When Allyssa Lawson was an infant, her doctors at Lucile Packard Children's Hospital Stanford struggled to understand her unusual symptoms. Allyssa, who was born in 2012, had signs of a connective-tissue disorder, including unusual facial features, crooked fingers and toes, and several hernias that needed surgical repair before she was out of toddlerhood.
But what was her diagnosis? A genetic test soon ruled out one prime suspect, a disease called Sotos syndrome. Her symptoms didn't really fit any other known disease. Maybe she had a genetic condition no one had seen before?
As a feature story I wrote recently for Stanford Medicine magazine explains, in the age of genetic medicine, it's still surprisingly difficult to diagnose rare genetic diseases, and even more complicated to identify brand-new ones. Several Stanford scientists are working on ways to change that.
To find an answer, Allyssa's geneticists proposed whole-exome genetic sequencing. Unlike the Sotos-syndrome test, which looks for a single genetic error, this much broader test would sequence all the protein-coding parts of Allyssa's genes, the first step in uncovering an unknown genetic disease. But her health insurance provider denied coverage for the test -- three times.
"It was very frustrating," said Allyssa's mom, Dara Lawson. The Lawsons longed for answers that might make Allyssa's medical journey easier. "She's been through more medical intervention in four years than I have in my whole life," Dara said. "The hard part is watching her take it so well and knowing that life can be different."
Fortunately for Allyssa, in 2014 Stanford was chosen as a site for the nationwide expansion of the National Institutes of Health's Undiagnosed Disease Network. The network is a federally-funded research project aimed at solving medical mysteries, and its grant covers research and clinical testing. Allyssa's case was among the first evaluated at the Stanford UDN site.
Her whole-exome sequence turned up a surprise: Rather than suffering from an unknown disease, she has two different rare diseases, Marfan syndrome and trichorhinophalangeal syndrome, neither of which occurs in any other members of her family. As described in a recent report, Allyssa's two genetic diseases affect the connective tissue in sometimes-similar, sometimes-conflicting ways. For instance, patients with Marfan syndrome tend to be unusually tall, while those with trichorhinophalangeal syndrome are unusually short. Allyssa's height is slightly below average, neither short nor tall enough to fit physicians' expectations for either diagnosis.
"She's basically unique in the world," said cardiologist Matthew Wheeler, MD, PhD, senior author of the case report about Allyssa. The team calculated that the chance of both of Allyssa's spontaneous mutations occurring in the same person is 1 in 5 billion to 1 in 10 billion. Had doctors relied on symptoms alone, they would almost certainly never have diagnosed her. "That really tells you that whole-exome sequencing is very powerful," Wheeler said. Another recent paper by scientists at Baylor College of Medicine, where Allyssa's whole-exome sequencing was performed, gives a broad look at the technique's ability to show when patients have two different single-gene diseases.
The Stanford Medicine magazine story was published before Allyssa's case report came out, so I couldn't give many details of her case in the story. But I did briefly explain one reason her diagnosis is meaningful to her family:
One child recently evaluated by Stanford's UDN was found to have Marfan syndrome, a connective-tissue disorder, which was combined in her case with a second, much rarer genetic disease that made it hard to recognize. People with undiagnosed Marfan syndrome can suffer rupture of the aorta; now that her diagnosis is known, cardiac monitoring may save her life.
"It's been a roller-coaster ride for sure," Dara said. "Now I finally feel like we're steady; we know what we need to watch for and who we need to talk to. We have access to a lot more help that is specific to these two disorders."
After years of wondering if they would ever have answers, she adds, "we couldn't have asked for a better outcome."
Previously: Mystery solved: Researchers use genetic tools to diagnose young girl's rare heart condition, Automating genetic analysis could speed diagnosis of rare diseases and A look at how social media helps connect patients with rare diseases
Image by Caroline Davis2010