Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, non-receptor-type 11

Abstract

Context: Noonan syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. Short-term effect of GH therapy in NS is beneficial, reports on the effect on adult height are scarce. Objective: To determine the effect of long-term GH therapy in children with NS. Design: Twenty-nine children with NS were treated with GH until final height was reached. Setting: Hospital endocrinology departments. Patients: Children with the clinical diagnosis of NS, with mean age at the start of therapy of 11.0 years, 22 out of 27 tested children had a mutation in the protein tyrosine phosphatase, non-receptor-type 11 gene (PTPN11 gene). Interventions: GH was administered subcutaneously at 0.05 mg/kg per day until growth velocity was 1 cm/6 months. Main outcome measure: Linear growth (height) was measured at 3-month intervals in the first year and at 6-month intervals thereafter until final height. Results: At the start of treatment, median height SDS (H-SDS) was K2.8 (K4.1 to K1.8) and 0.0 (K1.4 to C1.2), based on national and Noonan standards respectively. GH therapy lasted for 3.0-10.3 years (median, 6.4), producing mean gains in H-SDS of C1.3 (C0.2 to C2.7) and C1.3 (K0.6 to C2.4), based on national and Noonan standards respectively. In 22 children with a mutation in PTPN11 mean gain in H-SDS for National standards was C1.3, not different from the mean gain in the five children without a mutation in PTPN11C1.3 (PZ0.98). Conclusion: Long-term GH treatment in NS leads to attainment of adult height within the normal range in most patients.

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

“…Thus Kirk et al, observed a moderate increase in height SDS of 0.8 in 10 patients [22], which is in accordance with a rise of 0.87 in 24 patients reported by Raaijmakers et al, [29]. On the other hand, Osio et al, Noordam et al, and Romano et al, reported better outcomes of GH therapy, with increases in height SDS ranging from 1.3 to 1.7 on a total of 112 patients [26,28,30].…”

“…In agreement with this, individuals mutated in PTPN11 appeared to respond less to GH therapy than other NS patients [25,27]. Supporting the concept of GH resistance in patients with PTPN11 mutations, other clinicians subsequently reported that these individuals display, under GH therapy, smaller increments in IGF-1 levels or in short-term growth, compared with subjects without PTPN11 mutations [28,53]. However, in one of these studies which also measured patients growth, long-term GH treatment was not found to make a significant difference on the growth of children harboring PTPN11 mutations, in comparison with other NS patients [28].…”

“…An additional source of variation between the above studies could be due to different doses of GH used in these studies, even though no significant correlation of given dosage to final height has been found to date [22,26,28]. For example, Osio et al, did not observe a significant difference between two sets of nine patients receiving 0.23 or 0.46 mg of GH per kg and per week [26].…”

“…Supporting the concept of GH resistance in patients with PTPN11 mutations, other clinicians subsequently reported that these individuals display, under GH therapy, smaller increments in IGF-1 levels or in short-term growth, compared with subjects without PTPN11 mutations [28,53]. However, in one of these studies which also measured patients growth, long-term GH treatment was not found to make a significant difference on the growth of children harboring PTPN11 mutations, in comparison with other NS patients [28]. Supporting this later observation, a recent study failed to find different levels of basal IGF-1 and IGFBP-3 between patients with or without PTPN11 mutations, while this study did confirm that NS patients, harboring or not PTPN11 mutations, have abnormally low levels of IGF-1 and IGFBP-3 in comparison with normal subjects [54].…”

“…Despite these limitations, it is worthwhile to analyze the different reports which addressed this question [22][23][24][25][26][27][28][29][30][31]. Their data are summarized in Table 1.…”