title: Switch in FGFR3 and -4 expression profile during human renal development may account for transient hypercalcemia in patients with Sotos syndrome due to 5q35 microdeletions.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (H.A.M.M., L.M., M.L.), Unité 693, Faculté de Médecine Paris-Sud, 94276 Le Kremlin-Bicêtre, France; PremUP Foundation (L.M., M.L.), 75014 Paris, France; Departments of Pharmacology and Toxicology (H.A.M.M., J.C.L.M.P., R.M.), Physiology (L.A.H.M.), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; and Departments of Pediatrics and Growth and Regeneration (E.N.L., K.A.) and Center for Human Genetics (K.D.), University Hospitals Leuven and Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Henricus A M
authors.initials: HA
authors.lastname: Mutsaers
authors.forename: Elena N
authors.initials: EN
authors.lastname: Levtchenko
authors.forename: Laetitia
authors.initials: L
authors.lastname: Martinerie
authors.forename: Jeanne C L M
authors.initials: JC
authors.lastname: Pertijs
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.forename: Koenraad
authors.initials: K
authors.lastname: Devriendt
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
authors.forename: Leo A H
authors.initials: LA
authors.lastname: Monnens
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
mesh_terms: D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D005333:Fetus / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005812:Genes, Switch; D006801:Humans; D006934:Hypercalcemia / Q000150:complications / Q000235:genetics*; D007231:Infant, Newborn; D007668:Kidney / Q000196:embryology* / Q000378:metabolism; D008297:Male; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics* / Q000378:metabolism; D058495:Sotos Syndrome / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
chemical_list: C000717427:FGF23 protein, human; D000089703:Fibroblast Growth Factor-23; C496365:FGFR3 protein, human; C496371:FGFR4 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4