Costello syndrome (CS) is a rare autosomal dominant genetic disorder characterized by cardiac anomalies, distinctive craniofacial features, growth and developmental delays, as well as cutaneous abnormalities. Given the complexity of its clinical presentation and underlying pathogenic mechanisms, advances in genetic and molecular research are essential for deepening our understanding of CS and improving patient outcomes. This review systematically synthesizes recent progress on the genetics of CS from four interconnected perspectives: clinical manifestations, molecular pathogenesis, current diagnostic and therapeutic strategies, and future research directions. By critically integrating existing evidence, we aim to elucidate the core molecular mechanisms driven by dysregulated HRAS signaling and to consolidate both established and emerging genotype-phenotype correlations, which are critical for prognosis and clinical management. The HRAS gene, which encodes a pivotal GTPase in cellular signal transduction, lies at the heart of CS pathogenesis. Through a comprehensive analysis of published HRAS mutation data from CS cases worldwide, this review delineates the mutational spectrum, with emphasis on the predominant p.Gly12Ser variant, its functional consequences, and the associated range of clinical phenotypes. We describe how specific germline missense mutations, predominantly affecting codons 12 or 13, impair GTPase activity or accelerate GDP/GTP exchange, leading to constitutive activation of the HRAS protein. This persistent activation results in hyperactivation of the downstream RAS/MAPK signaling pathway, disrupting fundamental cellular processes such as proliferation, differentiation, and apoptosis, ultimately giving rise to the multisystem features of CS, particularly its hallmark cardiac, neurological, and dermatological manifestations. Beyond cataloging genetic variants, this review critically evaluates the translational implications of these findings for clinical practice. It examines how molecular confirmation through HRAS sequencing has refined diagnostic criteria, underscores the necessity of proactive, multidisciplinary management involving cardiology, neurology, and oncology, and highlights the importance of individualized genetic counseling for affected families. In conclusion, HRAS mutations represent the central molecular drivers of CS, with disease pathogenesis primarily mediated by sustained RAS/MAPK pathway activation. A clear understanding of this genetic basis not only facilitates accurate diagnosis, informed reproductive decision-making, and personalized surveillance but also establishes a robust scientific foundation for advancing prenatal diagnostics and developing targeted therapeutic interventions, including MEK inhibitors, for this complex and heterogeneous disorder.
LI et al. (Thu,) studied this question.