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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

Lilly Research Laboratories (W.F.B., H.J.), Eli Lilly & Company, D-61350 Bad Homburg, Germany; Lilly Research Laboratories (B.J.C., C.A.Q., D.C., L.B.), Eli Lilly & Company, Indianapolis, Indiana 46285; Department of Pediatrics (J.L.R.), Thomas Jefferson University, Philadelphia, Pennsylvania 19107; and Department of Molecular Human Genetics (G.R.), University of Heidelberg, D-69120 Heidelberg, Germany

Address all correspondence and requests for reprints to: Dr. Werner Blum, Eli Lilly & Company, Saalburgstrasse 153, D-61350 Bad Homburg, Germany. E-mail: Blum_Werner{at}Lilly.com.

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: Our objective was to determine the efficacy of GH in treating short stature associated with short stature homeobox-containing gene deficiency (SHOX-D).

Design and 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 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 height SDS during 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.

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