MEK-Inhibition Treatment with Trametinib in a 7.7-Year-Old Girl with Noonan's Syndrome and Life-Threatening Lymphangiopathy

Objectives: Germline mutations in genes of the RAS/MAPK signaling pathway have been identified as the underlying cause of so-called RASopathies which among others include Noonan's syndrome. Recently successful treatment of hypertrophic cardiomyopathy and lymphangiopathy has been reported with the MEK-inhibitor trametinib in patients with gain of function mutations of genes in this pathway.

Methods: We report a 7.7-year-old girl with Noonan's syndrome and a heterozygous PTPN11 mutation (ENST00000351677:c.854T > C; p.F285S). In the neonatal period, she presented with fetal hydrops and bilateral chylothoraces. Cardiac evaluation revealed dysplastic and stenotic pulmonary and aortic valves. She underwent patch enlargement of the RVOT followed by reconstruction and later replacement of the aortic and pulmonary valve at the age of 5.4 years. Despite of a good hemodynamic result, she developed chronic bilateral chylothoraces refractory to conservative treatment. At the age of 5.8 years, she underwent left pleurodesis. Progressive respiratory deterioration required tracheostomy and home ventilation. At the age of 7 years, she developed increasing dyspnea and edema of the left chest wall necessitating continuous ventilation and oxygen supplementation. She was bedridden, cachectic and required maximum diuretic treatment. Since all therapeutic options had failed, we proposed MEK-inhibition treatment based on the recent publication of Li et al which was approved by the parents and our ethical committee.

Result: Treatment with trametinib was started with 0.25 mg (0.010 mg/kg) every second day and increased after 7 weeks to 0.25 mg/day (0.02 mg/kg). At the beginning of the treatment our patient significantly retained fluid for several days requiring an increase in diuretics. Afterward, trametinib was tolerated well. Overall, 6 weeks of following initiation of trametinib, the patient was readmitted for treatment of sepsis. Since then the girl showed continuous improvement with resolution of the chest wall edema, cessation of oxygen supplementation, mechanical ventilation, and significant reduction of diuretics. She is doing well and without recognizable side effects 6 months after initiation of MEK-inhibition.

Conclusion: MEK inhibition appears to be a possible alternative in the treatment of refractory lymphangiopathies in patients with gain of function mutations in genes of the RAS/MAPK pathway. However this result has to be confirmed by larger numbers of patients.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
21 February 2021