CONTEXT: Sotos syndrome is a rare genetic disorder with a distinct phenotypic 
spectrum including overgrowth and learning difficulties. Here we describe a new 
case of Sotos syndrome with a 5q35 microdeletion, affecting the fibroblast 
growth factor receptor 4 (FGFR4) gene, presenting with infantile hypercalcemia.
OBJECTIVE: We strove to elucidate the evanescent nature of the observed 
hypercalcemia by studying the ontogenesis of FGFR3 and FGFR4, which are both 
associated with fibroblast growth factor (FGF) 23-mediated mineral homeostasis, 
in the developing human kidney.
DESIGN: Quantitative RT-PCR and immunohistochemical analyses were used on 
archival human kidney samples to investigate the expression of the FGFR 
signaling pathway during renal development.
RESULTS: We demonstrated that renal gene and protein expression of both FGFRs 
increased during fetal development between the gestational ages (GAs) of 14-40 
weeks. Yet FGFR4 expression increased more rapidly as compared with FGFR3 (slope 
0.047 vs 0.0075, P = .0018). Moreover, gene and protein expression of the 
essential FGFR coreceptor, Klotho, also increased with a significant positive 
correlation between FGFR and Klotho mRNA expression during renal development. 
Interestingly, we found that perinatal FGFR4 expression (GA 38-40 wk) was 7-fold 
higher as compared with FGFR3 (P = .0035), whereas in adult kidney tissues, 
FGFR4 gene expression level was more than 2-fold lower compared with FGFR3 (P = 
.0029), thus identifying a molecular developmental switch of FGFR isoforms.
CONCLUSION: We propose that the heterozygous FGFR4 deletion, as observed in the 
Sotos syndrome patient, leads to a compromised FGF23 signaling during infancy 
accounting for transient hypercalcemia. These findings represent a novel and 
intriguing view on FGF23 mediated calcium homeostasis.