PO88
Mavacamten in Noonan syndrome: clinical benefits mediated by an off-target mechanism

In November 2023, a 38-year-old woman was referred to our outpatient clinic with a new diagnosis of non-obstructive hypertrophic cardiomyopathy. Her medical history included systemic lupus erythematosus complicated by lupus nephritis requiring dialysis (2014–2017) followed by renal transplantation (2017), retinal vein thrombosis (2008), corticosteroid-induced osteoporosis, and hemorrhoidal prolapse (since 2023). She reported marked exercise intolerance, consistent with NYHA class III symptoms. Electrocardiography showed sinus rhythm at 70 bpm with normal atrioventricular and intraventricular conduction, high voltages, and repolarization abnormalities consistent with left ventricular hypertrophy. Transthoracic echocardiography demonstrated left ventricular outflow tract (LVOT) obstruction with a resting gradient of 68 mmHg, increasing to 95 mmHg with Valsalva manoeuvre, left ventricular ejection fraction (LVEF) of 60%, moderate mitral and aortic regurgitation, and preserved right ventricular systolic function. Cardiac magnetic resonance (CMR) confirmed asymmetric septal hypertrophy (maximal wall thickness 18 mm), LVOT obstruction, diffuse interstitial fibrosis, and patchy late gadolinium enhancement in mid inferolateral, inferior, anterolateral, and apical inferior segments. The HCM risk score was 4.18%. Metoprolol was initiated and later combined with disopyramide, which was discontinued due to gastrointestinal intolerance. Owing to persistent LVOT obstruction despite maximally tolerated metoprolol, a compassionate-use request for mavacamten was approved, and therapy was initiated at 5 mg daily. After four weeks, the patient reported symptomatic improvement, although LVOT gradients remained elevated (60–75 mmHg). At week 12, the dose was increased to 10 mg daily. Four weeks later, the patient improved to NYHA class II, with complete resolution of LVOT obstruction, LVEF decline to 53%, and relative apical hypokinesia. At week 20, non-contrast CMR revealed a reduction in maximal septal thickness from 18 to 16 mm, complete resolution of LVOT obstruction, and stable diffuse fibrosis. By week 24, the patient remained clinically stable (LVEF 53%), with no LVOT obstruction. From baseline, a reduction in ECG voltages was observed, with a 13 mm decrease in the Sokolow-Lyon index, alongside a marked reduction in NT-proBNP (973 pg/ml vs. 5000 pg/ml at initiation). Genetic testing revealed a heterozygous PTPN11 mutation (c.184T>A, p.Tyr62Asn, Class 4), consistent with Noonan syndrome. At 60 weeks, the patient remained stable in NYHA class II with preserved systolic function (LVEF 52%), absence of significant LVOT obstruction, and sustained symptomatic improvement.

Conclusion: This case illustrates the clinical and structural effects of mavacamten in obstructive hypertrophic cardiomyopathy ultimately linked to Noonan syndrome. In this patient, mavacamten provided symptomatic relief, resolution of LVOT obstruction, modest regression of left ventricular hypertrophy, and a substantial reduction in NT-proBNP, suggesting - despite its unselective mechanism of action – meaningful benefit in this complex setting.