ESPE Yearbook of Paediatric Endocrinology

Front. Pediatr. 2025 Feb;13:1475143.doi: 10.3389/fped.2025.1475143

Brief Summary: This case report describes acritically ill neonatal patient withNoonan Syndrome (NS)¹,who successfully received a course of the monoclonal selective allosteric MEK inhibitor, trametinib. This drug targets the final steps of the gain-of-function activation of the RAS/MAPK pathway common to the causative NS genes. Mouse models of this drug to rescue mutant animals have led to its compassionate use in humans, although it is better known as a cancer therapy. In addition to the authors’ detailed and successful use of trametinib (0.25mg/kg/d for 5 w) in their patient with a PTPN11 class 5 variant, the paper’s strength lies in its review of the 16 other cases given this drug since 2019. The findings reinforce the potential use of trametinib as a rescue therapy for critically ill patients with NS.

As found for the patient reported here (who had severe congenital pulmonary lymphangiectasia, chylothorax and hypoxia refractory to conventional management), in all 17 reported cases trametinib ameliorated the complications of lymphatic and/or cardiac disease. The case series includes patients with diverse genetic causes of NS. The majority were treated in the neonatal period or in early infancy (13/17), with differing exposure times to drug (5 w – 2 y) and differing periods of follow-up, off or on therapy (maximum 2 y). Of the series, 13/17 were noted to be stable and now at home. No universal efficacy criteria were defined, and 3 of 17 patients died– one who was withdrawn from therapy because of treatment failure, one because of a probable hypertrophic cardiomyopathic arrythmia following treatment with resolution of the congenital lymphangiectasia, and one with a non-NS related condition (pulmonary capillary hemangiomatosis), possibly related to the treatment. Long term outcome studies are lacking, and it will be important to build an international collaboration in order to pool clinical experience, define protocols and monitor safety.

Reference: 1. Romano AA et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 2010;126(4):746–59. doi: 10.1542/peds.2009-3207.