SAT-196 Noonan Syndrome: Genotype-Phenotype Correlations and Clinical Variability

Abstract Disclosure: G. Del Medico: None. E. Andreucci: None. S. Bargiacchi: None. G. Gori: None. G. Mancano: None. G. Traficante: None. F. Girolami: None. S. Favilli: None. A. Peron: None. I. Olivotto: None. M. Tartaglia: None. S. Stagi: None. Background: Noonan syndrome (NS) is a congenital genetic condition with an estimated incidence of 1 in 1,000-2,500 live births. Typical clinical features include congenital heart defects, short stature, distinctive facial characteristics, chest anomalies, and varying degrees of cognitive impairment. NS is caused by pathogenic variants in genes involved in the RAS/MAPK signaling cascade, resulting in significant clinical and genetic variability. Aims: To analyze the prevalence of specific genetic mutations and their correlation to clinical features in NS. Methods: This retrospective observational study included 111 individuals with genetically confirmed NS. Data collected comprised genotype, cardiac abnormalities, and anthropometric measurements (birth weight, birth length, height, and weight at the latest clinical visit). Standard deviation (SD) scores were determined using Italian population growth references. Results: Complete data were available for 60 NS patients (38% male). The most prevalent mutations were identified in PTPN11 (60%) and SOS1 (10%), with additional variants detected in LZTR1, RAF1, RIT1, CBL, KRAS, SOS2, BRAF, and MAP2K1. Cardiovascular abnormalities were present in 62% of the cohort, with PTPN11 and RIT1 mutations predominantly linked to pulmonary valve stenosis, while RAF1 mutations were associated with hypertrophic cardiomyopathy. Less frequent heart defects, such as atrial and ventricular septal defects and abnormalities of the mitral or aortic valves, showed no clear genotype correlation. Small for gestational age (SGA) was identified in 5% of individuals, all carrying PTPN11 mutations. At an average age of 9.8 ± 5.9 years, mean height and weight were -1.8 ± 1.18 SD and -1.5 ± 1.40 SD, respectively. Short stature was present in 42% of patients, with an average height of -2.84 SD. Growth hormone treatment was administered to 37% of patients, the significant majority of whom carried PTPN11 mutations (74%, p<0.05). Among those born SGA, two-thirds developed short stature. Interestingly, individuals with CBL, SOS2, or MAP2K1 mutations did not exhibit short stature. In 28% of the cohort, both short stature and heart defects coexisted, though no significant genotype association was observed for this combination. Conclusion: This study underscores the high frequency of cardiac defects and short stature in NS, with distinct genotype-phenotype correlation for cardiovascular abnormalities. While being born SGA was relatively rare, it was strongly associated with the PTPN11 genotype. Conversely, genotype-growth correlations were less evident, though some mutations appeared to reduce the likelihood of short stature. These findings highlight the genetic and clinical variability of NS and emphasize the necessity for larger studies to enhance our understanding of genotype-phenotype correlations. Presentation: Saturday, July 12, 2025