Genetic screening of the insulin-like growth factor 1 receptor gene in children born small for gestational age: the continuing importance of insulin-like growth factor 1 signaling.

Children born small for gestational age (SGA) who fail to experience catch-up growth often remain short-statured with heterogeneous etiologies, including genetic factors. This study aimed to investigate Insulin-like Growth Factor 1 Receptor (IGF1R) gene alterations and their clinical relevance in 66 Korean children born SGA with persistent short stature. All the subjects underwent detailed phenotyping and molecular analyses. Two patients carried heterozygous deletions encompassing the entire IGF1R gene, as confirmed by chromosomal microarray analysis. Both patients exhibited advanced bone age, with one showing a favorable response to growth hormone therapy. Additionally, 14 variants of uncertain significance were identified, with one rare missense variant (c.158C>T, p.Thr53Met) showing a high predicted pathogenicity. Subgroup analysis showed that severe SGA was associated with lower mid-parental height, and those with an insulin-like growth factor 1 standard deviation score of ≥0 had less bone age delay, but no clear auxological differences were observed between subgroups. These patterns, although not definitive, may help to identify SGA-short children who warrant further evaluation for IGF1R-related growth impairment. Exploratory clustering revealed two subgroups but failed to show distinct phenotypic separation. Although no strong genotype-phenotype correlations were observed, this study highlights the potential clinical value of identifying IGF1R deletions and suggests that molecular and phenotypic profiling may offer hypothesis-generating insights into SGA-related growth disorders. Our findings underscore the importance of integrating genetic screening into the diagnostic workup for children born SGA with unexplained growth failure, and the need for future studies to functionally characterize rare IGF1R variants.