NS and related RAS/MAPK pathway (RASopathy) disorders are the leading genetic cause of HCM presenting in infancy. HCM is a major cause of morbidity and mortality in children with Noonan spectrum disorders, especially in the first year of life. Previously, there have been only isolated reports of heart transplantation as a treatment for heart failure in NS. We report on 18 patients with NS disorders who underwent heart transplantation at seven US pediatric heart transplant centers. All patients carried a NS diagnosis: 15 were diagnosed with NS and three with NSML. Sixteen of eighteen patients had comprehensive molecular genetic testing for RAS pathway mutations, with 15 having confirmed pathogenic mutations in PTPN11, RAF1, and RIT1 genes. Medical aspects of transplantation are reported as well as NS‐specific medical issues. Twelve of eighteen patients described in this series were surviving at the time of data collection. Three patients died following transplantation prior to discharge from the hospital, and another three died post‐discharge. Heart transplantation in NS may be a more frequent occurrence than is evident from the literature or registry data. A mortality rate of 33% is consistent with previous reports of patients with HCM transplanted in infancy and early childhood. Specific considerations may be important in evaluation of this population for heart transplant, including a potentially increased risk for malignancies as well as lymphatic, bleeding, and coagulopathy complications.
BACKGROUND Noonan syndrome (NS) is one of several autosomal dominant multisystem disorders known as RASopathies. Common manifestations of NS include congenital heart defects and cardiomyopathy, lymphatic malformations, and predisposition to myeloproliferative disorders. Chylous fluid accumulation secondary to lymphatic malformations are seen in NS and are a major cause of morbidity and mortality often refractory to conventional medical management. There has been increasing interest in the use of pharmacologic MEK inhibition in the management of these patients given that activating RAS pathway mutations lead to downstream MEK activation that is causative of this pathology. DESIGN/METHODS Three patients with a confirmed diagnosis of NS are described. Each patient developed complications from chylous effusions refractory to conventional management and were subsequently enrolled on-study to treat with compassionate use oral trametinib from Novartis Pharmaceuticals on a single patient Investigational New Drug from the Food and Drug Administration (FDA). All patients were consented to be monitored for one year of therapy following a local protocol approved by the Colorado Institutional Review Board (COMIRB). Patient 1: a 4-year-old female with NS due to a pathogenic germline mutation of the RIT1 gene [c.246T>G, p.Phe82Leu] born with severe hypertrophic cardiomyopathy, mitral valve dysplasia, and pulmonary valve stenosis. She developed bilateral chylous pleural effusions that were refractory to dietary modification, diuretics, octreotide, and sirolimus. Patient 2: a 3-month-old female with NS due to a pathogenic germline mutation of the SOS1 gene [c.1322G>A; p.Cys441Tyr] born with esophageal atresia/tracheoesophageal fistula and moderate pulmonary valve stenosis. She developed bilateral chylous pleural effusions and ascites that were refractory to dietary modification and octreotide therapy. Patient 3: a 4-month-old male with NS due to a gain-of-function mutation of PTPN11 [c.854T>C; p.Phe285Ser] with hypertrophic cardiomyopathy, pulmonary valve stenosis, respiratory insufficiency with suspected pulmonary lymphangiectasia, and persistent chylous pleural effusions in addition to Noonan syndrome-associated myeloproliferative disorder (NS-MPD) that had been refractory to traditional management. RESULTS MEK inhibition with trametinib was used in three patients with NS and life-threatening complications with no medical or surgical treatment options. All three patients had dynamic contrast magnetic resonance lymphangiography (DCMRL) evidence of primary, central lymphatic dysplasia that manifested in lymphatic accumulation affecting cardiorespiratory function, nutrition, and the immune system. DCMRL imaging for patient 2 are highlighted in Figure 1 A and B. Within one month of initiating trametinib oral therapy, all three patients demonstrated response adequate to wean from mechanical ventilation and other supportive care modalities. Serum albumin levels improved as lymphatic leak resolved (Figure 1C). Patient 3 showed improvement in hypertrophic cardiomyopathy as evidenced by a decrease in both NT-proBNP and left ventricular mass by echocardiogram. Patients 1 and 2 demonstrated notable improvements in growth after one year of therapy, with increase in both weight and height percentiles. Patient 3 also presented with NS-MPD that responded with marked improvements in total WBC count as well as absolute monocyte count (Figure 1D). DISCUSSION Our experience adds to the growing body of evidence demonstrating the effectiveness of MEK inhibition on disease processes that are common in patients with NS and other RASopathies. None of the patients in our series experienced significant adverse effects from the medication aside from patient 2 who developed mild dermatitis. The efficacy of this therapy does not appear to be based on the underlying genotype, as each of the three patients we describe had different underlying molecular alterations (SOS1, RIT1, PTPN11). Substantial improvements in a variety of parameters including lymphatic malformations, cardiomyopathy, pulmonary valve stenosis, growth, and NS-MPD highlight the potential utility of trametinib in this patient population. Larger, prospective studies are necessary to confirm the efficacy of MEK inhibition and to assess the long-term safety of its use in this population. Figure 1 Figure 1. Disclosures Nakano: Novartis: Consultancy. OffLabel Disclosure: Trametinib is a MEK1/2 inhibitor that has been approved for the use in certain malignancies. Its off label use in children with Noonan Syndrome with significant lymphatic anomalies is based on the up regulation of the MAPK pathway in these patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.