Defining the variant-phenotype correlation in patients affected by Noonan syndrome with the RAF1:c.770C>T p.(Ser257Leu) variant.

Hypertrophic cardiomyopathy (HCM) is the major contributor to morbidity and mortality in Noonan syndrome (NS). Gain-of-function variants in RAF1 are associated with high prevalence of HCM. Among these, NM_002880.4:c.770C > T, NP_002871.1:p.(Ser257Leu) accounts for approximately half of cases and has been reported as associated with a particularly severe outcome. Nevertheless, comprehensive studies on cases harboring this variant are missing. To precisely define the phenotype associated to the RAF1:c.770C > T, variant, an observational retrospective analysis on patients carrying the c.770C > T variant was conducted merging 17 unpublished patients and literature-derived ones. Data regarding prenatal findings, clinical features and cardiac phenotypes were collected to provide an exhaustive description of the associated phenotype. Clinical information was collected in 107 patients. Among them, 92% had HCM, mostly diagnosed within the first year of life. Thirty percent of patients were preterm and 47% of the newborns was admitted in a neonatal intensive care unit, mainly due to respiratory complications of HCM and/or pulmonary arterial hypertension. Mortality rate was 13%, mainly secondary to HCM-related complications (62%) at the average age of 7.5 months. Short stature had a prevalence of 91%, while seizures and ID of 6% and 12%, respectively. Two cases out of 75 (3%) developed neoplasms. In conclusion, patients with the RAF1:c.770C > T pathogenic variant show a particularly severe phenotype characterized by rapidly progressive neonatal HCM and high mortality rate suggesting the necessity of careful monitoring and early intervention to prevent or slow down the progression of HCM.

MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease.

The RAF1:p.Ser257Leu variant is associated with severe Noonan syndrome (NS), progressive 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 introduced (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 contributed 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.

Interventional catheterisation of stenotic or occluded systemic veins in children with or without congenital heart diseases: early results and intermediate follow-up.

AIMS: Limited data exists on midterm results concerning paediatric interventions on stenotic or occluded systemic veins following indwelling lines, cardiac surgery, or catheterisations. The purpose of this study was to report our acute and intermediate results concerning patients with (Group A) and without (Group B) congenital heart diseases (CHD) over a 10-year period. METHODS AND RESULTS: From January 2000 to December 2010, 32 patients (23 in Group A and nine in Group B, respectively) underwent 39 interventional catheterisations aimed to dilate or recanalise occluded iliofemoral veins, inferior or superior venae cavae. Initial and follow-up catheterisation data were reviewed retrospectively. Midterm results were evaluated by means of echography, angiography, and CT scan in all 15 and 17 patients, respectively. Median age and weight of all patients at catheterisation were five years (range 0.1-18) and 15 kg (range 2-60), respectively. Fifty-two stents were implanted in 29 patients (32 vessels). In 25 patients 28 vessels were occluded and required recanalisation. There were no major complications. In all but three patients it was possible to treat the lesion. There were two procedural complications (5.1%): one acute stent occlusion and one local dissection. At a median follow-up of 2.5 years (range 1-10) we observed six complications of stenting (11.5%): two fractures, two occlusions and two restenoses. CONCLUSIONS: Interventional catheterisation of stenotic or occluded systemic veins grants good immediate results at a low rate of complication. Stent dilatation or recanalisation may open the vessel for use during future procedures. However, long-term results are yet to be established.