Pediatric endocrinologist Alison Boyce, MD, is leading efforts at the National Institutes of Health (NIH) Clinical Center and the National Institute of Dental and Craniofacial Research (NIDCR) to develop better diagnosis techniques and treatments for fibrous dysplasia/McCune Albright syndrome (FD/MAS), a rare disorder of the skeleton, skin, and endocrine system.
FD/MAS is caused by gene mutations that arise early in development. As the embryo grows, cells carrying the mutations spread unevenly into areas that eventually give rise to the skeleton, endocrine system, and skin. Due to this patchy pattern of growth, the affected parts of the body and the severity of the disease differ for each patient. When FD/MAS manifests in the endocrine system or bones, it can be disabling and painful, and it can impair quality of life.
Patients with FD/MAS are born with normal skeletons. But over the course of childhood, they may develop scar-like fibrous tissue that replaces healthy bone. These fibrous lesions cause bones to become soft, brittle, and prone to bowing and breaking, which can impair movement and cause pain. These lesions also can cause the skull bones to expand, leading to asymmetry of the head and face, as well as nerve compression that may causes hearing or vision loss.
Other NIH groups have developed interventions for the endocrine problems some patients experience, but “we have no treatments for the patients whose bones are affected. At NIDCR, we’ve gone a really long way trying to fill that gap,” said Boyce, who divides her time between the exam room and the lab.
Boyce divides her time between the exam room and the lab. At the NIH Clinical Center, she examines patients, characterizing signs and symptoms such as fragile bones, jagged dark patches on skin, and signs of early puberty. She also performs bone scans and collects blood and tissue samples.
“The very first thing parents do is ask what they did wrong,” said Boyce, who helps diagnose these patients. “I tell them that this is not an inherited disease, and they didn’t do anything to cause it. The disease just happens.”
In the lab, data from patients and animal models have helped Boyce’s team identify promising therapeutic targets such as a protein called receptor activator of nuclear factor kappa-B ligand (RANKL), which is abnormally elevated in FD/MAS patients.
In an ongoing clinical trial, Boyce’s group is investigating whether a drug that blocks RANKL is safe and effective in adults. Early results have been encouraging, NIDCR said, and Boyce now is hoping to launch a second trial to test whether the drug can prevent bone lesion development in children with FD/MAS.
Because the disorder has such as broad spectrum of effects, NIDCR said, it’s hard to predict which young patients will develop severe disease. But Boyce’s research has demonstrated that RANKL may serve as a useful market to help identify high-risk patients and intervene early to prevent disease progression, NIDCR said.
Boyce joined NIDCR in 2014 as a staff clinician to study FD/MAS alongside her mentor, endocrinologist Michael Collins, MD. The research to better understand FD/MAS began in the 1980s at NIH, and for the last 20 years, the program’s institutional home has been within NIDCR’s skeletal biology group.
In 2016, Boyce took the lead on one of the clinical studies in the NIDCR program. Since its start in 1998, the study has enrolled 300 patients between the ages of 1 and 102. And while the complex mechanism of the disease is a fascinating puzzle, NIDCR said, Boyce noted NIDCR’s longstanding engagement with patient communities to understand their hopes and needs.
“That’s why we have such a longstanding study at the NIH,” she said. “It’s important that the problems we’re trying to solve matter to the patients, because that’s how you really impact health.”