Endocrine Abstracts

JOINT2518

Background: Noonan syndrome (NS) is a congenital genetic disorder with an estimated incidence of 1 in 1, 000-2, 500 live births. It is characterized by congenital cardiac abnormalities, short stature, distinctive facial features, chest deformities and variable cognitive deficits. NS results from pathogenetic variants in genes involved in the RAS/MAPK signaling pathway, exhibiting significant genetic and clinical variability.

Aims: To assess the prevalence of specific genetic mutations and their impact on clinical outcomes in NS.

Methods: We conducted a retrospective observational study of 111 patients with genetically confirmed NS. Data collected included genotype, cardiac defects, and anthropometrics (birth weight, birth length, stature, and weight at the last visit). Standard deviation (SD) scores were calculated using Italian population growth charts.

Results: Complete data were available for 60 NS patients (38% males). The most common mutations occurred in PTPN11 (60%) and SOS1 (10%), with additional variants observed in LZTR1, RAF1, RIT1, CBL, KRAS, SOS2, BRAF, MAP2K1. Cardiovascular abnormalities were present in 62% of patients, with PTPN11 and RIT1 mutations predominantly linked to pulmonary valve stenosis and RAF1 mutations to hypertrophic cardiomyopathy. Less common cardiac defects, such as atrial and ventricular septal defects and mitral or aortic valve abnormalities, showed no clear genotype correlation. Small for gestational age (SGA) was observed in 5% of patients, all of whom carried PTPN11 mutations. At mean age of 9. 8 ± 5. 9 years, average height and weight were -1. 8 ± 1. 18 SD and -1. 5 ± 1. 40 SD, respectively. Short stature was observed in 42% patients, with a mean height of -2. 84 SD. Growth hormone therapy was used in 37% of patients, most of whom carried PTPN11 mutations (74%, P < 0. 05). Among SGA patients, two thirds developed short stature. Notably, patients with CBL, SOS2, or MAP2K1 mutations did not exhibit short stature. In 28% of the cohort, both short stature and cardiac defects co-occurred, though this combination was not significantly linked to a specific genotype.

Conclusion: This study highlights the high prevalence of cardiac abnormalities and short stature in NS, with clear genotype-phenotype correlations for cardiovascular defects. While being born SGA was relatively uncommon, it appeared to be specifically associated with the PTPN11 genotype. In contrast, genotype-growth correlations were less distinct, though certain mutations seemed to confer a lower risk of short stature. These findings underscore the genetic and clinical variability of NS and the need for larger studies to better understand genotype-phenotype correlations.