Abstract

Objective

This study aimed to describe the clinical manifestations and genetic variants of Noonan syndrome in a Colombian pediatric population and to identify the genes most frequently associated with specific phenotypic features.

Methods

A retrospective observational study was conducted on 45 patients under 18 years of age diagnosed with NS between 2013 and 2023. Clinical and molecular data were collected from medical records across several hospitals in Colombia. Molecular confirmation was achieved in all included patients through NGS-based clinical exome sequencing; however, parental samples were not available for segregation analysis in all cases. Descriptive statistical analyses were performed using R version 4.3.1 to evaluate demographic, clinical, and genetic variables.

Results

Among 45 patients (21 females, 24 males; the mean age at diagnosis was 7.5 ± 5.2 years), pathogenic variants were identified across 13 genes, with PTPN11 being the most frequent (26/45, 57.8%), followed by PPP1CB and several less frequent genes including SOS1, SOS2, LZTR1, RAF1, MAP2K1, KRAS, NRAS, BRAF, CBL, NF1, and SHOC2. The most common phenotypic features were congenital heart defects (80%, 36/45), predominantly pulmonary stenosis (31.1%, 14/45), short stature (66.7%, 30/45), and learning difficulties (51.1%, 23/45). Seven patients developed neoplasms. Juvenile myelomonocytic leukemia was the most frequent neoplasm and occurred mainly in patients with PTPN11 variants. Ten patients received growth hormone therapy.

Conclusion

This study represents the first genetically characterized Colombian cohort for NS. PTPN11 was the predominant gene identified, particularly the p.(Asn308Asp) variant. These findings underscore the genetic heterogeneity of NS and emphasize the importance of early molecular diagnosis to guide clinical management. Multidisciplinary follow-up is essential due to the risks of growth failure, cardiac anomalies, and malignancies.