Growth response to rhIGF-I 80 mu g/kg twice daily in children with growth hormone insensitivity syndrome: relationship to severity of clinical phenotype

BACKGROUND rhIGF-I has been used effectively to promote growth in growth ho rmone insensitivity syndrome (GHIS) in doses ranging from 40 mu g/kg twice daily to 150-200 mu g/kg once daily. It appears that the dose of 80 mu g/kg twice daily s.c. may induce an equivalent response to higher doses with le ss side-effects. OBJECTIVE To study the efficacy and safety of rhIGF-1, 80 mu g/kg twice dai ly s.c., in children with GHIS and to analyse the relationship of growth re sponse to severity of phenotype. PATIENTS AND DESIGN: Eleven prepubertal children (3 females, 8 males) with GHIS; basal GH > 2.5 mu g/l, IGF-I < 50 mu g/l, IGFBP-3 < -2SD; were treate d with IGF-I 80 mu g/kg twice daily in a multi-centre study. The baseline c haracteristics of these patients were as follows (mean +/- SD): age, 7.5 +/ - 2.5 years (range, 2.5-11.7 years), bone age (Tanner-Whitehouse -2 RUS), 5 .2 +/- 2.4 years (range, 2.3-9.1 years), mean height SDS, - 5.6 +/- 1.6 (ra nge, -3.1 to -8.1), height velocity (HV), 3.1 +/- 1.1 cm/year (range, 1.9-4 .9cm/ year). Height, HV, weight, skinfold thickness, puberty stage and bone age were measured at baseline and 6 monthly for 2 years. RESULTS During the first 12 months of IGF-I therapy, the mean +/- SD HV was 7.7 +/- 1.6 cm/year (range, 6.1-11.2 cm/year), the mean +/- SD increase in HV was 4.7 +/- 2 cm/year (range, 1.7-8.8 cm/year) and the mean +/- SD prog ression of bone age was 1.9 +/- 1.0 years (range, 0.8-3.8 years). Pre-treat ment height SDS at the start of IGF-I therapy correlated positively with pr etreatment serum IGFBP-3 SDS levels (r = 0.85; P < 0.01). There was a signi ficant inverse correlation between gain in height SDS and pre-treatment hei ght SDS (r= - 0.76; P < 0.01). During the 2nd 12 months of therapy, mean HV was 7.0 +/- 3.4cm/year (range 3.8-12. 4) change in height SDS from 12 to 2 4 months was not significantly correlated with pre-treatment height SDS. Su bscapular skinfold SDS decreased significantly (P < 0.05) during the study period, whereas there was no significant change in body mass index and tric eps skinfold thickness SDS. Adverse events reported in the patient group in cluded headache (2 patients), hypoglycaemia (2 patients), papilloedema (tra nsient, 1 patient), lipohypertrophy (5 patients) and tonsillectomy/adenoide ctomy (2 patients). CONCLUSION This study reveals that IGF-I treatment at a dose of 80 mu g/kg twice daily is effective in patients with growth hormone insensitivity synd rome. During the first 12 months of therapy, there was a significant invers e relationship between growth response to IGF-I therapy and the severity of the phenotype of growth hormone insensitivity syndrome, as measured by hei ght SDS, at the start of therapy. Patients with a more severe clinical phen otype of growth hormone insensitivity syndrome, who also had most severe IG FBP-3 deficiency, responded better than those who were more mildly affected . An analogous situation has been shown to be the case in GH-deficient pati ents treated with hGH.