Noonan Syndrome: A Glimmer of Hope for Rare and Sometimes Fatal Childhood Disorder | Opinion

Noonan syndrome is a genetic disorder that affects one in 2,000 children. It is characterized by unusual facial characteristics, cardiac abnormalities, short stature, anomalies of certain blood and lymph vessels, coagulation defects and learning difficulties—and has the dubious distinction of being the most common of all rare diseases.

The spectrum of symptoms and physical features vary greatly in range and severity, from very mild to severe, life-threatening disease. Early-onset hypertrophic cardiomyopathy, a condition in which the heart grows too thick and is essentially suffocating itself, has a particularly dismal prognosis in children below two years of age. Another frequent heart defect is blockage of the pulmonary valve, which is critical for the passage of blood from the heart towards the lungs.

The syndrome owes its name to the first comprehensive description by Jacqueline Noonan in 1963, but has probably been recognized as early as 1883. Fast forward to 2001: After decades of extensive clinical characterization, the first genetic cause of Noonan syndrome is identified. This study is remarkable for two reasons: First, with the identification of a gene called PTPN11 as the culprit in approximately half of the patients studied, a molecular cause for this multisystem disorder was apparent for the first time. This discovery placed Noonan syndrome in a genetic cascade involved in signaling through growth factors, cytokines and hormones.

Second, the authors realized early on that the most likely mechanism how these mutations caused Noonan syndrome is a gain of function.

Over the ensuing years, this insight was instrumental in identifying additional mutations and genes causing Noonan syndromes and related disorders. Collectively, this group of conditions is now termed RASopathies, since all subsequent studies confirmed both the originally identified cell signaling pathway—termed RAS-MAP kinase—as well as the gain-of-function character of all but a few mutations. As of 2019, 18 genes causing Noonan syndrome and related RASopathies are known (and counting…), explaining the vast majority of cases.

In fact, RAS-MAP kinases are some of the most well-studied genes due to their involvement in many biological processes, most notably cancer. Most all RASopathy mutations arise in the sperm cell before fertilization of the egg cell occurs, meaning that in RASopathies, all cells of the body carry the mutation (germline).

This is not the case in cancer, where one cell goes awry and acquires a mutation leading to uninhibited growth (somatic). Some data suggests that the biochemical effect of RAS-MAP kinase mutations is usually stronger in cancer—those mutations might not make it through the highly sensitive process leading from a fertilized egg to a fully formed embryo and a healthy newborn.

This is where our two patients come in. In late 2016, we were faced with a case of a newborn with the rapidly progressing form of hypertrophic cardiomyopathy described in Noonan syndrome.

Molecular testing confirmed our diagnosis, and conventional treatment options were rapidly exhausted. We also knew that for several years, inhibitors of the final step of the RAS-MAP kinase pathway were commercialized for the treatment of some forms of cancer in adults. Could we repurpose one of these molecules, called MEK inhibitors, to halt—or even reverse—the deleterious course of disease in our patient? A literature search yielded studies in cell culture and mouse models of Noonan syndrome. Reaching out to colleagues worldwide, we found a second, similar case in Europe, with another mutation in the same gene.

As described in our recent work in the Journal of the American College of Cardiology, we are now two years into treating two patients with the severe early-onset form of hypertrophic cardiomyopathy in Noonan syndrome with the MEK inhibitor trametinib.

The clinical course in these two patients deviates from the known natural history—for the first time, we see reversal of hypertrophic cardiomyopathy in two patients. Our work took advantage of the fact that other groups had described individual pieces of the puzzle already: the mechanism of the RAS-MAP kinase cascade, use of MEK inhibitors in cancer, and use of MEK inhibition in animal models of RASopathies.

However, treating patients such as ours with a drug not previously used in this indication, let alone with little pediatric safety data, bears its own set of challenges. We speculated that in RASopathies, low doses of MEK inhibition are sufficient, and should avoid side effects. This seemed to work. We did not anticipate that valvular blockages would disappear—they did. We saw improvement of growth—but both patients carry a mutation in a gene less frequently associated with growth retardation.

Still, the most difficult ethical dimension of our study is to balance the patient's right to treat with our duty not to harm. How far should we go? The initial decision was easy to reach—but will become more difficult with every day our patients do well. What are the long-term efficacy, long-term side effects, optimal dosing, optimal treatment windows, and impact on other RASopathy manifestations? Can we extrapolate our findings to patients with mutations in other RASopathy genes?

For us, collaborative prospective trials, additional basic and translational research and participation of all stakeholders— including patient organizations, pharmaceutical industry and funding agencies—are the only way forward. As a testimony to the power of genetics, we are optimistic that the most common rare disease may one day become a treatable one.

Gregor Andelfinger is a Clinician-Scientist at Sainte Justine University Hospital Center in Montreal and holder of the National Bank Research Excellence Chair in Cardiovascular Genetics

Marie-Ange Delrue is a Medical Geneticist in the Department of Medical Genetics at the CHU Sainte-Justine

Views expressed in this article are the authors' own.

Noonan syndrome
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Noonan Syndrome: A Glimmer of Hope for Rare and Sometimes Fatal Childhood Disorder | Opinion | Opinion