The RAF1:p.Ser257Leu variant is associated with severe Noonan syndrome (NS), pro-gressive hypertrophic cardiomyopathy (HCM), and pulmonary hypertension. Trametinib, a MEK-inhibitor approved for treatment of RAS/MAPK-mutated cancers, is an emerging treatment option for HCM in NS. We report a patient with NS and HCM, treated with Trametinib and documented by global RNA sequencing before and during treatment to define transcriptional effects of MEK-inhibition. A preterm infant with HCM carrying the RAF1:p.Ser257Leu variant, rapidly developed severe congestive heart failure (CHF) unresponsive to standard treatments. Trametinib was intro-duced (0.022 mg/kg/day) with prompt clinical improvement and subsequent amelioration of HCM at ultrasound. The appearance of pulmonary artery aneurysm and pulmonary hypertension con-tributed to a rapid worsening after ventriculoperitoneal shunt device placement for posthemorrhagic hydrocephalus: she deceased for untreatable CHF at 3 months of age. Autopsy showed severe obstructive HCM, pulmonary artery dilation, disarrayed pulmonary vascular anatomy consistent with pulmonary capillary hemangiomatosis. Transcriptome across treatment, highlighted robust transcriptional changes induced by MEK-inhibition. Our findings highlight a previously unappreciated connection between pulmonary vascular disease and the severe outcome already reported in patients with RAF1-associated NS. While MEK-inhibition appears a promising therapeutic option for HCM in RASopathies, it appears insufficient to revert pulmonary hypertension.

Mek inhibition in a newborn with raf1-associated noonan syndrome ameliorates hypertrophic cardiomyopathy but is insufficient to revert pulmonary vascular disease

Mussa A.;Carli D.;Giorgio E.;Villar A. M.;Cardaropoli S.;Carbonara C.;Campagnoli M. F.;Galletto P.;Olivieri S.;Isella C.;Botta G.;Brusco A.;Medico E.;Ferrero G. B.
2021

Abstract

The RAF1:p.Ser257Leu variant is associated with severe Noonan syndrome (NS), pro-gressive hypertrophic cardiomyopathy (HCM), and pulmonary hypertension. Trametinib, a MEK-inhibitor approved for treatment of RAS/MAPK-mutated cancers, is an emerging treatment option for HCM in NS. We report a patient with NS and HCM, treated with Trametinib and documented by global RNA sequencing before and during treatment to define transcriptional effects of MEK-inhibition. A preterm infant with HCM carrying the RAF1:p.Ser257Leu variant, rapidly developed severe congestive heart failure (CHF) unresponsive to standard treatments. Trametinib was intro-duced (0.022 mg/kg/day) with prompt clinical improvement and subsequent amelioration of HCM at ultrasound. The appearance of pulmonary artery aneurysm and pulmonary hypertension con-tributed to a rapid worsening after ventriculoperitoneal shunt device placement for posthemorrhagic hydrocephalus: she deceased for untreatable CHF at 3 months of age. Autopsy showed severe obstructive HCM, pulmonary artery dilation, disarrayed pulmonary vascular anatomy consistent with pulmonary capillary hemangiomatosis. Transcriptome across treatment, highlighted robust transcriptional changes induced by MEK-inhibition. Our findings highlight a previously unappreciated connection between pulmonary vascular disease and the severe outcome already reported in patients with RAF1-associated NS. While MEK-inhibition appears a promising therapeutic option for HCM in RASopathies, it appears insufficient to revert pulmonary hypertension.
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https://www.mdpi.com/2073-4425/13/1/6
Hypertrophic cardiomyopathy; MEK-inhibitor; Noonan syndrome; RASopathies; Therapeutics; Transcriptomics
Mussa A.; Carli D.; Giorgio E.; Villar A.M.; Cardaropoli S.; Carbonara C.; Campagnoli M.F.; Galletto P.; Palumbo M.; Olivieri S.; Isella C.; Andelfinger G.; Tartaglia M.; Botta G.; Brusco A.; Medico E.; Ferrero G.B.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1840030
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