Case Report: Proportionate short stature in a three-generation family harboring FGFR3 N540S: phenotypic expansion beyond hypochondroplasia and implications for genetic screening in idiopathic short stature.

OBJECTIVE: To report the identification of a FGFR3 gene variant in a family with idiopathic short stature, characterized by proportionate stature and the absence of dysmorphic features, and to highlight the importance of genetic investigation in ISS as well as the clinical heterogeneity of the FGFR3 N540S variant. METHODS: Based on clinical and genetic data collected from the proband and short-statured relatives, we analyzed the clinical characteristics of the pedigree and the pathogenicity of the genetic variant. RESULTS: A 3-year-old male presented with proportionate short stature and no dysmorphic features. Imaging studies revealed no significant skeletal abnormalities. Combined with the short stature observed in multiple family members, a clinical diagnosis of FSS was established. Whole-exome sequencing identified a maternally inherited heterozygous FGFR3 variant (c.1619A>G, p.N540S) in the proband. The mother and maternal grandfather also harbored this variant. ACMG classification deemed it likely pathogenic. Literature review revealed that all previously reported patients with the FGFR3 N540S variant exhibited clinical manifestations of HCH with abnormal radiographic features. CONCLUSION: This is the first report of proportionate short stature associated with the FGFR3 N540S variant, demonstrating substantial phenotypic heterogeneity at this site. Genetic testing is strongly recommended for patients with FSS, particularly those with severe short stature.