Severe Lymphatic Disorder and Multifocal Atrial Tachycardia Treated with Trametinib in a Patient with Noonan Syndrome and SOS1 Mutation

Abstract

Noonan syndrome (NS) is a multisystemic disorder caused by germline mutations in the Ras/MAPK cascade, causing a broad spectrum of phenotypical abnormalities, including abnormal facies, developmental delay, bleeding diathesis, congenital heart disease (mainly pulmonary stenosis and hypertrophic cardiomyopathy), lymphatic disorders, and uro-genital abnormalities. Multifocal atrial tachycardia has been associated with NS, where it may occur independently of hypertrophic cardiomyopathy. Trametinib, a highly selective MEK1/2 inhibitor currently approved for the treatment of cancer, has been shown to reverse left ventricular hypertrophy in two RIT1-mutated newborns with NS and severe hypertrophic cardiomyopathy. Severe lymphatic abnormalities may contribute to decreased pulmonary compliance in NS, and pulmonary lymphangiectasias should be included in the differential diagnosis of a newborn requiring prolonged oxygen administration. Herein we report the case of a pre-term newborn who was admitted to our unit for the occurrence of severe respiratory distress and subentrant MAT treated with trametinib.

New prospectives on treatment opportunities in RASopathies

“…Subsequent to the publication of the mechanistic treatment of two infants with NS‐related HCM with trametinib, several other publications described experiences with MEKi for severe manifestations in RASopathies (Dori et al, 2020; D. Li et al, 2019; Meisner, Bradley, & Russell, 2021; Mussa et al, 2021; Nakano et al, 2022). Excluding our initial study, the published evidence now reports amelioration in three additional cases with cardiovascular issues (Lioncino et al, 2022; Meisner et al, 2021; Mussa et al, 2021). In two of these cases, the leading symptom was intractable multifocal atrial arrhythmia, which improved within 48 hours of introduction of a MEKi without appreciable conduction anomalies (Lioncino et al, 2022; Meisner et al, 2021).…”

“…Excluding our initial study, the published evidence now reports amelioration in three additional cases with cardiovascular issues (Lioncino et al, 2022; Meisner et al, 2021; Mussa et al, 2021). In two of these cases, the leading symptom was intractable multifocal atrial arrhythmia, which improved within 48 hours of introduction of a MEKi without appreciable conduction anomalies (Lioncino et al, 2022; Meisner et al, 2021). In the third case, which described a multimorbid premature newborn, the cardiopulmonary status improved to a point that allowed extubation, however, acute decompensation after a surgical procedure for hydrocephalus resulted in an intractable relapse of HCM despite continuation of the MEKi.…”

“…A total of six patients with NS and severe lymphovascular disease have now been reported as well in addition to a report of two patients with ARAF pathogenic variants and central conducting lymphatic anomaly (this latter condition is extremely rare and has not usually been categorized as a RASopathy) (Dori et al, 2020;D. Li et al, 2019;Lioncino et al, 2022;Nakano et al, 2022). In all of these patients, significant improvement or resolution of lymphovascular disease was reported, with initial response starting at around 2 days to 1 month after treatment initiation to sustained response at 12 months after treatment initiation (example in Figure 5).…”

Successful treatment of refractory chylothorax with MEK inhibitor trametinib in a child with Noonan syndrome: case report

“…MEK inhibition with trametinib as a possible treatment has been described in few case reports of patients with Noonan syndrome and either hypertrophic cardiomyopathy or refractory life-threatening chylothorax. 4 , 5 , 6 , 12 , 13 The literature is sparse however and lacks guidelines regarding best treatment course. Doses between 0.01 to 0.027 mg/kg 4 , 5 , 12 have been reported, and all cases seem to continue on trametinib for a prolonged time and without a predetermined duration (Nakano et al .…”

Modeling (not so) rare developmental disorders associated with mutations in the protein-tyrosine phosphatase SHP2

“…Trametinib treatment in a NS patient with a SOS1 mutation and associated severe lymphatic defects completely resolved the lymphatic symptoms after 8 weeks of treatment (Dori et al, 2020). Severe respiratory Frontiers in Cell and Developmental Biology frontiersin.org distress related to lymphatic defects and multifocal atrial tachycardia (MAT) present in a NS patient with SOS1 mutation (Lioncino et al, 2022), as well as MAT present in a NS patient with RAF1 mutation (Meisner et al, 2021) were resolved upon trametinib treatment. The 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitor lovastatin decreases growth plate defects and cognitive deficits in NS SHP2-D61G mice (Tajan et al, 2018b).…”