Early-Life Presentation and Phenotypic Variability of the IGF1R c.3595G>A (p.Gly1199Arg) Variant: A Case Report.

Abstract

Most infants born small for gestational age (SGA) achieve spontaneous catch-up growth within the first two years of life; however, a subset remains growth-restricted and warrants further evaluation. Persistent short stature accompanied by microcephaly should prompt consideration of an underlying monogenic disorder. We report a term male infant born with severe SGA (birth weight -3.8 SDS; birth length -2.2 SDS) and microcephaly. At 16 months of age, his height was -2.7 SDS and head circumference -3.1 SDS. Initial insulin-like growth factor 1 (IGF-1) concentration was mildly decreased (-1.0 SDS) with normal insulin-like growth factor binding protein-3 (IGFBP-3, +1.0 SDS). Following nutritional optimization, IGF-1 increased to supranormal levels (+2.0 SDS), yet linear growth remained persistently below -2 SDS without sustained catch-up. Genetic analysis identified a heterozygous IGF1R c.3595G>A (p.Gly1199Arg) variant inherited from his short-statured mother. The variant was absent in population databases, localized within the intracellular tyrosine kinase domain, and predicted to be deleterious by multiple in silico tools (REVEL 0.98; AlphaMissense 1.0), supporting likely pathogenic classification. Previously reported individuals carrying this variant were evaluated later in childhood or adolescence. This case represents the earliest documented presentation and highlights a biochemical-auxological dissociation characterized by elevated IGF-1 levels without proportional linear growth, consistent with impaired receptor-mediated signaling. This report broadens the phenotypic and temporal spectrum of the IGF1R Gly1199Arg variant and underscores the importance of early molecular evaluation in SGA infants with persistent microcephaly and inadequate catch-up growth.