Italian long-term data on efficacy and safety of rhGH therapy in children with SHOX deficiency: the final report of a national survey performed into ISPED Growth Study Group

Background: Among children with idiopathic short stature, Italian data reported a prevalence of short stature homeobox-containing gene (SHOX) deficiency disorders (SHOX-D) near to 1/1.000-2.000 (1.1-15%) with a wide phenotypic spectrum. Current guidelines support recombinant human growth hormone (rhGH) therapy in SHOX-D children, but long-term data are still lacking. This national survey aims to evaluate long-term efficacy and safety of rhGH therapy in Italian 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, 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 therapy (T0), yearly during the first 4 years of rhGH therapy (T1, T2, T3, T4) and at final height (T5), when available. Statistical analysis was carried out on STATISTICA (StatSoft Inc, Tulsa, OK, USA). Results: 106 SHOX-D children started rhGH therapy (initial dose of 0.24±0.05 mg/kg/week) at a mean age of 8.67±3.28 years (81% prepubertal). During rhGH therapy (mean follow-up 5.94±2.04 years), height (H) SDS and growth velocity (GV) SDS improved significantly (H SDS: T0 -2.36±0.68, T1 -1.91±0.65, T2 -1.66±0.71, T3 -1.49±0.54, T4 -1.45±0.58, T5 -1.57±0.93, P<0.05 and GV SDS: T0 -1.40±1.66, T1 +1.77±2.02, T2 +1.24±2.31, T3 +0.86±2.05, T4 +0.40±2.40, P<0.05) together with sitting height/H ratio (T0 0.56±0.02 vs.T5 0.55±0.01, P<0.05). Mean H SDS gain from T0 was +1.14±0.58 at T4 and +0.83±0.99 at T5. Multiple regression analysis identified the initial dose of rhGH and GV SDS during the first year of treatment as independent positive predictive factors of H SDS gain at T4 (R2 0.40, SE 0.62). No adverse effects were reported apart from: transient impaired glucose metabolism (4/106 cases), elevated IGF-1 levels (1 case) and transient headache (1 case). Conclusions: Italian data confirm the efficacy and safety of rhGH therapy in SHOX-D children. Moreover, rhGH therapy seems to blunt SHOX-D phenotype improving body proportions as sitting height/height ratio. The response to rhGH in the first year of treatment significantly impacts the final height gain.