Author + information
- Gregor Andelfinger, MD∗ (, )@ChuSteJustine,
- Christopher Marquis, BPharm, MSc,
- Marie-Josée Raboisson, MD,
- Yves Théoret, BScPharm, PhD,
- Stephan Waldmüller, PhD,
- Gesa Wiegand, MD,
- Bruce D. Gelb, MD,
- Martin Zenker, MD,
- Marie-Ange Delrue, MD and
- Michael Hofbeck, MD
- ↵∗Service of Cardiology, CHU Sainte Justine, Cardiovascular Genetics, CHU Sainte Justine Research Center, 3175, Chemin Côte Sainte Catherine, Montréal, Quebec H4A 2S5, Canada
The RASopathies are developmental syndromes caused by germline gain-of-function mutations in genes of the RAS/MAPK signaling pathway. RIT1 mutations are particularly associated with cardiovascular disease, including hypertrophic cardiomyopathy (HCM) distinct from that seen in sarcomeric mutations. Here, we report 2 patients with severe, early-onset HCM caused by RIT1 mutations, who responded well to MEK inhibition.
Patient 1: At 33 weeks of gestation, fetal echocardiogram revealed dysplasia of all 4 valves as well as mild polyhydramnios. Three weeks later, HCM and subpulmonary stenosis developed. Postnatal examination showed macrosomia, hypertelorism, and low-set ears. Neonatal echocardiography confirmed prenatal findings. Propranolol was introduced (up to 9 mg/kg/day). An NS gene panel revealed a heterozygous RIT1 c.104G>C; p.Ser35Thr (reference transcript: NM_006912.5) de novo mutation. Despite high-dose propranolol, we observed progression of HCM.
Patient 2: At 13 weeks of pregnancy, increased nuchal translucency was diagnosed. Gestational diabetes and polyhydramnios developed at 24 weeks. Fetal echocardiography was normal. Postnatally, she required mechanical ventilation for 10 days, and thereafter, continuous noninvasive ventilation. Clinical examination showed hypertelorism and low-set ears. Genetic testing revealed a heterozygous RIT1 c.246T>G, p.Phe82Leu de novo mutation. Echocardiography showed progressive biventricular hypertrophy and subvalvular obstruction. Propranolol was started (up to 10 mg/kg/day). Chest x-rays revealed progressive pulmonary congestion. Cardiac catheterization at the age of 2 months revealed post-capillary pulmonary hypertension. An attempt to relieve concomitant pulmonary stenosis by balloon valvuloplasty remained unsuccessful. Clinical deterioration at the age of 3 months required resuscitation, mechanical ventilation, and pleural tubes for drainage of bilateral chylothoraces.
We discussed therapeutic options, including heart transplantation, and opted for off-label pharmacological MEK inhibition. We chose to seek approval from local ethics boards and obtained informed consent. We started trametinib, funded through the patients’ insurance, at 14 and 13 weeks of age for patients 1 (0.02 mg/kg/day) and 2 (0.027 mg/kg/day), respectively.
After 3 months of treatment, we observed dramatic improvement of clinical and cardiac status (Table 1). Hypertrophy regressed in both patients, with sustained improvement over a total of 17 months of treatment, and normalization of N-terminal pro–B-type natriuretic peptide. In patient 2, cardiac hypertrophy and pulmonary edema regressed, allowing extubation at 18 weeks of age. Cardiac magnetic resonance imaging confirmed the echocardiographic findings after 3.5 months of treatment. Valvular and subvalvular obstruction improved. Both patients showed better growth after treatment initiation.
Infants age <6 months with NS, HCM, and congestive heart failure have a poor prognosis with a 1-year survival of 34% (1). Trametinib, a highly selective reversible allosteric inhibitor of MEK1/2 activity, is approved to treat specific cancers with activation of the RAS/MAPK pathway. As RIT1 mutations cause RAS pathway activation, we postulated that MEK inhibition might limit myocardial hypertrophy. Such beneficial effects were demonstrated in preclinical mouse models for both cardiac and extracardiac manifestations of RASopathies (2,3). Trametinib was associated with reversal of progressive myocardial hypertrophy within 4 months after initiation of treatment, preceded by a favorable clinical response, in particular for patient 2, who was in critical condition at initiation of treatment. We also observed a catch-up pattern in somatic growth, which is rather unusual for RASopathy mutations and may, at least in part, reflect the recovery from heart failure (3). In patient 2, chylous effusions ceased within 33 days after initiation of treatment.
Trametinib treatment was associated with reversal of HCM and valvular obstruction in 2 patients with RIT1-associated NS. Although our case series is limited in patient number and allelic spectrum, it raises important questions for the treatment of such cases, in particular with respect to long-term efficacy, long-term side effects, optimal dosing, optimal treatment windows, and impact on other RASopathy manifestations. These outcomes suggest that MEK inhibition merits further study as a mechanistic treatment option for patients with RASopathies. It is conceivable that MEK inhibition may prove most effective during a fixed time window before the onset of irreversible cardiac remodeling in RASopathies, including those caused by genes other than RIT1.
Please note: Dr. Andelfinger is a Senior Research Scholar of the Fonds de Recherche du Québec–Santé and holder of the Banque Nationale Research Excellence Chair in Cardiovascular Genetics. Drs. Andelfinger, Gelb, Zenker, and Delrue have consulted with Novartis concerning the possibility of a prospective trial of trametinib in selected patients with RASopathies. Dr. Gelb has received support from the National Heart, Lung, and Blood Institute (HL135742); and has received royalties for genetic testing for Noonan syndrome from LabCorp, Prevention Genetics, GeneDx, and Correlegan. Dr. Zenker has received support from the German Federal Ministry of Education and Research (BMBF): NSEuroNet (FKZ 01GM1602A), and GeNeRARe (FKZ 01GM1519A). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Florian Rader, MD, MSc, served as Guest Associate Editor for this paper.