Noonan Syndrome and Pulmonary Valve Stenosis

Abstract

Source: Bell JM, Considine EM, McCallen LM, et al. The prevalence of Noonan spectrum disorders in pediatric patients with pulmonary valve stenosis. J Pediatr. 2021;234:134–141.e5; doi:10.1016/j.jpeds.2021.03.050Investigators from the University of Colorado School of Medicine, Denver, CO, and University of Colorado College of Engineering and Applied Science, Boulder, CO, conducted a retrospective study to estimate the prevalence of Noonan spectrum disorders (NSD) in children with pulmonary valve stenosis (PVS), and to identify characteristics that predicted NSD in PVS patients. Study participants were identified using the “Slicer/Dicer” function of the EPIC electronic medical system and included children seen in the Children’s Hospital Colorado Cardiology clinic between 2009 and 2018. The medical records of the identified patients were reviewed, and data on clinical characteristics abstracted. The presence of PVS was confirmed by reviewing echocardiogram reports.Study patients were classified as having NSD based on clinical diagnosis made by a medical geneticist and/or genetic test results. Data on other syndromic conditions present in participants also were recorded. The association of specific other cardiac conditions, including atrial septal defect (ASD), supravalvar pulmonary stenosis (SVPS), ventricular septal defect, hypertrophic cardiomyopathy, and patent ductus arteriosus, with NSD in patients with PVS was assessed by chi square tests. A similar process was used for extracardiac characteristic statistically associated with NSD in children with PVS, including cryptorchidism, lymphedema, hearing loss, pectus deformity, feeding issues, failure to thrive (FTT), developmental delay, short stature, and ocular findings. Bayes rule was used to determine the conditional probability of NSD in patients with one or more of these findings.Data were analyzed on 686 patients with PVS. Of these, a diagnosis of NSD was made in 59 (8.6%), with the diagnosis confirmed by genetic testing in 52 children. Other syndromic conditions were identified in 50 study participants (7.3%); Williams syndrome (N = 8) and trisomy 21 (N = 7) were the most common non-NSD syndromic conditions found. Clinical characteristics statistically significantly associated with a diagnosis of NSD in patients with PVS included lymphedema, cryptorchidism, hearing loss, pectus deformity, feeding issues, FTT, developmental delay, short stature, ocular findings, SVPS, hypertrophic cardiomyopathy, and ASD. Among these characteristics, the strongest predictors of NDS were cryptorchidism (conditional probability, 0.70), pectus deformity (conditional probability, 0.66), and ocular findings (conditional probability, 0.48). For children with PVS, pectus deformity, and developmental delay, the conditional probability of NDS was 0.82.The authors conclude that the prevalence of NSD is high in children with PVS, and that a diagnosis of NSD should be considered in PVS patients with other, specific, clinical characteristics.Dr Spar has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.PVS is the most common type of pulmonary stenosis (characterized by fused commissures with thickened leaflets of the pulmonary valve) and accounts for 8–12% of all CHD.1 PVS can range from mild to critical, with critical being the most severe form of pulmonary stenosis (PS) with inadequate pulmonary blood flow. In NSD the pulmonary valve is dysplastic with prominent leaflet thickening, with a small valve annulus and reduced mobility.2 Typical physical examination findings include an audible click, splitting of S2 and a systolic ejection murmur heard at the second left intercostal space. Echocardiogram confirms diagnosis with visualization of the pulmonary valve anatomy and provides determination of severity of stenosis by measuring the pressure gradient over the pulmonary valve.NSD has autosomal dominant inheritance with significant genetic heterogeneity. The most common pathogenic variants include PTPN11 gene (50% of patients with NSD). There are also at least 17 genes related to encoding of protein of the Ras-MAPK signaling pathway associated with NSD.1,3 Typical clinical manifestations are heterogeneous, with common features including widely spaced eyes, low-set ears, short stature, and PVS.4 Greater than 80% of patients with NSD have cardiac involvement, with the majority having PS and hypertrophic cardiomyopathy.5 Other cardiac lesions seen include ASD, ventricular septal defect, tetralogy of Fallot, pulmonary artery stenosis, coarctation of aorta, and primum type atrial septal defect.3The investigators of the current study reviewed all patients with a diagnosis of PVS without other cardiac lesions over a 10-year period. Patients with a clinical diagnosis after evaluation by a geneticist or confirmed by molecular testing were identified as having NSD. The investigators found that 59 of 686 (8.6%) patients with PVS had NSD. Of the 59, there were 52 children who had a molecular diagnosis, and 6 had a clinical diagnosis. Of patients with PVS, those with NSD were commonly had ASD, hypertrophic cardiomyopathy, and SVPS.PVS is commonly seen in patients with NSD. Genetic evaluation is a consideration in patients with PVS and other features known to be associated with NSD.