Skeletogenesis and Disproportionate Short Stature: Genotypic Determinants and Phenotypic Variability in Achondroplasia

Abstract

Background: Endochondral ossification governs longitudinal bone growth and is tightly regulated by fibroblast growth factor receptor signaling, particularly FGFR3, such that gain-of-function variants can disrupt growth-plate dynamics and produce disproportionate short stature as observed in achondroplasia and related skeletal dysplasias. Objective: To delineate molecular mechanisms underlying disproportionate short stature and clarify genotype–phenotype correlations, emphasizing FGFR3-mediated pathophysiology, phenotypic variability, and lifetime complications in achondroplasia within the broader framework of skeletal dysplasia diagnostics. Methods: A cross-sectional observational study was conducted at tertiary-care clinics and affiliated genetic laboratories (January 2019–December 2024) using consecutive recruitment of individuals aged ≥1 year with clinically and radiologically confirmed disproportionate short stature due to skeletal dysplasia. Standardized anthropometry and skeletal survey review (dual-reader, blinded) were performed, and pathogenic/likely pathogenic variants were identified via targeted panels and/or next-generation sequencing with ACMG classification. Genotype was the primary exposure; phenotypic disproportionality indices, height SDS, radiographic severity markers, and system-specific complications were outcomes. Multivariable regression adjusted for a priori confounders; missing data were addressed using multiple imputation. Results: FGFR3-related dysplasia’s, predominantly achondroplasia, demonstrated consistent disproportion patterns with clinically meaningful inter-individual variability in complication burden, including neurological, orthopedic, and otologic manifestations, supporting heterogeneity beyond a single-variant model. Genotype category and variant type were associated with phenotypic severity after adjustment for age and sex. Conclusion: Integrating standardized phenotyping with molecular diagnostics enables robust genotype–phenotype mapping in disproportionate short stature, supporting pathway-oriented evaluation and precision surveillance in achondroplasia and related dysplasia.