Impact of Growth Hormone Therapy on Adult Height in Patients with <b><i>PTPN11</i></b> Mutations Related to Noonan Syndrome

Abstract

Objectives: The aim of this study was to evaluate the response to recombinant human growth hormone (rhGH) treatment in patients with Noonan syndrome (NS). Materials and Methods: Forty-two patients (35 PTPN11+) were treated with rhGH, and 17 were followed-up until adult height. The outcomes were changes in growth velocity (GV) and height standard deviation scores (SDS) for normal (height-CDC SDS) and Noonan standards (height-NS SDS). Results: The pretreatment chronological age was 10.3 ± 3.5 years. Height-CDC SDS and height-NS SDS were –3.1 ± 0.7 and –0.5 ± 0.6, respectively. PTPN11+ patients had a better growth response than PTPN11– patients. GV SDS increased from –1.2 ± 1.8 to 3.1 ± 2.8 after the first year of therapy in PTPN11+ patients, and from –1.9 ± 2.6 to –0.1 ± 2.6 in PTPN11– patients. The gain in height-CDC SDS during the first year was higher in PTPN11+ than PTPN11– (0.6 ± 0.4 vs. 0.1 ± 0.2, p = 0.008). Similarly, the gain was observed in height-NS SDS (0.6 ± 0.3 vs. 0.2 ± 0.2, respectively, p &lt; 0.001). Among the patients that reached adult height (n = 17), AH-CDC SDS and AH-NS SDS were –2.1 ± 0.7 and 0.7 ± 0.8, respectively. The total increase in height SDS was 1.3 ± 0.7 and 1.5 ± 0.6 for normal and NS standards, respectively. Conclusions: This study supports the advantage of rhGH therapy on adult height in PTPN11+ patients. In comparison, PTPN11– patients showed a poor response to rhGH. However, this PTPN11– group was small, preventing an adequate comparison among different genotypes and no guarantee of response to therapy in genes besides PTPN11.

Effectiveness of growth hormone therapy in children with Noonan syndrome

“…Other studies have reported that the response to rhGH therapy was not significantly different according to genotype. 15,22,23) A prospective study of children with NS reported that there were no significant differences in height SDS or growth velocity between patients with and without PTPN11 mutations. 15) These studies were conducted with a very small number of patients and short treatment duration.…”

“…However, Jo et al [ 12 ] reported that the growth velocity in patients with PTPN11 mutations was greater than that in patients without mutations in NS-related genes. Malaquias et al [ 22 ] reported that patients without PTPN11 mutations showed a poor response to rhGH therapy compared to patients with PTPN11 mutations. Other studies have reported that the response to rhGH therapy was not significantly different according to genotype [ 15 , 22 , 23 ].…”

“…Malaquias et al [ 22 ] reported that patients without PTPN11 mutations showed a poor response to rhGH therapy compared to patients with PTPN11 mutations. Other studies have reported that the response to rhGH therapy was not significantly different according to genotype [ 15 , 22 , 23 ]. A prospective study of children with NS reported that there were no significant differences in height SDS or growth velocity between patients with and without PTPN11 mutations [ 15 ].…”

Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome

“…Many of these studies involved small numbers of patients and variations in duration of treatment, age at start of treatment, and definitions of NAH. For those studies of patients with NS who achieved adult or NAH after at least 5 years of GH with doses at or above 0.3 mg/kg/week, based on national growth references, the change in HSDS ranged from 1.3 to 1.7 [17, 18, 20, 22, 23]. A recent randomized, double-blind, multi-centre trial investigating the effect of dose on the growth-promoting effect of GH in pre-pubertal children with NS demonstrated a significant improvement in height gain with a dose of 66 versus 33 μg/kg/day [24].…”

“…Considering the inherent risk for the development of malignancies in NS patients, it is pertinent that there are only 4 published clinical reports of brain tumours being diagnosed in patients with NS treated with GH [26]. Although there does not appear to be an increased risk for the development or progression of scoliosis or hypertrophic obstructive cardiomyopathy in individuals with NS treated with GH [11, 20, 22], it has not been systematically studied. Thus, continued surveillance is necessary.…”