Abstract
Abstract
Background:
Noonan syndrome is an autosomal dominant RASopathy caused by germline gain-of-function variants in the renin-angiotensin system/mitogen-activated protein kinase signalling pathway. Hypertrophic obstructive cardiomyopathy is a serious and potentially fatal manifestation of Noonan syndrome, most characteristically associated with RAF1 and RIT1 variants. Trametinib, a selective MEK1/2 inhibitor, has demonstrated efficacy in Noonan syndrome-associated hypertrophic obstructive cardiomyopathy across several genotypes; however, real-world data pairing distinct genotypes with clinical response—particularly for PTPN11- and RAF1-related disease in older children with prior surgical intervention—remain limited.
Cases:
We report two 10-year-old males with genetically confirmed Noonan syndrome and severe hypertrophic obstructive cardiomyopathy refractory to conventional pharmacological management, both with prior surgical right ventricular outflow tract intervention. Case 1 carries a PTPN11 c.1528C>G; p. Gln510Glu variant; Case 2 carries a RAF1 c.770C>T; p. Ser257Leu variant, a well-characterised pathogenic variant strongly associated with Noonan syndrome-related hypertrophic obstructive cardiomyopathy. Trametinib was initiated as off-label therapy in both cases, producing rapid, significant reduction of left ventricular outflow tract gradients. Trametinib was well tolerated in Case 1, while Case 2 experienced mild cutaneous pruritus that resolved with antihistamine therapy without requiring dose modification. With continued therapy over subsequent months, both patients demonstrated further incremental haemodynamic improvement together with structural regression of ventricular wall thickness.
Conclusion:
These cases provide complementary evidence supporting the efficacy and tolerability of trametinib, including its rapid response time, across two distinct Noonan syndrome genotypes in older paediatric patients with established, surgically treated hypertrophic obstructive cardiomyopathy. Our findings support mitogen-activated protein kinase kinase inhibition as a genotype-agnostic targeted therapeutic strategy in Noonan syndrome-associated hypertrophic obstructive cardiomyopathy and reinforce the need for prospective trials to standardise protocols and define long-term outcomes.