Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: Two-year results of a randomized, controlled, multicenter trial

Background: The short stature homeobox- containing gene, SHOX, located on the distal ends of the X and Y chromosomes, encodes a homeodomain transcription factor responsible for a significant proportion of long- bone growth. Patients with mutations or deletions of SHOX, including those with Turner syndrome ( TS) who are haplo-insufficient for SHOX, have variable degrees of growth impairment, with or without a spectrum of skeletal anomalies consistent with dyschondrosteosis. Objective: Our objective was to determine the efficacy of GH in treating short stature associated with short stature homeoboxcontaining gene deficiency ( SHOX- D). Design and Methods: Fifty- two prepubertal subjects ( 24 male, 28 female; age, 3.0 - 12.3 yr) with a molecularly provenSHOXgene defect and height below the third percentile for age and gender ( or height below the 10th percentile and height velocity below the 25th percentile) were randomized to either a GH- treatment group ( n = 27) or an untreated control group ( n = 25) for 2 yr. To compare the GH treatment effect between subjects with SHOX- D and those with TS, a third study group, 26 patients with TS aged 4.5 - 11.8 yr, also received GH. Between- group comparisons of first- year and second- year height velocity, height SD score, and height gain ( cm) were performed using analysis of covariance accounting for diagnosis, sex, and baseline age. Results: The GH- treated SHOX-D group had a significantly greater first- year height velocity than the untreated control group ( mean +/- SE, 8.7 +/- 0.3 vs. 5.2 +/- 0.2 cm/ yr; P < 0.001) and similar first- year height velocity to GH- treated subjects with TS ( 8.9 +/- 0.4 cm/ yr; P = 0.592). GH- treated subjects also had significantly greater second-year height velocity ( 7.3 +/- 0.2 vs. 5.4 +/- 0.2 cm/ yr; P = 0.001), second- year height SD score (- 2.1 +/- 0.2 vs. - 3.0 +/- 0.2; P < 0.001) and second- year height gain ( 16.4 +/- 0.4 vs. 10.5 +/- 0.4 cm; P < 0.001) than untreated subjects. Conclusions: This large- scale, randomized, multicenter clinical trial in subjects with SHOX- D demonstrates marked, highly significant, GH- stimulated increases in height velocity and heightSDSduring the 2- yr study period. The efficacy of GH treatment in subjects with SHOX- D was equivalent to that seen in subjects with TS. We conclude that GH is effective in improving the linear growth of patients with various forms of SHOX- D.