ESPE Abstracts

Background: RASopathies are a group of diseases with common clinical features that occur as a result of pathogenic variants in genes encoding components of the RAS/MAPK pathway. The aim of this study was to evaluate the clinical and molecular features of RASopathy cases in our pediatric endocrinology unit.

Subjects and Methods: The clinical and molecular data of 42 patients (18 girls) from 39 families were evaluated, retrospectively. All cases with clinical and/or molecular genetic diagnoses of RASopathy were included in the study.

Results: The median age at admission was 3.8 years (range: 18 days – 15.1 years). Birth weight standard deviation scores (SDS) were 0.2±1.4. The ratio of consanguinity was 17.7% and the ratio of similar cases in the family was 20.0%. The reason for referral was short stature in 67.5% of the cohort. At admission, the mean±SD of height was -2.2±1.6 (target height SDS -1.2±1.1), body mass index was -0.6±1.4 SD, and 87.5% were prepubertal. Cryptorchidism was detected in 47.8% of the boys. Pulmonary stenosis and hypertrophic cardiomyopathy were detected in 27.5% and 12.5% of cases, respectively. Echocardiography was normal in 45%. The rate of intellectual disability was 47.5% when mild cases were also included. The molecular genetic analyses were performed in 34 (80.9%) of the cases, and the diagnosis was supported molecularly in 88.2% (n=30) of them. Pathogenic variants were detected more frequently in the PTPN11 (n=11, 32.3%) followed by NF1 (n=4), MAP2K2 (n=3), KRAS (n=3), RIT1 (n=2), RAF1 (n=2), MAP2K1 (n=1), HRAS (n=2), BRAF (n=1) and LZTR1 (n=1). For the patients followed for one year or longer, the median follow-up period was 7.5 years (range 1.9-18.1 years). Growth hormone (GH) deficiency (peak GH<7 ng/ml) was detected in 28.9%. GH treatment was commenced in 14 cases (33.3%). The duration of GH treatment was 4.9±2.7 years. The median final height was -1.9 SD in patients who received GH treatment (n=8), and -2.9 SD in patients who did not receive GH treatment (n=8) (P=0.083).

Conclusion: Similar to the previous reports, the ratio of PTPN11 gene variants in our RASopathy cohort was 39.0% and the diagnostic yield of our molecular genetic evaluation was 88.0%. Our approach to GH treatment in selected cases with RASopaties showed a +1 SD contribution to final height.