Update on the Clinical and Molecular Characterization of Noonan Syndrome and Other RASopathies: A Retrospective Study and Systematic Review

Abstract

RASopathies are a diverse group of genetic conditions caused by hyperactivation of the RAS-MAPK signaling pathway, mainly inherited in an autosomal dominant manner. They present with variable features such as short stature, congenital heart defects, facial dysmorphisms, and neurodevelopmental delays. This study retrospectively analyzed 143 cases from 2003 to 2022, aiming to improve genotype-phenotype correlation knowledge for personalized care. Patients with genetically confirmed Noonan syndrome (NS) and related disorders were included, with molecular analysis performed via Sanger or parallel sequencing. Data from 906 previously reported cases were also reviewed. Among the 143 patients, most had NS (n = 116). PTPN11 mutations were most frequent (61%), followed by SOS1 (10.3%) and RAF1 (8.6%). Cardiac anomalies were observed in 71%, with pulmonary stenosis (PS) prevalent in NS (48.3%) and hypertrophic cardiomyopathy (HCM) in NSML (40%). PTPN11 variants were linked to PS and atrial septal defects, SOS1 to multiple cardiopathies, and RAF1 to HCM. Additional features included facial dysmorphisms (74.1%), short stature (62.0%), skeletal anomalies (43.1%), cryptorchidism (59.7%), and brain abnormalities (17.2%). JMML and other malignancies were seen in eight patients. This study emphasizes the importance of genotype-guided care, improved diagnosis of mild cases, and the underrecognized prevalence of neurological anomalies.

Keywords: PTPN11; RAF1; RAS/MAPK pathway; SOS1; congenital disorders.

Figure 1

RAS-MAPK pathway and key proteins involved in its regulation. Positive modulators of signaling are divided into 3 groups according to the position in the cascade, appearing in blue, purple, and green, while negative regulators appear in orange. In RASopathies, pathway hyperactivation results from increased activity of RAS proteins, upstream regulators, and MAPK cascade components. Impaired feedback mechanisms, due to alterations in genes such as CBL, NF1, LZTR1, and SPRED, further contribute to prolonged signaling activation. “P” indicates phosphorylation.

Figure 2

PRISMA flowchart of the study selection process: the results of the PRISM-based process for literature selection illustrate the screening process and article counts resulting from our search. Selection and exclusion criteria are more widely reported in the text of the article.

Figure 3

Clinical findings in our population and in the expanded population, expressed as percentages.