In vitro and in vivo responses to short-term recombinant human insulin-like growth factor-1 (IGF-1) in a severely growth-retarded girl with ring chromosome 15 and deletion of a single allele for the type 1 IGF receptor gene

OBJECTIVES Patients with single allele defects in the gene encoding the typ e 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 recombinan t human IGF-I (rhIGF-I) in a severely growth-retarded girl with ring chromo some 15 and deletion of a single allele for the type 1 IGF receptor gene ha ve been investigated. DESIGN AND PATIENT The child exhibited prenatal and severe post-natal growt h failure, and delayed psychomotor development. Southern blotting revealed a 50% reduction in IGF-I receptor DNA, and in an RNase protection assay (RP A), 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 mu g/kg twice daily by subcutaneous injection for periods of 2-2.5 days each. RESULTS During rhIGF-I treatment, mean urinary nitrogen excretion was uncha nged and urinary calcium rose to 60% greater than in the pre-treatment peri od, rhIGF-I injections produced only a modest decrease in indices of GH sec retion, assessed by frequent (every 20 min) sampling over periods of 12 h. There was no significant difference between the mean GH concentrations duri ng rhIGF-I treatment (5.32+/-6.2mU/I) compared with that before rhIGF-I tre atment (8.46+/-10.2 mU/I). Mean IGFBP-3-values were increased (4.5 mg/l bef ore vs. 5.4 mg/l during rhIGF-I). TSH values after injection of TRH were no t significantly reduced by IGF-I (mean of all values, 18.6 mU/I vs. 15.5 mU /I during rhIGF-I treatment). In vitro binding of radiolabelled IGF-I to th e patient's fibroblasts was less than that bound by control fibroblasts (pa tient, 0.69% binding by 248000 cells, vs. 1 41% binding by 260000 fibroblas ts from an age-matched control). However, the patient's fibroblasts exhibit ed 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 observe d in such patients may be the direct result of the absence of one of the al leles encoding the type 1 IGF receptor.