Researchers reverse severe lymphatic disorder in patients with Noonan syndrome

Researchers at the Children’s Hospital of Philadelphia (CHOP) resolved a severe lymphatic disorder in a girl with Noonan syndrome that led to upper gastrointestinal bleeding, fluid collection around the lungs, and numerous surgeries that were unable to resolve your symptoms. By identifying a genetic mutation along a pathway related to lymphatic vessel development and function, the research team was able to target the pathway using an existing drug that they had used in a previous case to remodel a patient’s lymphatic system.

The case study, published today in Pediatrics, describes a resolution of the patient’s symptoms within three months during treatment.

“This study is quite significant,” said first author Yoav Dori, MD, Ph.D., Director of the Jill and Mark Fishman Center for Lymphatic Disorders at CHOP. “The inhibition of this pathway appears to have wide and widespread effects on the lymphatic system. How this process occurs is not fully understood, but it is remarkable for its speed and breadth. This gives us much hope for the treatment of other patients with genetic mutations along this same path in the future. “

The patient described in the paper, Maria, first came to CHOP when she was 14, after experiencing severe anemia due to upper gastrointestinal bleeding, as well as other symptoms including fluid accumulation in the cavity around her lungs. , chronic fatigue, delayed puberty and difficulty gaining weight. Maria was born with Noonan syndrome, a genetic disorder that prevents normal development in various parts of the body and often results in short stature, heart defects and other physical problems, including an abnormal lymphatic system. Despite aggressive medical therapy elsewhere, Maria continued to bleed internally and underwent multiple blood transfusions to try to stabilize her health.

Within two days of moving to CHOP, the lymphatic team, led by Dori, determined that Maria had many lymphatic irregularities, which were leading to internal bleeding and lung problems, so they scheduled Maria’s first surgery, an embolization procedure. lymphatic that would seal the leaking vessels in his intestine.

However, within two months of the procedure, Maria’s gastrointestinal bleeding recurred. Over the next 8 months, she underwent two additional procedures, as well as a cauterization procedure to close some blood vessels in the intestine, but the benefits of each procedure only lasted about three months before the bleeding and her symptoms returned.

Based on full-exome sequencing performed at CHOP’s Center for Applied Genomics, the research team learned that Maria had a genetic mutation in the SOS1 gene, which operates along the RAS-MAPK pathway. This pathway involves mitogen activated protein kinase (MEK) and the Maria mutation caused an overproduction of MEK, which resulted in the uncontrolled proliferation of her lymphatic vessels.

The research team had previously used a MEK inhibitor in another patient with a severe lymphatic disorder with great success. That patient had a mutation in the ARAF gene, which is also on the RAS-MAPK pathway. Within months of starting treatment with trametinib, a MEK inhibitor, the patient saw a resolution of his symptoms and a complete remodeling of his lymphatic system.

As SOS1 operates on the same path as ARAF, Jean Belasco, MD, an oncologist at CHOP’s Cancer Center who co-led the study, called for compassionate use of the drug in Maria’s case, given the lack of other treatment options. .

“The success of trametinib in another patient with a mutation on the RAS-MAPK pathway encouraged us to try this approach, as other procedures and therapies continued to be unsuccessful,” Belasco said. “Even though we are in the early stages of this type of personalized medicine, the hope is that by looking at patient mutations, we can find more drugs and better care for patients with genetic diseases.”

Within three months of starting the drug, Maria’s vital signs stabilized. The bleeding stopped, her electrolyte, hemoglobin, and albumin levels returned to normal, and she began to gain weight. Maria’s mother noticed that Maria was no longer going through periods of exhaustion and her pallor improved.

“He looks better than I’ve ever seen,” said his mother. “She looks like a normal teenager. She’s like night and day. She’s much happier too. I think she knew deep down she was dying. The medicine gave her hope.”

Hakon Hakonarson, Director of the Center for Applied Genomics and co-author of the paper, said that although Maria’s SOS1 mutation is markedly different from the ARAF mutation seen in the other patient, the drug was equally effective because it targets and blocks function. by MEK. He likened the scenario to a path where 15 events must occur for a cell to function. Maria’s SOS1 mutation could occur at step nine, while the ARAF mutation could occur at step three, but both genes are on a chain that eventually passes through a tunnel leading to MEK phosphorylation and hyperactivity. Since both mutations were so-called gain-of-function mutations, MEK – and hence lymphatic activity – was overexpressed in both patients. The MEK inhibitor puts the brakes on an overdriven system.

“Substantial advances in genetics have allowed us to discover these mutations and group them into selective pathways and determine effective gene mutation-based therapies with very high precision,” said Hakonarson. “No one could have imagined that this drug would work for Maria without knowing the underlying genetics. This finding is extremely important because Noonan syndrome has the largest patient population with alterations in MEK signaling. Not all Noonan patients will have mutations that they respond to this therapy, but a good number of them will. “

He added that the treatment could also benefit patients with other genetic defects, although he noted that continued use of the drug treats the symptoms caused by these mutations but does not fix the gene or cure the underlying condition.

“MEK inhibition has the potential to have significant effects on other organ systems affected by defects in the RAS-MAPK gene, such as the heart, eyes, skin and clotting system,” said Hakonarson.

Hakonarson is also part of CHOP’s Comprehensive Vascular Anomalies Program (CVAP), a CHOP Frontier Program that uses cutting-edge genomics and personalized research strategies to determine the causes of complex vascular conditions and identify targeted therapies. The program works closely with the Lymphatic Imaging and Interventions Frontier Program, which is led by Dori. CHOP’s frontier programs conduct cutting-edge research that results in advanced clinical care. The CVAP, in particular, draws on the vast clinical and genomic research capacity within the Cancer Center and Center for Applied Genomics.

Even with the success of the groundbreaking treatment introduced by these programs, it is not entirely clear why MEK inhibitors not only resolve patients’ symptoms, but also completely remodel their lymphatic systems. Hakonarson said one possibility is that when mutated genes cause the lymphatic system to grow uncontrolled, the body’s vessels leak fluid throughout the body. When unregulated growth is stopped, other homeostatic mechanisms that are balancing the system take effect, so hyperreactive cells that were growing out of control die and are replaced by normal cells that gradually build the lymphatic system.

Whatever the mechanism, Maria’s mother said her daughter didn’t hesitate to be the first patient with Noonan syndrome to try this treatment to solve a lymphatic problem.

“Maria saw the value from the start,” she said. “She saw the value for herself, but she was also thinking about other Noonan boys, some of whom died from lymphatic problems. She was available and eager.”