Mentored by the “father of medical genetics” at a time when few women were in the field, Clair Francomano, MD, has been studying connective tissue disorders for nearly four decades. Today, she’s one of the world’s foremost experts in Ehlers-Danlos syndromes and hypermobility spectrum disorders.
Although she started doing gene discovery before the advent of computer-assisted methods — manually moving test tubes from one water bath to the next with varying temperatures — Francomano has adeptly adopted new technologies for both research and education. She now has her own YouTube channel and co-founded the EDS ECHO initiative with the Ehlers-Danlos Society to educate health care professionals throughout the world and improve care for people living with EDS and related hypermobility disorders.
While she could have retired years ago, Francomano still sees EDS patients at Riley Hospital for Children every week. They travel from as far away as Europe to see an expert in this rare disease that affects about one in 5,000 people.
IU is among just 15 centers in the U.S. and 34 internationally designated by the Ehlers-Danlos Society as a center of excellence for EDS care, outreach, research and education — part of the society’s CORE Network. On one remarkable day, Francomano saw new patients from California, Maine and Alaska.
“I feel like I’m making a difference for these patients,” said Francomano, a professor of medical and molecular genetics and a researcher with the Indiana Center for Musculoskeletal Health at the Indiana University School of Medicine. “I really enjoy the intellectual challenges of the research and the interactions with my colleagues.”
Ehlers-Danlos syndrome has 13 types with hypermobile EDS (hEDS) being the most common. Symptoms of hEDS are similar to hypermobility spectrum disorder (HSD) with loose joint connections leading to pain. The journey to an EDS or HSD diagnosis is often long because symptoms differ from person to person and affect multiple body systems, including the nervous, cardiovascular, gastrointestinal and immune systems.
In 2023, Francomano and colleagues published a comprehensive, case-based handbook for EDS and HSD called “Symptomatic” describing the panoply of symptoms patients may describe to their clinicians — from head to feet.
“The biggest issue is that because there are problems in so many different organ systems and people look well, they’re often disbelieved even by medical professionals,” Francomano said. “It’s often very emotional for people to feel heard and understood and have some answers for why they’ve been struggling for so long.”
Living with an invisible disability
Fatigue is normal for someone recovering from mono, but for Sarah Vaught, it never went away. A few years later, she began having joint pain and repeated wrist and ankle sprains. Next it was low blood pressure, a slow heartbeat and persistent nausea. Although she’d known since elementary school that she was more “bendy” than other kids, Vaught wouldn’t be diagnosed with hypermobility spectrum disorder until age 20 — more than 11 years after her first symptoms appeared.
“It was a very long and frustrating process because I felt like some of the doctors I saw only cared about addressing one symptom rather than finding an underlying cause for all of them, and at least one dismissed me as a kid trying to get out of class, despite the fact that I loved school and was always upset when I had to stay home,” said Vaught, now a medical student on the IU School of Medicine—West Lafayette campus.
Her own research led her to suspect HSD or hEDS. Her primary care doctor referred her to a geneticist who ruled out other hereditary disorders of connective tissue and made the HSD diagnosis.
Vaught’s frustrating diagnostic odyssey is typical, according to research done by Francomano and Colin Halverson, PhD, an assistant professor of medicine and researcher with the IU Center for Bioethics who lectures on “pain and prejudice.”
“I think the most striking and startling thing we’ve found is the high rates of trauma-like responses patients in this population have to health care delivery,” Halverson said. “This can result from dramatic, negative encounters with their clinicians, but more often, it is due to the slow accumulation over years of clinicians’ skepticism and dismissal of the reality or severity of their symptoms. In fact, patients spend more than a decade on average seeking a diagnosis.”
Hypermobility exists on a spectrum with hEDS on the extremely symptomatic end. Many people, like Vaught, don’t meet all the requirements for Ehlers-Danlos but experience many of the same symptoms and require the same multidisciplinary care.
“HSD is more common than you’d think, but it’s often misunderstood and frequently misdiagnosed,” Francomano said in an educational video for the Ehlers-Danlos Society. “HSD is not just bendy joints and can involve multiple different organ systems and have a profound effect on a person’s ability to live their life.”
Vaught has found swimming the best activity for managing joint pain; other forms of exercise can trigger drops in blood pressure or overheating. She also maintains a high salt intake and builds time to rest into her weekly routine.
While battling pain and fatigue is challenging, Vaught said dealing with the social aspects of her disability is even harder.
“There are times when I would really benefit from using a mobility aid, but I know it would make things more difficult for other people or limit our options on what to do or where to go, so I try to push through without one and end up regretting it,” she said. “It’s also weird for me to alternate between using my wheelchair and walking when I’m in a public place like an amusement park because people will give me dirty looks or assume I’m faking a disability to skip the lines.”
In her first phase of medical school — primarily classroom learning — Vaught hasn’t needed many accommodations beyond having a chair in the anatomy lab. When her clinical rotations begin, she anticipates needing to use her wheelchair more often.
Vaught doesn’t let her disability stop her from living an active life. She’s an avid skydiver, loves riding four-wheelers (with an adaptation to the throttle) and is currently training to swim a 10k. What she wishes people understood about hypermobility disorders is that they are dynamic, meaning the symptoms are different day-to-day.
“If they see someone using a mobility aid one day and walking unassisted on another, it doesn't mean they didn't need the mobility aid,” Vaught said. “They may be having a lower-symptom day, or they may need an aid for some activities and not others. Everyone is just different in what tools they need.”
Halverson has been following a small cohort of EDS patients for almost six years.
“Each time I run an interview study with them, I learn new, unnecessary challenges they face, and that definitely inspires me to keep working on improving their experience with biomedicine,” he said.
Bringing the Human Genome Project to the practice of medicine
Francomano is closing out a three-year project with the Ehlers-Danlos Society that aims to refine the diagnostic criteria for hypermobile Ehlers-Danlos syndrome. She’s also on a team of genetic sleuths that’s trying to discover what gene defects lead to hEDS — the only one of the 13 types of Ehlers-Danlos that does not have a known genetic cause.
Francomano trained in medical genetics at John Hopkins University, where she was mentored by Victor McKusick, MD, the first to define hereditary disorders of connective tissue (HDCTs) and link them to issues with multiple organ systems.
After joining the faculty at Johns Hopkins, Francomano went on to positions with the National Institutes of Health and the Harvey Institute for Human Genetics at the Greater Baltimore Medical Center.
“It was time to bring the fruits of the Human Genome Project to the practice of medicine, and this was something that really appealed to me,” Francomano said. “At that time, there were people taking care of other hereditary disorders of connective tissue like Marfan syndrome and skeletal dysplasia, but there really wasn’t anybody taking care of Ehlers-Danlos syndrome. So, I started learning and making connections with people in multiple specialties who could help take care of the different complications we see in Ehlers-Danlos syndromes.”
At the NIH, Francomano spearheaded a longitudinal study on the natural history of EDS which ran for over 20 years. She’s now planning a similar study with the Ehlers-Danlos Society, drawing from over two decades of her own patient records and establishing a new registry for EDS patients.
“That will be very important to understand their long-term prognosis and how the disease affects people over the course of their lifetimes,” she said.
Francomano has authored over 160 publications and is a frequent lecturer at international conferences. Through her work with the society and her social media channels, Francomano educates both colleagues and the general public. She also passes her knowledge to residents in IU’s medical and molecular genetics program.
In 2022, Francomano coauthored a report for the National Academies of Sciences, Engineering and Medicine with the goal of helping patients and their providers navigate the Social Security Administration system for disability coverage.
“From my perspective, Dr. Francomano is universally acclaimed for her scientific and medical expertise, but even more importantly, she is viewed as a conscientious advocate for her patients,” Halverson said. “Her waitlist is so long because she spends so much time one-on-one with her patients, which is necessary because of the complexity of their care but also because of the attention and care needed to build trust with patients who have spent far too many visits with new clinicians having their symptoms discounted.”
