Aslı GENÇ, Esra KILIÇ
Türkiye Çocuk Hastalıkları Dergisi - 2026;20(3):211-218
The RAS/Mitogen-Activated Protein Kinase (MAPK) pathway is a core developmental signaling cascade that regulates proliferation, differentiation, survival, and tissue growth across multiple organ systems. Germline dysregulation of this pathway results in RASopathies. Although the causal variants affect different components of the pathway, they converge on abnormal downstream signaling. This explains why these disorders share a recognizable clinical core despite clear syndrome-specific differences. The most prevalent and well-known entity is Noonan syndrome, while other major subtypes include cardiofaciocutaneous syndrome, Costello syndrome, and Noonan syndrome with multiple lentigines. RASopathies are characterized by distinctive craniofacial features and multisystem involvement. Congenital heart disease is a significant cause of morbidity. Neurodevelopmental difficulties are common across the spectrum and may be particularly pronounced in Cardiofaciocutaneous and Costello syndromes. Short stature, pectus anomalies, scoliosis, and other musculoskeletal findings are also recurrent features. Another important concern is the malignancy risk, which varies significantly by genotype. Although these disorders share a common pathway, genotype-phenotype correlations are increasingly relevant in daily practice. Molecular findings now directly inform risk assessment and long-term follow-up. In parallel, early experience with pathway-directed therapies is beginning to influence the management of selected complications. MEK inhibitors have shown promising results in selected manifestations, particularly hypertrophic cardiomyopathy and refractory lymphatic complications. In this review, we discuss the biological organization of the RAS/MAPK pathway and relate it to the clinical spectrum of RASopathies. We focus on shared and distinguishing phenotypic features, clinically relevant genotype-phenotype correlations, and the emerging role of targeted therapies.
