis.

The network reviews her case periodically, but has still found no explanation for her problems. "In the UDN right now, there are 1,988 participants that I know of and she's number 58," Chantel said. Still no diagnosis.

"I am happy for those other families. They have answers," she said, adding that she hopes the science will eventually catch up to her family.

"There's nobody in the world that we know of that is like her," Chantel said. "Yet."

Contact Karen Weintraub at kweintraub@usatoday.com

Health and patient safety coverage at USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competition in Healthcare. The Masimo Foundation does not provide editorial input.

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This article originally appeared on USA TODAY: Medical diagnosis a struggle for families dealing with rare diseases