title: In vitro and in vivo responses to short-term recombinant human insulin-like growth factor-1 (IGF-I) in a severely growth-retarded girl with ring chromosome 15 and deletion of a single allele for the type 1 IGF receptor gene.
abstract: OBJECTIVE
  Patients with single allele defects in the gene encoding the type 1 IGF receptor have been reported to have growth failure, but fibroblasts from affected patients have not exhibited insensitivity to the effects of IGF-I in vitro. The in vitro and in vivo responses to short-term recombinant human IGF-I (rhIGF-I) in a severely growth-retarded girl with ring chromosome 15 and deletion of a single allele for the type 1 IGF receptor gene have been investigated.
  
  
  METHODS
  The child exhibited prenatal and severe post-natal growth failure, and delayed psychomotor development. Southern blotting revealed a 50% reduction in IGF-I receptor DNA, and in an RNase protection assay (RPA), a quantitatively similar reduction in steady-state mRNA for type 1 IGF receptor. rhIGF-I was administered in graded doses of 40, 60 and 80 microg/kg twice daily by subcutaneous injection for periods of 2-2.5 days each.
  
  
  RESULTS
  During rhIGF-I treatment, mean urinary nitrogen excretion was unchanged and urinary calcium rose to 60% greater than in the pre-treatment period. rhIGF-I injections produced only a modest decrease in indices of GH secretion, assessed by frequent (every 20 min) sampling over periods of 12 h. There was no significant difference between the mean GH concentrations during rhIGF-I treatment (5.32 +/- 6.2 mU/l) compared with that before rhIGF-I treatment (8.46 +/- 10.2 mU/l). Mean IGFBP-3-values were increased (4.5 mg/l before vs. 5.4 mg/l during rhIGF-I). TSH values after injection of TRH were not significantly reduced by IGF-I (mean of all values, 18.6 mU/l vs. 15.5 mU/l during rhIGF-I treatment). In vitro binding of radiolabelled IGF-I to the patient's fibroblasts was less than that bound by control fibroblasts (patient, 0.69% binding by 248 000 cells, vs. 1.41% binding by 260 000 fibroblasts from an age-matched control). However, the patient's fibroblasts exhibited a growth response in vitro to the addition of IGF-I in a fashion similar to that of control fibroblasts.
  
  
  CONCLUSIONS
  These studies show evidence in each of the indices examined of in vivo resistance to IGF-I and suggest that the growth retardation observed in such patients may be the direct result of the absence of one of the alleles encoding the type 1 IGF receptor.
authors.affiliation: Department of Paediatrics, Federal University of Parana, Curitiba, Brazil. lacerda@hc.ufpr.br
authors.forename: L
authors.initials: L
authors.lastname: de Lacerda
authors.forename: J A
authors.initials: JA
authors.lastname: Carvalho
authors.forename: B
authors.initials: B
authors.lastname: Stannard
authors.forename: H
authors.initials: H
authors.lastname: Werner
authors.forename: M C
authors.initials: MC
authors.lastname: Boguszewski
authors.forename: R
authors.initials: R
authors.lastname: Sandrini
authors.forename: S N
authors.initials: SN
authors.lastname: Malozowski
authors.forename: D
authors.initials: D
authors.lastname: Leroith
authors.forename: L E
authors.initials: LE
authors.lastname: Underwood
mesh_terms: D015139:Blotting, Southern; D002478:Cells, Cultured; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D006130:Growth Disorders / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use; D012303:Ring Chromosomes
chemical_list: D012333:RNA, Messenger; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D017526:Receptor, IGF Type 1