Long-term efficacy and safety of rhGH in children with SHOX deficiency: preliminary data of a national Italian survey (on behalf of ISPED Study Group on Growth Factors and Puberty)

Background: The phenotypic spectrum of short stature homeobox-containing gene deficiency disorders (SHOX-D) ranges from non-specific short stature to Leri-Weill dyschondrosteosis. Current guidelines support rhGH in SHOX-D children, but long-term data are still lacking. Moreover, no correlation has been established yet between the severity of phenotype, including the response to rhGH, and the underlying SHOX pathogenic variant. Aims: To evaluate long-term efficacy and safety of rhGH in children with SHOX-D and to identify potential predictive factors influencing response to rhGH therapy. Methods: This is an Italian multicentric, observational study collecting anamnestic, anthropometric [height SDS (H-SDS), arm span/height ratio (AS/H), sitting height/height ratio (S/H), pubertal status, growth velocity (GV) SDS, target height (TH)], clinical (Rappold score), instrumental (bone age) and therapeutic data (rhGH dose, side effects) in children and adolescents with a genetic confirmation of SHOX-D treated on rhGH. Data were collected at the beginning of rhGH (T0), yearly during the first 4 years of rhGH (T1, T2, T3, T4) and at final height (T5), when available. Statistical analysis was carried out on STATISTICA (StatSoft Inc, Tulsa, OK, USA). Results: 67 SHOX-D children (93% Caucasian, 85% prepubertal) started rhGH (initial dose 0.24±0.04 mg/kg/week) at a mean age of 8.27±3.06 years. During rhGH (mean follow-up 6.64±1.47 years), H-SDS and GV SDS improved significantly (H-SDS: T0 -2.46±0.66, T1 -1.97±0.66, T2 -1.70±0.74, T3 -1.52±0.55, T4 -1.47±0.49, T5 -1.72±0.60, χ2 64.54, P <0.05 and GV SDS: T0 -1.04±1.87, T1 2.02±1.99, T2 1.37±2.39, T3 1.27±1.67, T4 0.76±2.72, χ2 43.51, P <0.05) without changes in AS/H ratio (χ2 1.02, p 0.90), S/H ratio (χ2 7.61, p 0.17) and Rappold score (χ2 2.80, p 0.59). Mean H-SDS gain at T5 vs. T0 was +0.96±0.80. H-SDS at T4 positively correlated with H-SDS at T0 (r 0.64, P < 0.05) and H-SDS at T5 with TH-SDS (r 0.52, P < 0.05). No differences in clinical and therapeutic data were detected between patients carrying mutations involving enhancers (35/67) and ones with no-sense and missense mutations in SHOX gene, both at the beginning of rhGH and along follow-up. No adverse effects were reported a part from transient impaired glucose metabolism (2/67 cases) and transient headache (1 case). Conclusions: Our preliminary data confirm the efficacy and safety of rhGH in SHOX-D children. Besides wide phenotypic spectrum, all SHOX-D genotypes seem to adequately respond to rhGH.