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.

Keywords: Noonan syndrome; RASopathy; congenital heart disease.

FIGURE 1

Spectrum of RAS-MAPK pathway disease genes and associated RASopathies. Proteins having roles in the RAS-MAPK are shown, and the ones for which pathogenic variation in the encoding genes results in one or more RASopathies are indicated. The proteins depicted within the boxes largely reside at the cell membrane (indicated with the schematic of lipid bilayers, except LZTR1, which is associated with the Golgi apparatus). The proteins shown outside of the boxes principally reside in the cytosol. Abbreviations: CFCS, cardiofaciocutaneous syndrome; CS, Costello syndrome; NF1, neurofibromatosis type 1; NFNS, neurofibromatosis-Noonan syndrome; NS, Noonan syndrome; NSLAH, Noonan syndrome with loose anlagen hair; NSML, Noonan syndrome with multiple lentigines; NS-like JMML, Noonan syndrome-like disorder with juvenile myelomonocytic leukemia; RTK, Receptor tyrosine kinases. Copyright, Ni-ka Ford, Icahn School of Medicine at Mount Sinai

FIGURE 2

Effect of MEK inhibitor treatment on lymphatic abnormalities in a patient with a gain-of-function pathogenic ARAF variant. Coronal maximal intensity projections of contrast lymphangiograms of the pelvis and thighs before (left) and after (right) MEK-inhibitor treatment of proband. Pretreatment, the patient presents distinct dilation and beading of the lymphatic system; after a 12-month treatment, the patient displays resorption of the dilated ducts and formation of new and symmetrical lymphatic networks. Figure reprinted with permission from Springer Nature (Li, D et al., 2019)