ESPE Abstracts

Introduction: Noonan syndrome (NS) is one of a group of diseases known as rasopathies, which share a common molecular substrate: alterations in the RAS-MAPK signaling pathway. NS is characterized by clinical and genetic heterogeneity. Up to 50% of cases are caused by variants in the PTPN11 gene, although more than 10 genes have been identified as involved in the pathogenesis of this disease with marked clinical overlap.

Objectives: To establish phenotypic differences in patients with NS based on whether it is caused by PTPN11 or another gene.

Materials and Methods: Retrospective observational study that included all patients diagnosed with NS (genetic and/or clinical) between 2005 and 2022 in the Paediatric Endocrinology unit of a single tertiary health care centre. The IBM SPSS software package was used for statistical analysis, using the chi-square test for quantitative variables, and Fisher's exact test when expected values were <5.

Results: A total of 56 patients were included, with a median age at diagnosis of 4.3 years (IQR 1.4-10.4). The genetic cause was identified in 53 patients (94.6%), with 34 of them having variants in PTPN11 (66.1%), 5 in SOS1 and RIT1 (8.9% respectively), 2 patients in RAF1 (3.6%) and one patient in KRAS, MAP2K1, RASA2, and LZTR1 (1.8% respectively). Regarding clinical features, 75.5% of patients had typical facial features. 89.3% had some type of cardiovascular abnormality, with pulmonary stenosis (62.5%) and hypertrophic cardiomyopathy (8.9%) being the most frequent and characteristic. Short stature was observed in 55.3% of patients, with 55% of them receiving growth hormone treatment. Other less characteristic abnormalities included lymphatic disorders (21.4%), cryptorchidism (80%), palmoplantar keratosis (23.2%), musculoskeletal anomalies (76.8%), and hematologic abnormalities (23.3%). The statistical association of all phenotypic characteristics with the presence or absence of mutation in PTPN11 was studied. Only a significant result was obtained in the association of low height and mutation in PTPN11 (P=0.022).

Conclusions: Since NS is an entity with great clinical variability and all known causative genes participate in the same signaling pathway, it is difficult to establish phenotypic differences based on the affected gene. The phenotypic overlap described in the literature is confirmed.