Recombinant human growth hormone (rhGH) has been used to improve growth in children with Noonan syndrome (NS). This study aimed to investigate the efficacy of rhGH therapy in Korean children with NS.
Seventeen prepubertal children (10 boys, 7 girls) with NS who received rhGH therapy for at least 3 years between 2008 and 2017 were included. To compare the response, age- and sex-matched children with GH deficiency (GHD; n=31) were included. Height and growth velocity before and during treatment were analyzed.
The mean age of NS patients was 6.34±2.32 years. After treatment, the height standard deviation score (SDS) increased from -2.93±0.81 to -1.51±1.00 in patients with NS and from -2.45±0.42 to -1.09±0.47 in patients with GHD. There were no significant differences in growth velocity or change in height SDS between patients with NS and GHD. Growth velocity in the first year of treatment was higher in patients with
rhGH therapy can increase linear growth in prepubertal children with NS. The growth response between patients with NS and patients with GHD was not significantly different. Furthermore, we observed that lower doses of growth hormone have a similar effect on height compared to previous studies in patients with NS. Our study indicates that rhGH treatment is useful for growth promotion.
Noonan syndrome (NS) is a normal karyotype genetic disorder characterized by distinctive facial features, postnatal short stature, and cardiac anomalies. NS is observed in 1 per 1,000 to 2,500 live births, with males and females equally affected [
Short stature is a common manifestation of NS. The mean height of patients with NS is reported to be more than 2 standard deviations (SDs) below that of the normal population, with the average adult height being 162.5 cm in men and 152.7 cm in women [
In this study, we aimed to compare the effects of rhGH therapy in Korean children with NS to those in children with GH deficiency (GHD).
We retrospectively reviewed the data of 33 patients who were diagnosed with NS at Ajou University Hospital between March 2008 and May 2017. Among the 33 patients, we enrolled 17 prepubertal patients who received rhGH therapy for at least 3 years. Patients were clinically diagnosed with NS based on van der Burgt scores [
To compare the response to rhGH therapy, patients with GHD who were matched by age and sex were recruited as the control group. A total of 31 GHD patients with height below the third percentile and delayed bone age were enrolled. Patients with GHD had a GH peak <10 ng/mL on provocation with a combination of at least 2 stimulants. All patients with GHD received rhGH at 0.7 IU/kg (initial mean dose, 32.9±3.2 μg/kg/day) for 6 days per week.
rhGH was administered subcutaneously at a dose of 1 IU/kg (initial mean dose, 47.3±9.3 μg/kg/day) for 6 days per week in patients with NS. Patients' height, weight, bone age, insulin-like growth factor-1 (IGF-1) level, pubertal status, and thyroid function were collected from medical records at the time of evaluation and every 6 months. The IGF-1 SDS for age and sex was calculated according to normal IGF-1 levels for age and sex [
Of the 17 NS patients, 7 underwent GH stimulation tests. Dopamine (Sinemet; 10-mg carbidopa/100-mg levodopa; 150–175 mg/m2) or insulin (0.05 IU/kg) was administered at time 0. Blood was collected before testing (0 minutes) to obtain the baseline level and at 30-minute intervals for 2 hours after administration of the test. Serum GH (BioSource, Nivelles, Belgium) and IGF-1 (Biocode, Hycel, Liége, Belgium) levels were measured using immunoradiometric assays.
Results are reported as mean±SD unless otherwise noted. To assess differences between groups, an independent
The baseline characteristics of patients with NS and GHD are shown in
There were no significant differences in age or height SDS between the 2 groups, but the rhGH dose was significantly higher in patients with NS than in those with GHD (
The height SDS in patients with NS was -2.11±1.00 after 1 year of treatment, -1.74±1.06 after 2 years of treatment, and -1.51±1.00 after 3 years of treatment (
The height SDS in patients with GHD significantly increased from -2.45±0.42 to -1.64±0.47, to -1.34±0.45, and to -1.09±0.47 at the first, second, and third years of treatment, respectively (
During rhGH therapy, no patients in either group showed significant adverse effects such as glucose intolerance, tumor development, or thyroid dysfunction.
In the patients with NS, mutations in
In this study, rhGH therapy in patients with NS increased height SDS during the follow-up period. The response to rhGH therapy was not significantly different between patients with NS and GHD, but the rhGH dose was higher in patients with NS. Moreover, there was no difference in the efficacy of rhGH therapy between NS patients with and without
Numerous studies have reported increased height SDS and growth velocity with rhGH therapy [
Various factors have been reported to affect height gain or final adult height in patients with NS. Age at initiation of rhGH therapy, duration of treatment, genotype, and rhGH dose have been shown to be associated with growth outcome [
Lee et al. [
Our study has a few limitations. The main limitation is the retrospective study design. In addition, the patient population is small and the duration of rhGH therapy is relatively short.
In conclusion, rhGH therapy in prepubertal patients with NS increased height SDS and growth velocity after 3 years of treatment. Furthermore, the response to rhGH therapy was similar between patients with NS and those with GHD. Our study provides evidence that rhGH therapy is helpful in improving growth in these patients and that a lower dose of rhGH than what was previously shown may be effective during the first 3 years of treatment.
The study was approved by the Institutional Review Board (IRB) of Ajou University Hospital (AJIRB-MED-MDB-19-325), and the IRB waived the requirement for written informed consent due to the retrospective study design.
No potential conflict of interest relevant to this article was reported.
Change in height SDS (A) and growth velocity (B) before and after rhGH therapy in children with NS and GHD. SDS, standard deviation score; rhGH, recombinant human growth hormone; NS, Noonan syndrome; GHD, growth hormone deficiency.
Change in height SDS (A) and growth velocity (B) before and after rhGH therapy in the PTPN11 and non-PTPN11 groups. *
Baseline characteristics and comparison of the rhGH responses in patients with NS and GHD
Variable | NS ( |
GHD ( |
|
---|---|---|---|
Age (yr) | 6.34±2.32 | 6.35±1.84 | 0.996 |
Sex, male:female | 10:7 | 22:9 | 0.524 |
Height SDS | -2.93±0.81 | -2.45±0.42 | 0.037 |
Weight SDS | -2.22±1.18 | -1.85± 0.92 | 0.242 |
BMI SDS | -0.40±1.10 | -0.36±1.10 | 0.902 |
IGF-1 SDS | -0.27±1.09 | -0.56±1.06 | 0.371 |
Bone age (yr) | 5.22±1.93 | 4.77±1.60 | 0.416 |
BA–CA | -1.35±0.95 | -1.57±0.64 | 0.417 |
Initial mean GH dose (μg/kg/day) | 47.3±9.3 | 32.9±3.2 | <0.001 |
Values are represented as mean±standard deviation or number.
GH, growth hormone; rhGH, recombinant human GH; NS, Noonan syndrome; GHD, GH deficiency; SDS, standard deviation score; BMI, body mass index; BA–CA, difference between bone age and chronological age.
The proportion of sex was compared using the chi-square test.
Baseline characteristics according to the mutation type for patients with NS
Variable | PTPN11 ( |
Non-PTPN11 |
|
---|---|---|---|
Age (yr) | 5.96±2.02 | 7.07±2.86 | 0.362 |
Sex, male:female | 7: 4 | 3: 3 | 0.643 |
Height SDS | -2.73±0.60 | -3.27±1.07 | 0.201 |
Weight SDS | -1.89±1.39 | -2.54±0.50 | 0.431 |
BMI SDS | -0.27±1.35 | -0.64±0.37 | 0.523 |
IGF-1 SDS | 0.04±0.75 | -0.83±1.45 | 0.211 |
Bone age (yr) | 4.86±1.80 | 6.18±2.19 | 0.254 |
BA–CA | -1.09±0.77 | -2.06±1.15 | 0.080 |
Initial mean GH dose (μg/kg/day) | 50.3±7.8 | 41.7±9.9 | 0.067 |
Values are represented as mean±standard deviation NS, Noonan syndrome; SDS, standard deviation score; BMI, body mass index; IGF-1, insulin-like growth factor-1; BA–CA, difference between bone age and chronological age; GH, growth hormone; non-PTPN11, patients for which PTPN11 mutations were not found.
The non-PTPN11 group included patients for which PTPN11 mutations was not found.
The proportion of sex was compared using chi-square test.