Phenotypic and genotypic characteristics of pediatric patients with neurofibromatosis type 1: a 12-year single-center cohort study.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by pathogenic variants in the NF1 gene. The NF1 gene product neurofibromin, acts as a tumor suppressor primarily by negatively regulating the mitogen-activated protein kinase signaling pathway. This study aimed to characterize both the genotypic and phenotypic spectrum of pediatric NF1 patients at a single center and further explore potential genotype-phenotype correlations. METHODS: Pediatric patients diagnosed with NF1 who were treated and followed up at our center from July 2013 to August 2025 were included. All patients underwent genetic testing, both phenotypic and genotypic data were collected and curated. Statistical analyses were performed using SPSS, GraphPad Prism, and Python. Growth curves and variant distribution maps were generated based on the integrated dataset. RESULTS: A total of 301 patients were included. They exhibited a broad multisystem phenotype with several clinical manifestations and notable sex-related differences, particularly skeletal abnormalities and developmental or intellectual impairments. Males had significantly lower height standard deviation scores (SDS) than females, and P50 growth curves were consistently below those of healthy reference values. Truncating variants were the most common (60.8%). Among 229 patients with known parental origin, 77.29% carried de novo variants, and 37 novel variants were identified. Patients harboring single amino acid variations exhibited a significantly higher prevalence of short stature than those with truncating variants, whereas splice variants were associated with unidentified bright objects (UBOs) and optic nerve abnormalities. CONCLUSIONS: This study provides a comprehensive characterization of the genotypic and phenotypic landscape of pediatric NF1 in a large cohort. By incorporating growth data from childhood, we construct sex-specific growth curves and provide a precise reference for the evaluation of growth abnormalities. These findings expand the current understanding of phenotypic heterogeneity and genotype-phenotype correlations in pediatric NF1.