Results from this 4-year analysis of GH therapy of NS subjects from the ANSWER Program registry demonstrate an increase in HSDS over the course of treatment. The mean HSDS (n = 120) at start of treatment was –2.6. By the end of 3 years of GH therapy, mean HSDS had increased to –1.66 (n = 31), and by the end of 4 years to –1.32 (n = 17). This increase in mean HSDS is similar to data from a clinical trial conducted by MacFarlane et al., in which HSDS (SD) of NS patients (n = 23) increased from –2.7 (0.4) at the start of GH therapy to –1.9 (0.9) following 3 years of treatment . Our findings are consistent with, and perhaps better than, results from the National Cooperative Growth Study (NCGS), which reported an increase in HSDS from –3.3 (0.9) at baseline to –2.4 (1.1) at 3 years and –2.1 (1.2) at 4 years (n = 42) , and to the Pharmacia & Upjohn International Growth Study (KIGS), which reported an increase from –2.9 (0.7) at baseline to approximately –2.3 at 4 years (n = 25) . We also found an increase in HSDS corrected for target height from –2.4 (1.02) at baseline to –1.0 (1.50) at Y4.
Furthermore, for patients for whom longitudinal data were available (n = 7), mean HSDS increased consistently over the 4 years of treatment, indicating that GH therapy of NS patients results in sustained growth over multiple years of treatment. The yearly incremental change in mean HSDS for these patients was 0.19, 0.41, 0.34, and 0.32 for Y1, Y2, Y3, and Y4 respectively. This trend of sustained growth is consistent with a previous registry-based study conducted by Romano et al. In 1996, the group analyzed data of 150 children with NS who were enrolled in the NCGS . For the 42 children in the study who were monitored for at least 4 years of GH therapy, yearly incremental change in mean HSDS was 0.5, 0.2, 0.2, and 0.3 for Y1, Y2, Y3, and Y4 of treatment, respectively, with some patients exceeding their predicted height by the end of treatment..
However, even after 4 years of GH therapy, 29% (5/17) of patients remained short for age and gender (as defined by HSDS < –2 SD). Possible reasons for this could include an innate resistance to GH therapy among some with NS or advanced bone age/chronologic age at treatment start. Without treatment, height in NS follows the 3rd percentile during the first several years of life, and then generally declines further at puberty, with mean final height approximately 2 SDS below normal limits [3, 21].
The mean increase in HSDS was similar for boys and girls in this study, suggesting that gender does not significantly affect the outcome of treatment. This trend differs from previous clinical trial studies in which gender was shown to affect the outcome of GH therapy in patients with NS [6, 16].
In contrast to what was observed in this analysis, previous registry-based studies have assessed the short- and long-term effects of GH therapy in patients with NS and found that the increase in height of NS patients treated with GH therapy is highest after 1 year, but wanes in subsequent years of treatment. In 2001, Kirk et al. conducted an analysis of NS patients involved in the KIGS study . The yearly incremental change in HSDS for these patients waned significantly after 1 year of treatment. Mean HSDS increased by 0.3 over the first year, but further increase was not observed over the next 4 years. A similar trend was observed by Raaijmakers, et al., who analyzed the growth response in 402 NS patients enrolled in the KIGS database who were treated with GH therapy . After 1 year of treatment, mean HSDS increased by 0.54, but the incremental increases were significantly lower (0.13 and 0.13) following years 2 and 3 of GH therapy. Finally, in the clinical trial conducted by MacFarlane et al., ΔHSDS was 0.5 during the first year of treatment, but the yearly incremental increase in mean HSDS dropped to 0.1 and 0.2 for the second and third years of treatment, respectively. It was confirmed in the MacFarlane clinical trial that the lower incremental increase in HSDS for years 2 and 3 of treatment could not be attributed to reduced growth rate caused by non-adherence to therapy . Potential explanations for waning growth may be related to older age at treatment onset, GH sufficiency status, GH dosage, and the presence of other genetic findings specific to NS. The presence of a specific mutation may be a factor in the response to GH treatment, although the type of mutation does not necessarily correlate with the severity of short stature or the patient’s response to GH therapy [16, 22–25]. In the current study, the incremental gain in HSDS among the 7 patients for whom longitudinal data were available was lowest during Year 1. The mean GH dose among these patients increased each year, which may explain, in part, why the incremental gains were higher after Year 1.
The mean (SD) weight determined for the patients enrolled in the ANSWER Program registry increased from 23.9 (9.4) kg at baseline to 44.7 (15.9) kg following 4 years of treatment, whereas body mass index (BMI) remained stable. The small magnitude of the change in BMI suggests that increases in weight were proportional to increases in height, indicating that GH therapy for NS patients did not significantly impact body composition in ways unrelated to linear growth. Although the number of children with post-baseline IGF-1 SDS data was limited, analysis of the available data showed that mean (SD) IGF-1 SDS increased. Previous studies have indicated a positive linear relationship between the change in IGF-1 and ΔHSDS for patients undergoing GH treatment .
In addition to sustained growth over the course of GH treatment, and a positive correlation between ΔHSDS at Year 1 and ΔHSDS at Years 2 and 3, analysis of data from boys and girls in the ANSWER Program registry also showed that a negative correlation exists between the age at the start of treatment and ΔHSDS (Figure 2). That is, ΔHSDS decreased as age at initiation of treatment increased. In an analysis using age 11 as a cutoff for younger versus older age, boys who began treatment before the age of 11 years showed a mean ΔHSDS of 0.53 after 1 year of treatment and 0.94 after 2 years (Table 2). On the other hand, when treatment was initiated for boys at an age greater than 11 years, mean ΔHSDS was only 0.24 after 1 year (P = 0.046) and 0.47 after 2 years (P = 0.0284). The same trend was observed for girls in this study, although differences were not statistically significant. Although the age cut-offs of 11 years for boys and 10 years for girls did correspond to baseline pubertal stage (ie, all patients in the younger age groups were pre-pubertal), the relative contribution of the accelerated growth rate during the pubertal growth spurt is unclear. A similar pattern was observed by Romano et al. in data from the NCGS , which showed that greater near adult height (NAH) for NS patients was associated with earlier initiation and longer duration of GH therapy.
These results emphasize the importance of early diagnosis and initiation of therapy for optimal height outcomes. However, diagnosing NS is a difficult task, even for many specialists, due to the fact that it is primarily based on clinical features. Therefore, the Noonan Syndrome Support Group recently coordinated a conference comprised of professionals with extensive knowledge of various aspects of the disease to develop guidelines for the diagnosis and management of the disorder . These guidelines provide pediatricians and other healthcare professionals with a comprehensive description of genetic factors associated with NS and key clinical features of the disorder.
One limitation of the current study is the lack of data regarding the underlying genetic defect, particularly the presence or absence of the PTPN11 mutation, responsible for causing NS in these patients. Nonetheless, this analysis provides valuable information, such as expectations for treatment outcomes and the potential to optimize growth by initiating GH treatment early, which can help to guide clinicians who treat patients with NS.
In conclusion, this analysis of the ANSWER Program registry shows that continued increase in HSDS after 4 years of treatment with GH could be achieved in GH-naïve subjects with NS, with no significant differences in treatment outcome between genders at years 1 and 2. The data also show that baseline age was negatively corty related with ΔHSDS following 1 and 2 years of treatment. Whether longer-term therapy will have a beneficial effect on adult height remains to be investigated.