Genetic Discovery Leads to Precise Treatment for Child With Severe Lymphatic Disorder

Genetic Discovery Leads to Precise Treatment for Child With Severe Lymphatic Disorder

Daniel, an athletic preteen who played sports and had recently run a 5k, suddenly was in pain and struggling to breathe, with swelling in his lower body. Visits to his primary care doctor revealed no answers, and he was referred to a rheumatologist. When the specialist examined Daniel, there was so much fluid around Daniel’s heart, it blocked the sound of his heartbeat.

His family learned lymphatic fluid was leaking into his pericardium, the outer layer of the heart. Cardiologists inserted a drain to remove the fluid, but the area kept filling back up, causing swelling throughout his body. It was at this point that Daniel transferred to Children's Hospital of Philadelphia for evaluation by experts in the Center for Lymphatic Imaging and Interventions, world renowned for its expertise in diagnosing and treating lymphatic system disorders. The team uses an innovative procedure to image and close lymphatic leaks, and they diagnosed Daniel with a severe and rare lymphatic condition.

In a breakthrough discovery, a team of researchers, co-led by Yoav Dori, MD, PhD, a cardiologist and director of the Center for Lymphatic Imaging and Interventions, and Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics, developed an innovative, precision medicine therapy that would lead Daniel back to health.

Moving Science Forward

At CHOP, researchers worked to isolate the genetic root of Daniel’s disease so they could target therapy to correct his abnormal lymphatic system. Dr. Hakonarson’s team performed whole-exome sequencing on Daniel’s DNA and that of an adult patient from another center who also had a severe lymphatic condition. The sequencing identified a previously undiscovered gain-of-function mutation in the ARAF gene. This gene mutation was driving uncontrolled proliferation of abnormal lymphatic vessels, causing the leak of lymphatic fluid, edema, and respiratory difficulties that Daniel was experiencing.

The researchers explored the function of the ARAF mutation by inserting it into the embryos of zebrafish, which are frequently used to model genetic diseases; the zebrafish developed similar abnormal lymphatic channels. The next step was to use a drug called an MEK inhibitor, typically approved for use in patients with melanoma and known to act on biological pathways affected by ARAF. Then came some great news: The drug “rescued” the structural defect in the zebrafish, causing them to develop normal lymphatic vessels.

The physician-scientists had saved the fish – and they were determined to save Daniel, too.

With no time to waste, Drs. Dori and Hakonarson consulted with Jean Belasco, MD, from the CHOP Oncology team, who helped obtain compassionate permission from the U.S. Food and Drug Administration to treat Daniel with an MEK inhibitor called trametinib.

Within two months after starting the experimental treatment in March 2017, Daniel’s breathing improved. Three months after starting the treatment, he had reduced fluid retention and was able to cut back on supplemental oxygen, start breathing room air, and begin more physical activity. An MRI showed that his lymphatic vessels were remodeling themselves, with no signs of leaks. The heavy swelling in Daniel’s legs gradually disappeared.

Setting a New Course

“This case is a dramatic example of implementing a precision medicine treatment for a life-threatening rare disease,” Dr. Hakonarson said. “We discovered a causative gene mutation in two patients, identified an existing drug that acts on that gene’s pathway, showed that the drug relieves the condition in lab animals, and then successfully treated the original patient.”

What Dr. Hakonarson summarizes here was, of course, a years’ long journey through pain, uncertainty, surgical procedures, treatment, and perseverance that ultimately led to discovery.

The result may form the basis of a new therapy for this type of defective lymphatic circulation. Drs. Dori and Hakonarson said this research is the first real evidence for complete remodeling of an entire organ system by a drug, and it offers potential new research pathways to explore for many patients with similar lymphatic flow disorders. The discovery appeared in Nature Medicine in July 2019.

As a result of Daniel’s case, all lymphatics patients are now also seen by the genomics team, and CHOP is expanding a Frontier program in complex vascular anomalies that investigates underlying genetic mutations that impair normal development of blood or lymphatic vessels.

“As difficult as this process of discovery, experimentation and treatment has been, we are so grateful for the perseverance and skill of his medical team, in addition to Daniel’s resilience and optimism,” said Daniel’s mother, Anna. “The fact that Daniel’s case has the potential to help countless other patients is a silver lining for sure.”

Back to Being a Teen

Now 15-years-old, Daniel has been able to resume many normal activities, such as riding his bicycle, playing basketball, weight training, and helping to coach soccer camps. As he prepared to begin his freshman year of high school, his mother couldn’t help but recall the long way he’s come in a relatively short time.

“Just over two years ago, Daniel was getting measured for a wheelchair and had to be tutored at home,” she said. “Now he’s back at school full time and is able to be active with his friends.”