Growth response to rhIGF-I 80 μg/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 hormone 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 less side-effects. OBJECTIVE To study the efficacy and safety of rhIGF-1, 80 mu g/kg twice daily s.c., in children with GHIS and to analyse the relationship of growth response 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 treated with IGF-I 80 mu g/kg twice daily in a multi-centre study. The baseline characteristics 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 (range, -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 progression of bone age was 1.9 +/- 1.0 years (range, 0.8-3.8 years). Pre-treatment height SDS at the start of IGF-I therapy correlated positively with pretreatment serum IGFBP-3 SDS levels (r = 0.85; P < 0.01). There was a significant inverse correlation between gain in height SDS and pre-treatment height 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 24 months was not significantly correlated with pre-treatment height SDS. Subscapular skinfold SDS decreased significantly (P < 0.05) during the study period, whereas there was no significant change in body mass index and triceps skinfold thickness SDS. Adverse events reported in the patient group included headache (2 patients), hypoglycaemia (2 patients), papilloedema (transient, 1 patient), lipohypertrophy (5 patients) and tonsillectomy/adenoidectomy (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 syndrome. During the first 12 months of therapy, there was a significant inverse relationship between growth response to IGF-I therapy and the severity of the phenotype of growth hormone insensitivity syndrome, as measured by height SDS, at the start of therapy. Patients with a more severe clinical phenotype of growth hormone insensitivity syndrome, who also had most severe IGFBP-3 deficiency, responded better than those who were more mildly affected. An analogous situation has been shown to be the case in GH-deficient patients treated with hGH.