The Efficacy and Safety of Growth Hormone Therapy in Children with Noonan Syndrome: A Review of the Evidence

Abstract

Noonan syndrome is a genetic disorder associated with short stature. We reviewed 15 studies in which growth hormone (GH) therapy was used in children with Noonan syndrome. Data show consistent increases in mean height standard deviation score (SDS), with first-year changes of up to 1.26 SDS. Among studies reporting adult or near-adult height, GH therapy over 5-7 years resulted in adult height SDS from -0.6 to -2.1, with up to 60% of subjects in some studies achieving adult height within 1 SDS of mid-parental height. GH treatment results in an acceleration of bone age, likely reflecting normalization from the retarded bone age common in Noonan syndrome patients at the start of therapy. BMI is not affected by GH treatment, but favorable changes in fat mass and body composition are achievable. Longer-term studies and observational studies suggest a waning of the effect of GH therapy over time, as is seen in other GH-treated conditions, and early initiation of therapy and prepubertal status are important predictors of response. GH treatment does not appear to be associated with adverse cardiac or metabolic effects, and data on malignancy during GH treatment give no cause for concern, although they are limited.

Efficacy and safety of two doses of Norditropin^® (somatropin) in short stature due to Noonan syndrome: a 2-year randomized, double-blind, multicenter trial in Japanese patients

“…Previous studies of GH in Noonan syndrome have consistently reported increases in mean height SDS values or mean height velocity using doses of 0.026-0.066 mg/kg/day (reviewed in [11]. An earlier study in Japan in 15 children with Noonan syndrome were treated with a dose of 0.5 IU/kg/week (i.e.…”

“…This study has several strengths: it was double-blind, included a comparison between two dose groups, and the number of patients was relatively large compared to previous studies of the use of GH in Noonan syndrome [11,[16][17][18]. A further strength is the use of reference values for height SDS for Japanese patients with Noonan syndrome, in addition to Japanese national reference data for children, to evaluate the growth promoting effect of GH.…”

“…Children with Noonan syndrome are usually not GH deficient, but may be deficient in insulin-like growth factor-I (IGF-I), particularly those with PTPN11 mutations [1]. Treatment with recombinant human GH (rhGH) has been shown to improve height velocity with no clinically significant adverse events (AEs) [11]. The response to GH therapy in NS can be affected by a number of factors, such as dose of rhGH and type of genetic mutation involved.…”

“…The registration submission in these countries was based on two pivotal trials in Sweden: a 2-year, prospective, randomized, paralleldose group trial (S/GHD/004/NOO) and a follow-up trial which lasted until adult height was attained and involved retrospective data collection (GHNOO-1658) [16]. A number of studies, including clinical trials, case reports and observational studies, have also reported on the efficacy and safety of GH in Noonan syndrome (reviewed in [11]), all involving small numbers of patients. Reports on the use of GH in Japanese children with Noonan syndrome were published in 1995 (N = 39) [17], and 2004 (N = 15) [18].…”

Treatment with Growth Hormone in Noonan Syndrome Observed during 25 Years of KIGS: Near Adult Height and Outcome Prediction

“…Several trials have shown that rhGH increases adult height (AH) SDS, but most trials were of limited size and none had the design of a randomized clinical trial [12, 13]. Despite the limited AH data, rhGH treatment is included in the current guidelines for the management of short patients with NS [14] and was approved in some countries, including the United States, for this indication.…”