{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:16:52Z","timestamp":1792023412756,"version":"4.4.0"},"reference-count":109,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian National Association of Noonan Syndrome and RASopathies"},{"name":"Italian Ministry of Health (Current Research Funds)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2013phenotype 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.<\/jats:p>","DOI":"10.3390\/ijms26083515","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T07:49:02Z","timestamp":1744184942000},"page":"3515","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Update on the Clinical and Molecular Characterization of Noonan Syndrome and Other RASopathies: A Retrospective Study and Systematic Review"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0447-2112","authenticated-orcid":false,"given":"Giuseppe","family":"Reynolds","sequence":"first","affiliation":[{"name":"Department of Public Health and Pediatrics, Postgraduate School of Pediatrics, University of Torino, 10126 Turin, Italy"},{"name":"Department of Public Health and Pediatric Sciences, University of Torino, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5230-2831","authenticated-orcid":false,"given":"Andrea","family":"Gazzin","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Torino, 10126 Turin, Italy"},{"name":"Clinical Pediatrics Genetics Unit, Regina Margherita Children\u2019s Hospital, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5690-6504","authenticated-orcid":false,"given":"Diana","family":"Carli","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Massuras","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Torino, 10126 Turin, Italy"},{"name":"Clinical Pediatrics Genetics Unit, Regina Margherita Children\u2019s Hospital, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8927-8900","authenticated-orcid":false,"given":"Simona","family":"Cardaropoli","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Torino, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1239-0829","authenticated-orcid":false,"given":"Maria","family":"Luca","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Defilippi","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Torino, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-9672","authenticated-orcid":false,"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni Battista","family":"Ferrero","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Mussa","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Torino, 10126 Turin, Italy"},{"name":"Clinical Pediatrics Genetics Unit, Regina Margherita Children\u2019s Hospital, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1001\/archpedi.1968.02100020377005","article-title":"Hypertelorism with Turner Phenotype: A New Syndrome with Associated Congenital Heart Disease","volume":"116","author":"Noonan","year":"1968","journal-title":"Am. 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