Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment

Abstract

Noonan syndrome is a pleomorphic genetic disorder, in which a high percentage of affected individuals have cardiovascular involvement, most prevalently various forms of congenital heart disease (i.e., pulmonary valve stenosis, septal defects, left‐sided lesions, and complex forms with multiple anomalies). Care includes attentiveness to several comorbidities, some directly impacting cardiac management (bleeding diatheses and lymphatic anomalies). More than 50% of patients with Noonan syndrome harbor PTPN11 pathogenic variation, which results in hyperactivation of RAS/mitogen‐activated protein kinase signaling. Several other disease genes with similar biological effects have been uncovered for NS and phenotypically related disorders, collectively called the RASopathies. Molecular diagnosis with gene resequencing panels is now widely available, but phenotype variability and in some cases, subtlety, continues to make identification of Noonan syndrome difficult. Until genetic testing becomes universal for patients with congenital heart disease, alertness to Noonan syndrome's broad clinical presentations remains crucial. Genotype–phenotype associations for Noonan syndrome enable better prognostication for affected patients when a molecular diagnosis is established. We still lack Noonan syndrome‐specific treatment; however, newly developed anticancer RAS pathway inhibitors could fill that gap if safety and efficacy can be established for indications such as pulmonary valve stenosis.

Phenotype–genotype analysis of 242 individuals with RASopathies: 18‐year experience of a tertiary center in Brazil

“…As some of the variants already reported could be deep intronic (Johnston et al, 2018), there is still a possibility that, in the two individuals, another variant in trans in LZTR1 is present but not detected by the performed NGS. For PVS, this CHD was more prevalent in individuals harboring variants in PTPN11 and SOS1, compared mainly with RAF1, similar to the described in the literature (Linglart & Gelb, 2020) (Table S2).…”

“…Cardiac anomalies are the ones that pose the greatest morbidity and mortality in RASopathies and they could be grouped into two main categories: congenital heart disease (CHD), most frequently pulmonary valve stenosis (PVS), and hypertrophic cardiomyopathy (HCM). Their frequencies differ between the distinct RASopathies, with HCM more frequently seen in CS and NSML and PVS in NS and CFCS (Gelb, Roberts, & Tartaglia, 2015; Linglart & Gelb, 2020). Our data is in accordance to the literature, with NSML and CS presenting the highest prevalence of HCM, a difference statistically significant compared with NS.…”

“…Albeit the increased knowledge in the etiology of NS along the past two decades, the molecular basis remains unknown for approximately 15% of individuals clinically diagnosed as NS (Linglart & Gelb, 2020). It is possible that more complex mechanisms could play a role.…”

The state of congenital heart disease

“…Medical Genetics Part C focusing on CHD, prominent investigators in the field of genetics and CHD review current knowledge on syndromic CHD (Lalani, 2020;Lin, Santoro, High, Goldenberg, & Gutmark-Little, 2019;Meisner & Martin, 2019, Linglart & Gelb, 2020, nonsyndromic CHD (Nees & Chung, 2019), and CHD animal models (Gabriel & Lo, 2020).…”

“…Congenital heart disease (CHD) is the most common birth defect occurring in approximately 1% of all live births and affecting millions of individuals internationally. In this special issue of the American Journal of Medical Genetics Part C focusing on CHD, prominent investigators in the field of genetics and CHD review current knowledge on syndromic CHD (Lalani, ; Lin, Santoro, High, Goldenberg, & Gutmark‐Little, ; Meisner & Martin, , Linglart & Gelb, ), nonsyndromic CHD (Nees & Chung, ), and CHD animal models (Gabriel & Lo, ). Using this knowledge, the editors have provided an updated diagnostic algorithm for CHD (Jerves, Beaton, & Kruszka, ).…”