Change In Height SD Score Research Articles

A Digital Health Solution for Child Growth Monitoring at Home: Testing the Accuracy of a Novel “GrowthMonitor” Smartphone Application to Detect Abnormal Height and Body Mass Indices

ObjectiveTo develop and evaluate a smartphone application that accurately measures height and provides notifications when abnormalities are detected. Patients and MethodsA total of 145 (75 boys) participants with a mean age ± SD of 8.7±4.5 years (range, 1.0-17.0 years), from the Children’s Hospital at Barts Health Trust, London, United Kingdom, were enrolled in the study. “GrowthMonitor” (UCL Creatives) iPhone application (GMA) measures height using augmented reality. Using population-based (UK-WHO) references, algorithms calculated height SD score (HSDS), distance from target height (THSDSDEV), and HSDS change over time (ΔHSDS). Pre-established thresholds discriminated normal/abnormal growth. The GMA and a stadiometer (Harpenden; gold standard) measured standing heights of children at routine clinic visits. A subset of parents used GMA to measure their child’s height at home. Outcome targets were 95% of GMA measurements within ±0.5 SDS of the stadiometer and the correct identification of abnormal HSDS, THSDSDEV, and ΔHSDS. ResultsBland-Altman plots revealed no appreciable bias in differences between paired study team GMA and stadiometer height measurements, with a mean of the differences of 0.11 cm with 95% limits of agreement of −2.21 to 2.42 cm. There was no evidence of greater bias occurring for either shorter/younger children or taller/older children. The 2 methods of measurements were highly correlated (R=0.999). GrowthMonitor iPhone application measurements performed by parents in clinic and at home were slightly less accurate. The κ coefficient indicated reliable and consistent agreement of flag alerts for HSDS (κ=0.74) and THSDSDEV (κ=0.88) between 83 paired GMA and stadiometer measurements. GrowthMonitor iPhone application yielded a detection rate of 96% and 97% for HSDS-based and THSDSDEV-based red flags, respectively. Forty-two (18 boys) participants had GMA calculated ΔHSDS using an additional height measurement 6-16 months later, and no abnormal flag alerts were triggered for ΔHSDS values. ConclusionGrowthMonitor iPhone application provides the potential for parents/carers and health care professionals to capture serial height measurements at home and without specialized equipment. Reliable interpretation and flagging of abnormal measurements indicate the potential of this technology to transform childhood growth monitoring.

Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status.

IntroductionMutations in PTPN11 are associated with Noonan syndrome (NS). Although the effectiveness of growth hormone therapy (GHT) in treating short stature due to NS has been previously demonstrated, the effect of PTPN11 mutation status on the long-term outcomes of GHT remains to be elucidated.MethodsThis analysis included pooled data from the observational American Norditropin Studies: Web-Enabled Research Program (NCT01009905) and the randomized, double-blinded GHLIQUID-4020 clinical trial (NCT01927861). Pediatric patients with clinically diagnosed NS and confirmed PTPN11mutation status were eligible for inclusion. The effectiveness analysis included patients who were GHT-naïve and pre-pubertal at GHT start. Growth outcomes and safety were assessed over 4 years of GHT (Norditropin®, Novo Nordisk A/S).ResultsA total of 69 patients were included in the effectiveness analysis (71% PTPN11 positive). The proportion of females was 32.7 and 30.0% in PTPN11-positive and negative patients, respectively, and mean age at GHT start was 6.4 years in both groups. Using general population reference data, after 4 years of GHT, the mean (s.d.) height SD score (HSDS) was −1.9 (1.1) and −1.7 (0.8) for PTPN11-positive and PTPN11-negative patients, respectively, with no statistical difference observed between groups. The mean (s.d.) change in HSDS at 4 years was +1.3 (0.8) in PTPN11-positive patients and +1.5 (0.7) in PTPN11-negative patients (no significant differences between groups). Safety findings were consistent with previous analyses.ConclusionsGHT resulted in improved growth outcomes over 4 years in GHT-naïve, pre-pubertal NS patients, irrespective of PTPN11 mutation status.

Clinical characteristics of short-stature patients with an NPR2 mutation and the therapeutic response to rhGH

CONTEXT The natriuretic peptide receptor 2 gene (NPR2) is a causative gene of idiopathic short stature (ISS) with an incidence rate of 2% to 6%. The clinical characteristics of patients with NPR2 heterozygous mutations are atypical, and data on the efficacy of recombinant human growth hormone (rhGH) treatment in patients with NPR2 mutations are limited. OBJECTIVES This work reports 6 cases with NPR2 mutation and explores the characteristics of patients with an NPR2 mutation and their therapeutic response to rhGH. DESIGN, SETTINGS, AND PATIENTS Six Chinese short-stature patients in our hospital with NPR2 mutations by whole-exome sequencing were included. We also searched all previously published NPR2 mutation cases as of August 10, 2020, and information about their medical history, mutations, and rhGH treatment were recorded and summarized. RESULTS The clinical characteristics of patients with an NPR2 heterozygous mutation mainly included short stature, facial anomalies, and skeletal dysplasia. Skeletal dysplasia mainly included brachydactyly (56.2%), shortened metacarpals or metatarsals (particularly fourth to fifth; 26.1%), and clinodactyly (21.7%). rhGH treatment significantly improved the height SD score (SDS) of patients with NPR2 heterozygous mutations (median, -2.1 vs -2.9, P < .001), especially in girls. The height SDS change correlated negatively with initial age of treatment (r = -0.477; P = .034), and height SDS change of patients with NPR2 heterozygous mutations in the carboxyl-terminal guanylyl cyclase catalytic domain was significantly higher than that of the extracellular ligand-binding region domain (median, 1.9 vs 0.6, P = .019). CONCLUSIONS ISS patients with skeletal deformities should be tested for an NPR2 mutation. rhGH treatment is beneficial for short-stature patients with NPR2 heterozygous mutations and needs further study.

Corroboration of Height Velocity Prediction Markers for rhGH With an Oral GH Secretagogue Treatment in Children With GHD.

ContextRecombinant human growth hormone (rhGH) is approved for treatment of pediatric growth hormone deficiency (GHD), with greatest growth responses observed in those with severe GHD. Orally administered GH secretagogues (GHS) may be useful treatment in patients with moderate GHD. Distinguishing children with severe vs moderate GHD could identify children who would be better treated with rhGH or GHS.ObjectivesEvaluate baseline insulin-like growth factor-I (IGF-I) and stimulated peak GH response as predictors of 12-month height velocity (HV) in children with GHD.DesignData on children with GHD were analyzed in a legacy data base (GeNeSIS data).Participants514 naïve to rhGH-treatment, prepubertal children with idiopathic isolated GHD for whom stimulated GH, baseline serum IGF-I, and first-year HV during rhGH treatment data are available.Outcome MeasuresChildren with severe or moderate GHD were categorized based on GH and IGF-I data and evaluated based on baseline auxologic and hormone profiles and first-year growth response to rhGH.ResultsCohorts of severe and moderate GHD were 81/514 (15.8%) and 433/514 (84.2%). Cohorts differed significantly with regard to indicators of GHD [eg, baseline height SD score (SDS), height SDS minus target height SDS, HV, HV SDS, and change in height SDS during rhGH treatment]. Multiple regression analysis showed IGF-I and stimulated GH were significant predictors of HV independent of other known variables. Expected first-year HV in moderate GHD was 8.3 cm/y.ConclusionsThe combination of peak GH to GH stimulation testing and baseline IGF-I concentration are predictive enrichment markers for annualized HV responses to rhGH therapy.

Monitoring Adherence Rate to Growth Hormone Therapy and Growth Outcomes in Taiwanese Children Using Easypod Connect: Observational Study.

BackgroundAdherence to growth hormone therapy is difficult to detect reliably. Devices such as easypod have been developed for electronic recording of injections. The easypod connect observational study (ECOS) was an open-label, observational, multinational, phase IV study conducted in 24 countries around the world. The final results from ECOS in the Taiwanese cohort are reported in this paper.ObjectiveThis study aimed to evaluate the adherence and long-term outcomes of growth hormone therapy in pediatric subjects using the easypod electromechanical device.MethodsSubjects (aged 2-18 years or >18 years without fusion of growth plates) who received Saizen (recombinant human growth hormone, somatropin) via the easypod device were enrolled in this study. The primary objective was to assess the level of adherence in subjects receiving Saizen via easypod.ResultsIn Taiwan, a total of 35 and 13 children fulfilled the criteria of full analysis set and complete analysis set, respectively. The mean (SD) age of the complete analysis set was 12.08 (2.72) years. All subjects were growth hormone–naïve, with 38% (5/13) females. The mean adherence rates of 13 subjects were 87.6% at 3 months and 84.3% at 6 months, that of 8 subjects was 81.0% at 9 months, and that of 4 subjects was 91.6% at 1 year. After 1 year of treatment, subjects had a median (Q1:Q3) change in height SD score of 0.30 (0.06:0.48), median height velocity of 6.50 (4.33:8.24) cm/year, and median change in height velocity SD score of 1.81 (–0.04:3.52).ConclusionsWith the easypod device, patients with inadequate adherence and poor response to treatment can be identified. Adherence to growth hormone therapy administered via easypod was generally high in the first year of treatment but the adherence gradually decreased over time. Overall, growth outcomes after 1 year indicated a positive growth response to growth hormone treatment. Future efforts should be focused on personalized management of adherence by using the easypod system.

Delayed Bone Age Might Accelerate the Response to Human Growth Hormone Treatment in Small for Gestational Age Children with Short Stature.

Purpose Growth hormone (GH) treatment is recommended to improve growth and psychosocial problems in short stature children born small for gestational age (SGA). Although GH therapy in these patients has been extensively studied, the impact of therapy according to delays in bone age (BA) is not known well. Objective To investigate the effects of GH therapy in SGA patients with short stature according to BA delay. Methods We retrospectively analyzed changes in height SD score (SDS) and BA/chronological age (CA) after 6 and 12 months of GH therapy in patients grouped according to BA delay. We studied 27 SGA children with short stature in the pediatric endocrinology clinic of Kyungpook National University Children's Hospital. Results Of the 27 patients, 9 had <2 years of BA delay, while 18 had >2 years of delay. There were no significant differences between the two groups in terms of gestational age and weight at birth, height SDS, IGF-1 SDS, and growth hormone dosage at the beginning of therapy. However, height SDS increased significantly in the group with >2 years of BA delay after 6 months of GH therapy (−2.50 ± 0.61 vs −1.87 ± 0.82; p=0.037) and 12 months (−2.27 ± 0.70 vs −1.63 ± 0.65; p=0.002). When height SDS was compared between with and without GHD, there were no significant differences. Conclusions Delayed BA (>2 years) may impact the response to GH treatment in SGA children with short stature.

Efficacy and Safety of Gonadotropin-Releasing Hormone Agonist Treatment to Suppress Puberty in Gender Dysphoric Adolescents

IntroductionPuberty suppression using gonadotropin-releasing hormone agonists (GnRHas) is recommended by current guidelines as the treatment of choice for gender dysphoric adolescents. Although GnRHas have long been used to treat precocious puberty, there are few data on the efficacy and safety in gender dysphoric adolescents. Therefore, the Endocrine Society guideline recommends frequent monitoring of gonadotropins, sex steroids, and renal and liver function. AimTo evaluate the efficacy and safety of GnRHa treatment to suppress puberty in gender dysphoric adolescents. MethodsForty-nine male-to-female and 67 female-to-male gender dysphoric adolescents treated with triptorelin were included in the analysis. Main Outcome MeasuresPhysical examination, including assessment of Tanner stage, took place every 3 months and blood samples were drawn at 0, 3, and 6 months and then every 6 months. Body composition was evaluated using dual energy x-ray absorptiometry. ResultsGnRHa treatment caused a decrease in testicular volume in 43 of 49 male-to-female subjects. In one of four female-to-male subjects who presented at Tanner breast stage 2, breast development completely regressed. Gonadotropins and sex steroid levels were suppressed within 3 months. Treatment did not have to be adjusted because of insufficient suppression in any subject. No sustained abnormalities of liver enzymes or creatinine were encountered. Alkaline phosphatase decreased, probably related to a slower growth velocity, because height SD score decreased in boys and girls. Lean body mass percentage significantly decreased during the first year of treatment in girls and boys, whereas fat percentage significantly increased. ConclusionTriptorelin effectively suppresses puberty in gender dysphoric adolescents. These data suggest routine monitoring of gonadotropins, sex steroids, creatinine, and liver function is not necessary during treatment with triptorelin. Further studies should evaluate the extent to which changes in height SD score and body composition that occur during GnRHa treatment can be reversed during subsequent cross-sex hormone treatment.

Growth failure starts from early infancy in children with short stature at age 6

We compared the growth of 183 children with short stature (≤ 2SD) and 73 children of normal height at age six who were visiting the Tanaka Growth Clinic. We classified these short children as suffering from either idiopathic short stature (ISS, n = 119), GH deficiency (GHD, n = 33) or small-for-gestational-age short stature (SGASS, n = 31) on the basis of subsequent test results and other factors. We also conducted a retrospective study of changes in their height, wt and nutritional intake over time. The mean changes in height SD score from birth to 6 yr were –0.24 SD in normal height children with a normal birth length and +2.27 SD in normal height children with a low birth length. In short children, these changes were –1.93 SD for children with ISS, –2.41 SD for those with GHD and +0.58 for those with SGASS. The mean changes from birth to 6 mo were –0.84 SD, −1.03 SD and +0.38 SD in children with ISS, GHD and SGASS, respectively. The mean change in height SD score from birth to age 1 yr was –1.07 SD, –1.44 SD and +0.35 SD, respectively. The decrease in height SD score from birth to 6 mo accounted for 43.5% of the decrease in height SD score from birth to 6 yr in children with ISS and it accounted for 42.6% of the decrease in children with GHD. Only 19% of short children bottle-fed well, and 53% fed poorly, as opposed to 56% and 16% of normal height children who fed well and poorly, respectively. Post weaning, only 22% of short children ate well, and 56% fed poorly, as opposed to 53% and 17% of normal height children who fed well and poorly, respectively. These findings demonstrated that growth failure started from early infancy in ISS and GHD children. It was suggested that poor nutritional intake in infancy and early childhood was a partial cause of short stature at age 6.

Therapeutic Efficacy and Safety of GH in Japanese Children with Down Syndrome Short Stature Accompanied by GH Deficiency.

In this study, we investigated the effects of GH treatment in children with Down syndrome who had been diagnosed with GH deficiency (GHD). A total of 20 subjects were investigated in this study. Fourteen Down syndrome children (5 boys and 9 girls) with short stature due to GHD were treated with GH at Okayama Red Cross General Hospital, and 6 Down syndrome children (4 boys and 2 girls) with short stature due to GHD were registered in the Pfizer International Growth Database (KIGS). Height SD score (SDS) increased throughout the three-year GH treatment period. The overall mean height SDS increased from -3.5 at baseline to -2.5 after 3 yr of treatment. The mean change in height SDS during these 3 yr was 1.1. In addition, height assessment of SD score based on Down syndrome-specific growth data in the Japanese population revealed that the height SDS (Down syndrome) also increased across the 3-yr GH treatment period. The mean change in height SDS (Down syndrome) during these three years was 1.3. GH therapy was effective for Down syndrome short stature accompanied by GHD, and no new safety concerns were found in this study.

P.11.15 Recombinant human insulin-like growth factor-I (IGF-I) therapy in Duchenne Muscular Dystrophy (DMD): A 6-month prospective randomized controlled trial

Glucocorticoids (GC) delay motor decline in DMD, but cause significant endocrine adverse effects. IGF-I offers potential as a therapeutic agent; it may improve or preserve muscle function and counter GC effects of growth failure and insulin resistance. To determine if IGF-I therapy (1) improves or preserves muscle function and (2) improves linear growth in DMD. Prospective randomized controlled trial of IGF-I therapy in pre-pubertal, ambulatory, GC-treated DMD boys (n = 17) compared to controls (GC alone, n = 21). IGF-I 160 mcg/kg was given daily subcutaneously for 6 months. Primary motor outcome was 6-min walk distance (6MWD), and endocrine outcomes were height velocity and change in height SD score (ΔHtSDS). Other outcomes included changes in timed motor tests, cardiopulmonary function, insulin sensitivity and safety. The difference of 6MWD between control and IGF-I groups at 6 months was 8.5 ± 7.0 m (mean ± SEM, p > 0.5). There were no significant differences between groups for changes in cardiopulmonary and other motor functional outcomes. Height velocity in IGF-I treated subjects was double that of controls at 6 months (6.5 ± 0.4 vs. 3.3 ± 0.3 cm/yr, p In this first study of IGF-I therapy in DMD boys, 6 months of daily IGF-I significantly increased height velocity and HtSDS compared to controls, but there was no difference in motor functional outcomes.

Effects of Recombinant Human Growth Hormone for 1 Year on Body Composition and Muscle Strength in Children on Long-Term Steroid Therapy: Randomized Controlled, Delayed-Start Study

Recombinant human GH (rhGH) improves growth and body composition in glucocorticoid-treated children. Its effects on muscle strength are poorly evaluated. Our objective was to evaluate rhGH effects on muscle strength in children receiving long-term glucocorticoid therapy; effects on height SD score (SDS) and body composition were assessed also. A randomized, controlled, delayed-start study of rhGH for 12 months was started after randomization (baseline) or 6 months later (M6). Patients included 30 children with various diagnoses. rhGH was administered at 0.065 mg/kg/d for 6 months and then in the dosage maintaining serum IGF-I levels below +2 SDS for chronological age. The primary criterion was the between-group difference in composite index of muscle strength (CIMS) change at M6. Secondary criteria included between-group differences in CIMS SDS(height), lean mass (LM), thigh muscle area (MA), and height SDS changes at M6; these parameters were also assessed in the overall population after 1 year of rhGH therapy. At M6, rhGH therapy did not significantly affect changes in CIMS or CIMS SDS(height) (+17.6% vs +7.5% and +0.14 ± 0.38 vs +0.11 ± 0.62, respectively); the rhGH-treated group had significantly larger changes in height SDS (+0.2 [0.3] vs -0.2 [0.3]; P = 0.003), LM (+7.3% [+3.7%; +21.6%] vs 0% [-4.7%; +3.2%]; P = 0.002), and MA (+8.8% [+5%; +15.6%] vs. -0.6% [-6.3%; +7.7%]; P = 0.01) compared with the untreated group. After 1 year of rhGH, height SDS, LM, and MA increased significantly, CIMS increased by 24.7% (+5.8%; +34.2%), and CIMS SDS(height) remained within the normal range. rhGH increased height, LM, and MA. However, muscle strength did not improve significantly.

Therapeutic Efficacy and Safety of GH in Japanese Children with Down Syndrome Short Stature Accompanied by GH Deficiency

In this study, we investigated the effects of GH treatment in children with Down syndrome who had been diagnosed with GH deficiency (GHD). A total of 20 subjects were investigated in this study. Fourteen Down syndrome children (5 boys and 9 girls) with short stature due to GHD were treated with GH at Okayama Red Cross General Hospital, and 6 Down syndrome children (4 boys and 2 girls) with short stature due to GHD were registered in the Pfizer International Growth Database (KIGS). Height SD score (SDS) increased throughout the three-year GH treatment period. The overall mean height SDS increased from –3.5 at baseline to –2.5 after 3 yr of treatment. The mean change in height SDS during these 3 yr was 1.1. In addition, height assessment of SD score based on Down syndrome-specific growth data in the Japanese population revealed that the height SDS (Down syndrome) also increased across the 3-yr GH treatment period. The mean change in height SDS (Down syndrome) during these three years was 1.3. GH therapy was effective for Down syndrome short stature accompanied by GHD, and no new safety concerns were found in this study.

Variable Degree of Growth Hormone (GH) and Insulin-Like Growth Factor (IGF) Sensitivity in Children with Idiopathic Short Stature Compared with GH-Deficient Patients: Evidence from an IGF-Based Dosing Study of Short Children

We recently showed that, in IGF-based GH therapy, the IGF-I target chosen affects GH dose requirements, and higher IGF-I targets are associated with more robust growth parameters. The objective of the study was to compare the response of GH-deficient (GHD) vs. idiopathic short-stature (ISS) children to IGF-based GH therapy. This was a 2-yr, open-label, randomized trial. The setting was multicenter and outpatient. Prepubertal short children [height sd score (SDS) < -2] with low IGF-I levels (<or=-1 SDS), subclassified based on the peak stimulated serum GH concentration at baseline, into two subgroups: GHD (n = 63, GH < 7 ng/ml) and ISS (n = 102, GH >or= 7 ng/ml). Patients were randomized 2:2:1 to three treatment groups: IGF-I target of 0 SDS (IGF0T), 2 SDS (IGF2T), or a conventional weight-based GH dosing of 40 microg/kg x d (Conv). Change in (Delta) height SDS, IGF-I SDS, and GH dose was measured. ISS subjects required higher GH doses than GHD patients in the IGF2T (but not IGF0T) arm (medians 119 and 65 microg/kg x d, respectively), indicating that ISS represents a partial GH-insensitive state that manifests during treatment with higher doses of GH. GHD children grew more than those with ISS in both IGF-targeted dosage groups despite similar IGF-I levels (suggesting a degree of IGF insensitivity in ISS subjects): Delta height SDS of 2.04 +/- 0.17 for GHD and 1.33 +/- 0.09 for ISS groups in IGF2T, 1.41 +/- 0.13 for children with GHD, and 0.84 +/- 0.07 for those with ISS in IGF0T. IGF-based GH dosing is clinically feasible in both GHD and ISS patients, although GH dose requirements and auxological outcomes are distinct between these groups. This suggests a degree of both GH and IGF insensitivity in subjects with ISS that requires specific management strategies to optimize growth during GH therapy.

Effectiveness of the Combined Recombinant Human Growth Hormone and Gonadotropin-Releasing Hormone Analog Therapy in Pubertal Patients with Short Stature due toSHOXDeficiency

Isolated heterozygous SHOX defects are the most frequent monogenic cause of short stature, and combined therapy with recombinant human GH (rhGH) and GnRH analog (GnRHa) in pubertal patients has been suggested, but there are no data on final height. The aim of the study was to analyze adult height after rhGH and GnRHa therapy in patients with SHOX haploinsufficiency. Ten peripubertal patients with isolated SHOX defects participated in the study. Five patients were followed without treatment, and five were treated with rhGH (50 mug/kg/d) and depot leuprolide acetate (3.75 mg/month). Adult height sd score (SDS) was measured. All patients followed without treatment had marked downward growth shift during puberty (height SDS, -1.2 +/- 0.7 at 11.4 +/- 1.4 yr; adult height SDS, -2.5 +/- 0.5). Conversely, four of five patients treated with rhGH for 2 to 4.9 yr associated to GnRHa for 1.4 to 5.8 yr improved their height SDS from -2.3 +/- 1.3 at 11.8 +/- 2.1 yr to a final height SDS of -1.7 +/- 1.6. The difference between the mean height SDS at the first evaluation and final height SDS was statistically significant in nontreated vs. treated patients (mean height SDS change, -1.2 +/- 0.4 vs. 0.6 +/- 0.4, respectively; P <0.001). A gain in adult height of patients with isolated SHOX defects treated with combined rhGH and GnRHa therapy was demonstrated for the first time, supporting this treatment for children with SHOX defects who have just started puberty to avoid the loss of growth potential observed in these patients during puberty.

Bone Mineral Density and Body Composition in Adolescents with Childhood-Onset Growth Hormone Deficiency

Background/Aims: The aim of the present study was to evaluate bone mineral density (BMD) and body composition of patients with childhood-onset growth hormone (GH) deficiency (GHD) treated with GH during the transition period. Methods: BMD and body composition, measured by dual-energy X-ray absorptiometry, were evaluated at final height and yearly thereafter during 2 years. Twenty-nine of the 40 patients had also been measured before start and during GH therapy. Results: Mean lumbar spine BMD and bone mineral apparent density (BMAD) as well as total body BMD and lean body mass (LBM) SD score (SDS) were significantly lower than normal at final height and during the 2 years thereafter for all patients. Final-height SDS was related to the change in height SDS as well as in LBM SDS during the first year of GH treatment. LBM SDS decreased significantly in the group of patients with GHD without GH treatment (p < 0.01, n = 19). Fat mass SDS increased in all patients. Conclusion: Mean BMD, BMAD and LBM SDS were significantly lower than normal in adolescents with childhood-onset GHD at and 2 years after the attainment of final height.

Growth Response, Near-Adult Height, and Patterns of Growth and Puberty in Patients with Noonan Syndrome Treated with Growth Hormone

Noonan syndrome (NS) is a heterogeneous genetic disorder characterized by short stature. The National Cooperative Growth Study (NCGS), a postmarketing observational study of recombinant human GH (rhGH)-treated children, includes a large cohort of children with NS. We studied NCGS-enrolled prepubertal and pubertal children with NS. Baseline characteristics and growth responses in NS patients with reported near-adult height (NAH) (n = 65) were compared to patients with idiopathic GH deficiency (n = 3007) and Turner syndrome (TS; n = 1378) with reported NAH to identify factors contributing to NAH optimization in NS. NS patients (mean enrollment age, 11.6 yr) received rhGH (mean, 0.33 mg/kg . wk) for a mean of 5.6 yr. No significant difference was observed in Delta height sd score (SDS) between NS (+1.4 +/- 0.7) and TS (+1.2 +/- 0.9). However, Delta height SDS for NS and TS differed significantly from idiopathic GH deficiency (+1.7 +/- 1.0) (P < 0.0001). Mean gain in NAH above projected was 10.9 +/- 4.9 cm (males) and 9.2 +/- 4.0 cm (females). Duration of prepubertal rhGH was an important contributor to prepubertal change in height SDS (r(2) = 0.97). Height SDS at pubertal onset highly correlated with NAH SDS (rho = 0.783; P < 0.0001). Duration of puberty highly correlated with pubertal height gain in centimeters for males (rho = 0.941) and females (rho = 0.882) (P < 0.01). No new adverse events were observed. rhGH significantly improved height SDS for children with NS at NAH. Duration of prepubertal rhGH and height SDS at puberty were important contributors to NAH. Because starting age of the patients in this report was 11.6 yr, these data suggest that greater growth optimization is possible with earlier initiation of therapy.

Recombinant human growth hormone for children born small for gestational age: Meta-analysis confirms the consistent dose-effect relationship on catch-up growth

The optimal treatment regimen of recombinant human GH (r-hGH) for short children born small for gestational age (SGA) is still under discussion. A meta-analysis was performed of existing clinical trials that investigated the treatment of r-hGH in short children diagnosed SGA or with intrauterine growth retardation to determine the relationship between the daily r-hGH dose (placebo/no treatment; 0.033 mg/kg/day; 0.067 mg/kg/day) and the effect on growth [change in height-SD score (SDS) for chronological age]. A mathematical model describing the dose-response relationship was produced, and growth response (gain in height-SDS) to 2 yr of r-hGH 0.033 mg/kg/day [somatropin (rDNA origin) for injection; Serono] was estimated and compared with the response to other r-hGH formulations. The relationship between r-hGH dose and 2-yr growth response was described by an equation. The equation yielded a mean difference in height- SDS gain of 0.48 (0.35) between r-hGH 0.033 and 0.067 mg/kg/day in favor of the higher dose. The height-SDS gain after 2 yr of Serono r-hGH formulation, 0.033 mg/kg/day was estimated as 1.2. Comparison of this estimate to the growth response to 2-yr treatment at 0.033 mg/kg/day of other r-hGH formulations (mean difference in height-SDS 0.05, lower limit of the 95% confidence interval=-0.15) confirmed that growth response to Serono r-hGH formulation 0.033 mg/kg/day is an inferred response estimated to be within the range of observed responses to a (non-Serono formulation) r-hGH dose of 0.033 mg/kg/day. There is a clear dose-response relationship for r-hGH in the treatment of short children born SGA and the analysis confirmed that treatment with Serono r-hGH formulation 0.033 mg/kg/day should provide a meaningful therapeutic response.

The Endocrine Phenotype in Silver-Russell Syndrome Is Defined by the Underlying Epigenetic Alteration

Around 50% of children with Silver-Russell syndrome (SRS) carry a hypomethylation of the imprinting control region 1 at the IGF2/H19 locus on 11p15, the functional significance of which is unknown. We aimed to compare the genotype in SRS with the endocrine phenotype. The retrospective study included all SRS children who were treated during the last 18 yr at our hospital and for comparison a cohort of GH treated nonsyndromic short children born small for gestational age (SGA). The 61 patients with SRS included were defined by the presence of intrauterine growth retardation, lack of catch-up growth, and at least two of the criteria: typical face, relative macrocephaly, and skeletal asymmetry. Routine karyotype and GH secretion was normal in all children studied. A subgroup of 53 patients was treated with GH. Genomic DNA was available from 44 children. Multiplex ligation probe-dependent amplification analysis was performed to detect hypomethylation at the imprinting control region 1 on 11p15. Uniparental disomy of chromosome 7 (UPD7) was analyzed by short tandem repeats typing. Serum levels of GH, IGF-I, and IGF-binding protein (IGFBP)-3 were measured by RIA. Epimutations at 11p15 were found in 19 of 44, UPD7 in five of 44, and small structural aberrations of the short arm of chromosome 11 in two of 44 children. Of 44 cases, 18 were negative for any genetic defect known (41%). The most severe phenotype was found in children with 11p15-SRS. Children with UPD7-SRS had a significantly higher birth length (P < 0.004) but lost height sd score (SDS) postpartum, whereas children with 11p15-SRS showed no change in height SDS. IGF-I and IGFBP-3 serum levels were inadequately high in 11p15-SRS at -0.02 SDS (1.07, sd) and +1.38 SDS (1.01), compared with the low levels in UPD7-SRS and in the cohort of 58 nonsyndromic SGA children (P < 0.0009). During GH therapy, IGFBP-3 serum levels increased above normal values in 11p15-SRS (P < 10(-4)), whereas IGF-I increase was moderate. There was a trend toward more height gain in children with UPD7 than in those with 11p15 epimutation under GH therapy (+2.5 vs. +1.9 height SDS after 3 yr) (P = 0.08). Children with SRS and an 11p15 epimutation have IGFBP-3 excess and show endocrine characteristics suggesting IGF-I insensitivity, whereas children with SRS and UPD7 were not different from nonsyndromic short children born SGA. This phenotype-genotype correlation implicates divergent endocrine mechanisms of growth failure in SRS.

Growth Hormone Treatment of Early Growth Failure in Toddlers with Turner Syndrome: A Randomized, Controlled, Multicenter Trial

Typically, growth failure in Turner syndrome (TS) begins prenatally, and height sd score (SDS) declines progressively from birth. This study aimed to determine whether GH treatment initiated before 4 yr of age in girls with TS could prevent subsequent growth failure. Secondary objectives were to identify factors associated with treatment response, to determine whether outcome could be predicted by a regression model using these factors, and to assess the safety of GH treatment in this young cohort. This study was a prospective, randomized, controlled, open-label, multicenter clinical trial (Toddler Turner Study, August 1999 to August 2003). The study was conducted at 11 U.S. pediatric endocrine centers. Eighty-eight girls with TS, aged 9 months to 4 yr, were enrolled. Interventions comprised recombinant GH (50 mug/kg.d; n = 45) or no treatment (n = 43) for 2 yr. The main outcome measure was baseline-to-2-yr change in height SDS. Short stature was evident at baseline (mean length/height SDS = -1.6 +/- 1.0 at mean age 24.0 +/- 12.1 months). Mean height SDS increased in the GH group from -1.4 +/- 1.0 to -0.3 +/- 1.1 (1.1 SDS gain), whereas it decreased in the control group from -1.8 +/- 1.1 to -2.2 +/- 1.2 (0.5 SDS decline), resulting in a 2-yr between-group difference of 1.6 +/- 0.6 SDS (P < 0.0001). The baseline variable that correlated most strongly with 2-yr height gain was the difference between mid-parental height SDS and subjects' height SDS (r = 0.32; P = 0.04). Although attained height SDS at 2 yr could be predicted with good accuracy using baseline variables alone (R(2) = 0.81; P < 0.0001), prediction of 2-yr change in height SDS required inclusion of initial treatment response data (4-month or 1-yr height velocity) in the model (R(2) = 0.54; P < 0.0001). No new or unexpected safety signals associated with GH treatment were detected. Early GH treatment can correct growth failure and normalize height in infants and toddlers with TS.

Insulin Growth Factor-Based Dosing of Growth Hormone Therapy in Children: A Randomized, Controlled Study

Weight-based dosing of GH is the standard of care for short children, although IGF-I is thought to be the main mediator of GH actions on growth. The objective of the study was to test whether IGF-I levels achieved during GH therapy are determinants of the growth responses to GH treatment. This was a 2-yr, open-label, randomized, IGF-I concentration-controlled trial. Prepubertal short children [n = 172, mean age 7.53 yr, mean height sd score (HT-SDS) -2.64] with low IGF-I levels (mean IGF-I SDS -3.56) were randomized to receive one of two GH dose-titration arms in which GH dosage was titrated to achieve an IGF-I SDS at the mean [IGF((low)) group, n = 70] or the upper limit of the normal range [+2 SDS, IGF((high)) group, n = 68] or to a comparison group of conventional GH dose of 40 microg/kg/d (n = 34). The study was conducted in a multicenter, outpatient setting. Change in HT-SDS over 2 yr was measured. One hundred forty-seven patients completed the trial. Target IGF-I levels were achieved in the dose-titration arms within 6-9 months. The changes in HT-SDS were +1.0, +1.1, and +1.6 for conventional, IGF((low)), and IGF((high)), respectively, with IGF((high)) showing significantly greater linear growth response (P < 0.001, compared with the other two groups). The IGF((high)) arm required higher doses (>2.5 times) than the IGF((low)) arm, and these GH doses were highly variable (20-346 microg/kg/d). Multivariate analyses suggested that the rise in the IGF-I SDS significantly impacted height outcome along with the GH dose and the pretreatment peak-stimulated GH level. IGF-I-based GH dosing is clinically feasible and allows maintaining serum IGF-I concentrations within the desired target range. Titrating the GH dose to achieve higher IGF-I targets results in improved growth responses, although at higher average GH doses.