Abstract 13869: The Impact of Genotype on Aortic Dilation in Pediatric Patients With RASopathy

Abstract

Introduction: Proximal aortic dilation is an important cause of morbidity and mortality secondary to rupture, dissection, and complications of repair. It has been described as a rare finding in RASopathy, but data is limited regarding prevalence, severity, and genetic factors. This study aims to examine outcomes and genotype associations in pediatric patients with aortic dilation and RASopathy. Methods: A retrospective review performed at a single pediatric referral center. Study population included children with a molecularly confirmed RASopathy diagnosis evaluated between January 2000 and August 2019. Baseline data included demographics, genetic data, cardiac diagnostic data, clinical course, and mortality outcome. Results: Ninety patients were identified (mean age 10.4, female 48%). Aortic dilation was found in 28%. Of these, 68% had mild dilation, while moderate and severe dilation were each seen in 16%. Aortic dilation occurred in all major RASopathy types (Noonan, Noonan with Multiple Lentigenes, Costello, and Cardiofaciocutaneous). Hypertrophic cardiomyopathy was seen in 30% and pulmonary stenosis in 53% of RASopathy patients, with similar prevalence among those with aortic dilation (p=1 and 0.45, respectively). Aortic dilation was more prevalent in RAS ( KRAS , HRAS , NRAS ) variants (4/9 versus 12/81, p=0.0494). It was also seen in 16 of 60 patients with PTPN11 variants in association with all three commonly involved regions (exon 3 of N-SH2 region and exons 8 and 13 of PTP domain). The two patients with extreme dilation (z-score > 6) had variants of amino acids 61 and 63 in exon 3 of PTPN11 . No surgical interventions targeting aortic dilation were performed in any patient, and there were no reports of dissection or rupture. There was no clear progression of dilation, and two patients had complete resolution with time. Discussion: Aortic dilation occurred in all four major types of RASopathy and was associated with most of the affected genes, with distribution along the PTPN11 gene being similar to the distribution of RASopathy. The dilation was not progressive and there were no complications or interventions. RAS genes and exon 3 of the PTPN11 gene demonstrated a possible higher association with aortic dilation and warrant further investigation.