pyrimidinones and Noonan-Syndrome

To evaluate the effect of the RAS-MAPK pathway inhibitor trametinib on medically refractory chylous effusions in 3 hospitalized patients with Noonan syndrome.. Pharmacologic MEK1/2 inhibition has been used to treat conditions associated with Noonan syndrome, given that activation of RAS-MAPK pathway variants leads to downstream MEK activation. We describe our experience with 3 patients with Noonan syndrome (owing to variants in 3 distinct genes) and refractory chylous effusions treated successfully with MEK inhibition. A monitoring protocol was established to standardize medication dosing and monitoring of outcome measures.. Subjects demonstrated improvement in lymphatic leak with additional findings of improved growth and normalization of cardiac and hematologic measurements. Trametinib was administered safely, with only moderate skin irritation in 1 subject.. Improvements in a variety of quantifiable measurements highlight the potential utility of MEK1/2 inhibition in patients with Noonan syndrome and life-threatening lymphatic disease. Larger, prospective studies are needed to confirm efficacy and assess long-term safety.

Topics: Antineoplastic Agents; Child; Humans; Mitogen-Activated Protein Kinase Kinases; Noonan Syndrome; Pyridones; Pyrimidinones

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.

Topics: Cardiomyopathy, Hypertrophic; Humans; Infant, Newborn; Mutation; Noonan Syndrome; Oxygen; Pyridones; Pyrimidinones; ras Proteins; Tachycardia

Topics: Female; Humans; Infant, Newborn; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Noonan Syndrome; Point Mutation; Proto-Oncogene Proteins c-raf; Pyridones; Pyrimidinones; Tachycardia

Noonan syndrome is a multiorgan system disorder mediated by genetic defects along the RASknown as RASopathies. It is the second most common syndromic cause of congenital heart disease and, in ∼20% of the cases, is associated with severe lymphatic disorders, including chylothorax and protein-losing enteropathy. Recently, we reported on the use of mitogen-activated protein kinase inhibition in a patient with an ARAF mutation and severe lymphatic disorder leading to an abrupt improvement in symptoms and complete remodeling of the central lymphatic system. Here, we present a patient with Noonan syndrome and severe lymphatic abnormality, leading to transfusion-dependent upper gastrointestinal bleeding and protein-losing enteropathy. The patient stopped responding to medical therapy and underwent several lymphatic interventional procedures, which led only to a temporary improvement in symptoms. Because of a lack of other treatment options, an expanded access approval was obtained, and the patient initiated treatment by mitogen-activated protein kinase inhibition using trametinib. This led to resolution of her symptoms, with complete normalization of her electrolyte levels, hemoglobin, and albumin within 3 months of starting the drug. Similar to the previously reported case, she also had complete and generalized remodeling of her lymphatic system. In patients with RAS pathway defects complicated by a severe lymphatic disorder, inhibition of the RAS-MAPK pathway should be considered as a possible treatment option in patients who failed conventional treatment and might be a first-line treatment in the future.

Topics: DNA; DNA Mutational Analysis; Female; Humans; Infant, Newborn; Mitogen-Activated Protein Kinase Kinases; Mutation; Noonan Syndrome; Phenotype; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; SOS1 Protein

Topics: Cardiomyopathy, Hypertrophic; Female; Gestational Age; Humans; Infant, Newborn; MAP Kinase Kinase Kinase 1; Mutation; Noonan Syndrome; Pregnancy; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Rare Diseases; Risk Assessment; Sampling Studies; Treatment Outcome; Ultrasonography, Prenatal

Topics: Anti-Arrhythmia Agents; Antineoplastic Agents; Cardiomyopathy, Hypertrophic; Cardiovascular Agents; Drug Repositioning; Echocardiography; Gene Expression Regulation; Heart Valves; Heterozygote; Humans; Infant; MAP Kinase Kinase 1; Mutation; Natriuretic Peptide, Brain; Noonan Syndrome; Peptide Fragments; Propranolol; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; ras Proteins; Signal Transduction; Treatment Outcome