**Background:** Noonan syndrome is an autosomal dominant multisystem disorder with an estimated prevalence of 1 in 1000–2500, often accompanied by congenital heart disease, hypertrophic cardiomyopathy (HCM), and lymphatic malformations. Pathogenic mutations result in activation of the RAS-MAPK pathway. Trametinib is a reversible, highly selective allosteric inhibitor of MEK1 and MEK2, which are critical components of the ERK pathway hyperactivated in Noonan syndrome. Refractory chylous effusions due to lymphatic dysplasia cause significant morbidity and mortality from protein and immunoglobulin losses, and very few cases of successful trametinib treatment after failed conventional therapy have been published.
**Methods:** This is a single case report of a 3-year-old Caucasian girl with Noonan syndrome (heterozygous RIT1 mutation) who initially presented at 18 months with a heart murmur and was diagnosed with HCM causing mid-cavity LVOT obstruction, severe RVOT obstruction, and a dysplastic stenotic pulmonary valve. She underwent surgical relief at 22 months and required an epicardial pacemaker for post-operative complete heart block. At 2 years and 8 months (10 months post-surgery), she was admitted to intensive care for respiratory failure due to parainfluenza 3 infection and developed significant bilateral pleural effusions. Fluid analysis confirmed chylothorax (fluid triglycerides 1.9 mmol/L, reference >1.24 mmol/L; fluid protein 30 g/L). She was treated with a low-fat, high-MCT diet and octreotide infusion but continued losing significant chyle, resulting in low immunoglobulin levels. She acutely deteriorated with spontaneous bowel perforation requiring 10 cm of terminal ileum resection and stoma formation. Acquired immunodeficiency led to bacterial and candida sepsis, treated with multiple antibiotics, antifungals, and immunoglobulin replacements. Parenteral nutrition was started due to ongoing refractory pleural effusions and high stoma losses. After 3 months of hospital stay, she was discharged but repeatedly represented with reaccumulation of pleural effusions despite MCT diet, requiring multiple chest drains. Pulmonary lymphangiectasia secondary to the underlying syndrome or residual cardiac anomalies was considered. Surgical damage to the thoracic duct was deemed unlikely given the 10-month interval between surgery and first chylothorax presentation. Invasive haemodynamics showed elevated bi-atrial pressures at 14 mmHg (reference 3–6 for right atrium, 6–9 for left atrium in children), mean pulmonary artery pressure of 20 mmHg (reference 15 mmHg), mildly increased pulmonary vascular resistance at 2.1 indexed Wood units (reference <2), and cardiac index of 3.8 L/min/m². Innominate vein wedge angiogram did not demonstrate the thoracic duct entry point. After exhausting all conventional options, the family was offered a trial of trametinib as last resort. She received trametinib 0.032 mg/kg/dose once daily following paediatric oncology dosing guidelines (0.032 mg/kg/day for patients <6 years). Monitoring included weekly blood tests (full blood count, urea and electrolytes, creatine kinase, liver function tests, HbA1c), monthly ophthalmology review, and weekly echocardiograms. Both pleural spaces were drained before commencing treatment.
**Key Results:** The patient developed severe eczema affecting arms, legs, and trunk, which responded to emollients and topical steroids. Stoma output increased but remained manageable with parenteral nutrition and stayed below the discontinuation cut-off of 30 mL/kg/day. No other significant side effects were observed. Reduction in left ventricular mass was noted on serial echocardiograms. After completing the planned 3-month course of trametinib, she was gradually transitioned to enteral feeds (initially MCT diet, then normal fat content) and discharged home. She has remained free of chylothorax recurrence for 8 months since completing treatment and 11 months since commencing treatment and last pleural drainage, as monitored by chest X-ray and ultrasound. Her stoma has subsequently been reversed.
**Clinical Implications:** This case demonstrates that MEK inhibition with trametinib can achieve complete lymphatic remodelling and resolution of refractory chylothorax in Noonan syndrome even after life-threatening complications. The 3-month treatment duration used here is the shortest reported so far, compared to 12–24 months in other cases, suggesting that a defined shorter course may be sufficient. The higher dose (0.032 mg/kg/day) used for this child under 6 years has not been previously reported in Noonan syndrome cases. However, the literature remains sparse with no established guidelines for optimal dosing, duration, or long-term outcomes. More centres are encouraged to report their experience to establish best treatment approaches and patient safety.