Clinical and Molecular Portraits of Pediatric RASopathies: A Study of 118 Genotype-Confirmed Cases

RASopathies are clinically and genetically heterogeneous disorders resulting from dysregulation of the RAS/MAPK pathway. We present a single-center retrospective cohort of 118 genotype-confirmed pediatric patients diagnosed with RASopathy. Noonan syndrome was the most common clinical diagnosis, followed by NF-Noonan syndrome, Legius syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome. The most frequent clinical features included short stature, pulmonary stenosis, pectus deformities, and neurocognitive delay. Through molecular analysis, we identified distinct variants across major RAS/MAPK pathway genes, with a considerable proportion of patients carrying rare or less frequently reported variants, including those in LZTR1, RIT1, RAF1, HRAS, BRAF, RASA2, KRAS, CBL, SHOC2, and MAP2K2. In addition to well-established genotype-phenotype correlations, we report several uncommon or previously unrecognized features: microcephaly in multiple PTPN11-positive patients and renal agenesis in a child with a novel HRAS variant diagnosed with Costello syndrome. Furthermore, we identified three patients harboring RASA2 variants, providing additional support for its emerging role in Noonan syndrome. This study expands the clinical and molecular spectrum of pediatric RASopathies. It emphasizes the need for comprehensive genetic evaluation and regular follow-up in the context of overlapping clinical features, supporting accurate diagnosis and identifying candidates for emerging targeted therapies.