Targeted Therapy for Complex Lymphatic Anomalies in Patients with Noonan Syndrome and Related Disorders

Area of Science:

• Genetics and Molecular Biology
• Pediatric Cardiology
• Vascular Biology

Background:

• Lymphatic disease in Noonan syndrome (NS) and related RASopathies often results from central conducting lymphatic anomalies (CCLAs).
• The RAS/MAPK-ERK pathway is crucial for lymphangiogenesis, making it a therapeutic target.

Purpose of the Study:

• To assess the clinical outcomes of MEK-inhibitor trametinib therapy in patients with NS-like RASopathies and CCLA.
• To evaluate the efficacy of trametinib based on patient age and disease severity.

Main Methods:

• A case series of eight patients with NS-like RASopathies and CCLA treated with trametinib.
• Analysis of clinical outcomes, including symptom alleviation and lymphatic phenotype rescue.
• Comparison of outcomes between infants and older children/adolescents.

Main Results:

• Trametinib therapy, particularly at a lower dose (0.01 mg/kg/day) and with earlier discontinuation in infants, effectively alleviated congenital chylothorax and improved the lymphatic phenotype.
• Older patients (>11 years) exhibited slower responses and incomplete symptomatic recovery.
• Individual patient responses to trametinib varied, suggesting the need for personalized treatment approaches.

Conclusions:

• Trametinib is a potential therapy for severe, refractory CCLA in NS-like RASopathies.
• Age and potentially other genetic or physiological factors influence treatment response.
• Further research is needed to identify factors predicting treatment efficacy for optimizing CCLA management.