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 haploinsufficient for SHOX, have variable degrees of growth impairment, with or without a spectrum of skeletal anomalies consistent with dyschondrosteosis.

Objective: To determine the efficacy of growth hormone (GH) in treating short stature associated with SHOX deficiency (SHOX-D).

Design/Methods: Fifty-two prepubertal subjects (24 male, 28 female; age 3.0-12.3 yr) with a molecularly-proven SHOX gene defect and height below the 3rd 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, comprised 26 pts with TS aged 4.5-11.8 yr, who also received GH. Between-group comparisons of first-year and second-year height velocity, height SD score (SDS) 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/y, P < 0.001) and similar first-year height velocity to GH-treated subjects with TS (8.9 ± 0.4 cm/y, P = 0.592). GH-treated subjects also had significantly greater second-year height velocity (7.3 ± 0.2 vs. 5.4 ± 0.2 cm/y, P < 0.001), second-year height SDS (-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 height SDS during the two-year 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.