Effectiveness of the triptorelin stimulation test compared with the classic gonadotropin-releasing hormone stimulation test in diagnosing central precocious puberty in girls.

PURPOSE: The gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard for diagnosing central precocious puberty (CPP). Gonadorelin (Relefact) is used for the test but is not always readily available; triptorelin is used as an alternative. The purpose of this study was to evaluate the diagnostic validity of the triptorelin test compared with the GnRH test in the diagnosis of CPP in girls. METHODS: This retrospective study included 100 girls with premature thelarche (PT) who underwent a hypothalamic-pituitary-gonadal axis evaluation. In the overall group, 50 girls were tested with intravenous gonadorelin (Relefact) and 50 girls were tested with subcutaneous triptorelin acetate (Decapeptyl). Luteinizing hormone (LH) and follicle-stimulating hormone levels were measured at baseline and 30, 45, 60, and 90 minutes after gonadorelin injection or 30, 60, 90, and 120 minutes after triptorelin injection. RESULTS: Clinical characteristics of age, height, weight, body mass index, and bone age were similar between the 2 groups. The highest LH level was reached 60 minutes after stimulation in both groups. Approximately 20% of the gonadorelin group and 24% of the triptorelin group were diagnosed with CPP (P=0.52). Among those diagnosed with CPP, the mean peak LH concentrations were 8.15 mIU/mL and 9.73 mIU/mL in the gonadorelin and triptorelin groups, respectively. CONCLUSION: The triptorelin test showed similar trends of LH elevation and diagnostic rate compared with the traditional GnRH test for diagnosing CPP. This suggests that the triptorelin test may be a valid alternative to the GnRH test for differentiating CPP from self-limiting PT. Our study also demonstrated that a triptorelin stimulation test for up to 120 minutes was sufficient to diagnose CPP.

Long-term efficacy of triptorelin 3-month depot in girls with central precocious puberty.

Purpose: Three-month gonadotropin-releasing hormone agonists (GnRHa) are expected to achieve better compliance in patients with central precocious puberty (CPP). However, 1-month depot remains the dominant choice for conventional treatment worldwide. Our study aimed to investigate the long-term efficacy of a 3-month GnRHa for CPP treatment. Methods: In this retrospective study, 69 Korean girls with CPP were prescribed with either triptorelin pamoate (TP) 3-month depot (n = 29) or triptorelin acetate (TA) 1-month depot (n = 40) and were followed up for 1 year after the end of treatment. Auxological, radiological, and biochemical data were collected every 6 months. Results: Baseline characteristics of the subjects were similar between the two groups. In the TP 3-month depot group, 27/29 (93.1 %) of patients exhibited suppressed LH levels (below 2.5 IU/L) after 6 months of treatment, and this suppression level was reserved until the final injection. The degree of bone age advancement in the TP 3-month depot group decreased from 1.8 ± 0.4 years at the start of treatment to 0.6 ± 0.5 years at 1 year post-treatment. The gain in predicted adult height (PAH) at 1 year after the end of treatment was similar between the TP 3-month and TA 1-month depot groups (5.2 ± 3.1 and 5.3 ± 2.4 cm, respectively; P = 0.875). Conclusion: The 3-month depot of triptorelin effectively inhibited gonadal and sex hormones, suppressed bone maturation, and increased PAH. For the patients' convenience, we suggest a 3-month GnRHa regimen as a promising CPP treatment option.

Clinical validation of a deep-learning-based bone age software in healthy Korean children.

PURPOSE: Bone age (BA) is needed to assess developmental status and growth disorders. We evaluated the clinical performance of a deep-learning-based BA software to estimate the chronological age (CA) of healthy Korean children. METHODS: This retrospective study included 371 healthy children (217 boys, 154 girls), aged between 4 and 17 years, who visited the Department of Pediatrics for health check-ups between January 2017 and December 2018. A total of 553 left-hand radiographs from 371 healthy Korean children were evaluated using a commercial deep-learning-based BA software (BoneAge, Vuno, Seoul, Korea). The clinical performance of the deep learning (DL) software was determined using the concordance rate and Bland-Altman analysis via comparison with the CA. RESULTS: A 2-sample t-test (P<0.001) and Fisher exact test (P=0.011) showed a significant difference between the normal CA and the BA estimated by the DL software. There was good correlation between the 2 variables (r=0.96, P<0.001); however, the root mean square error was 15.4 months. With a 12-month cutoff, the concordance rate was 58.8%. The Bland-Altman plot showed that the DL software tended to underestimate the BA compared with the CA, especially in children under the age of 8.3 years. CONCLUSION: The DL-based BA software showed a low concordance rate and a tendency to underestimate the BA in healthy Korean children.

Brain magnetic resonance imaging (MRI) findings in central precocious puberty patients: is routine MRI necessary for newly diagnosed patients?

PURPOSE: The overall incidence of central precocious puberty (CPP) has increased in recent decades, and brain magnetic resonance imaging (MRI) evaluations are recommended in cases of suspected brain lesions. This study aimed to investigate the prevalence of MRI abnormalities and to evaluate the need for routine brain MRI in patients with newly diagnosed CPP. METHODS: This retrospective study reviewed the data of patients newly diagnosed with CPP who underwent routine pituitary MRI at Korea University Anam Hospital from March 2020 to September 2021. A total of 199 girls and 24 boys was enrolled in this study. Positive MRI findings were categorized as abnormal pituitary, nonpituitary incidental, and pathological. In addition, we investigated the incidence of MRI abnormalities and evaluated their associations with clinical and biochemical factors. RESULTS: Positive brain MRI findings were observed in 84 patients (37.7%). Pituitary abnormalities were found in 54 patients (24.2%), with Rathke cleft cysts being the most common (16.1%). Incidental nonpituitary findings were observed in 29 patients (13.0%), while a pathological brain lesion (diagnosed as hypothalamic hamartoma) was observed in only 1 female patient (0.4%). No significant differences in sex or age were found in incidence of pituitary abnormalities or nonpituitary incidental findings. Compared with headache controls, significant associations were observed between abnormal pituitary findings on MRI and CPP (unadjusted odds ratio, 3.979; 95% confidence interval, 1.726-9.173). CONCLUSION: True pathological findings were rare, even though the prevalence of abnormalities on pituitary MRI in patients with CPP was relatively high. Considering its cost-effectiveness, MRI screenings should be carefully considered in patients with CPP.

The association between idiopathic scoliosis and growth hormone treatment in short children.

PURPOSE: Idiopathic scoliosis is the most common form of scoliosis, and the risk of onset and progression has been found to correlate with growth spurts. Therefore, treatment with recombinant human growth hormone (GH) treatment in short children may initiate and/or aggravate scoliosis. The aim of this study was to investigate the relationship between idiopathic scoliosis and GH treatment in short children. METHODS: The medical records of 113 subjects seen at the participating institution between January 2010 and December 2020 and who were diagnosed with GH deficiency and small for gestational age, had idiopathic short stature, and were treated with GH for at least one year were reviewed. Scoliosis was defined as a Cobb angle greater than 10 degrees as assessed using a spine x-ray. Clinical data and laboratory findings before and 12 months after GH treatment were compared. RESULTS: There was significant increase in height, height-standard deviation score, insulin-like growth factor 1, and insulin-like growth factor binding protein 3 (p<0.001) with GH treatment. However, there were no significant differences in the average Cobb angle (6.2°±3.3° vs. 6.1°±3.5°, p=0.842) and the prevalence of scoliosis (9.7% vs. 13.3%, p=0.481) before and after one year of GH treatment. A comparative analysis of both initial Cobb angle and change in Cobb angle during GH treatment showed no relationship with other factors. CONCLUSION: Although GH treatment in short children increased height and growth velocity, it was not associated with development or aggravation of idiopathic scoliosis.

Single Point Insulin Sensitivity Estimator for predicting type 2 diabetes mellitus in obese adolescents.

PURPOSE: The prevalence of adolescents with type 2 diabetes mellitus (T2DM) has rapidly increased in Korea over the past few decades with the increase in the number of obese adolescents. The single point insulin sensitivity estimator (SPISE) was recently introduced as a surrogate marker for insulin sensitivity to predict T2DM in adults. We aimed to determine risk factors for T2DM in obese adolescents, including SPISE. METHODS: This retrospective study included 104 adolescents diagnosed with T2DM at Korea University Hospital between January 2010 and December 2020. We compared clinical and biochemical parameters and the SPISE of normoglycemic overweight and obese individuals with those of prediabetic and diabetic adolescents to determine risk factors for T2DM. Receiver operating characteristic analysis was performed with the Youden index to determine the cutoff point of SPISE. RESULTS: Frequency of fatty liver and family history of T2DM were significantly higher and SPISE level was significantly lower in patients with T2DM than in normoglycemic overweight/obese and prediabetic adolescents (p<0.01). A family history of T2DM, fatty liver, and SPISE value below the cutoff point (4.49) were identified as significant risk factors for T2DM in multiple logistic regression analysis after controlling for age, sex, and body mass index standard deviation score (p<0.01). CONCLUSION: Family history of T2DM, fatty liver, and low SPISE (<4.49) are risk factors that can independently affect the occurrence of T2DM in obese adolescents. Among these risk factors, SPISE is a promising marker for predicting adolescent T2DM; careful monitoring of these individuals is needed to prevent progression to T2DM.

Weight changes of children in 1 year during COVID-19 pandemic.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has changed everyday life. The Korean government urged schools to close as a measure of social distancing, and children and adolescents seemed to gain weight due to home confinement. We aimed to investigate the trends in weight changes in children during the pandemic period. MATERIALS AND METHODS: This retrospective study included 139 children aged between 6 and 12 years who visited the pediatric endocrine clinic for regular growth follow-up for 1 year during the COVID-19 pandemic. We analyzed changes in the body mass index (BMI), BMI z-score, and proportion of children who were overweight or obese over a period of 1 year. RESULTS: The BMI and BMI z-scores of the 139 children increased significantly over the year. The increase was maximum during the first three months of the COVID-19 pandemic, with little change between the third and sixth month of the pandemic. The proportion of children who were overweight or obese increased over time, from 24.5% at the COVID-19 pandemic baseline to 38.1% 1 year later (p < 0.001). CONCLUSIONS: The COVID-19-related lockdown resulted in significant weight gain in Korean children. Changes in BMI showed different trends depending on the degree of school closure. An overall shift from normal weight to overweight or obesity was observed during the pandemic period.

Recombinant growth hormone therapy in children with Turner Syndrome in Korea: a phase III Randomized Trial.

BACKGROUND: Short stature is the most consistent characteristic feature of Turner syndrome (TS). To improve final heights of children with TS effectively, it is important to provide them with early and appropriate treatment using growth hormone (GH). The objective of this study was to assess the efficacy and safety of a new recombinant human GH, Growtropin®-II (DA-3002, Dong-A ST Co., Ltd) versus a comparator (Genotropin®, Pfizer Inc.) for Korean children with TS. METHODS: This open-label, active-controlled, parallel-group, randomized controlled phase III trial was conducted at 11 hospitals in Korea. Eligible patients (n = 58) were randomized to two groups: 1) DA-3002 group (administrated with DA-3002 at 0.14 IU [0.0450-0.050 mg] /kg/day); and 2) comparator group (administrated with the comparator at 0.14 IU [0.0450-0.050 mg] /kg/day). RESULTS: The change from baseline in annualized height velocity (HV) after a 52-week treatment period was 4.15 ± 0.30 cm/year in the DA-3002 group and 4.34 ± 0.29 cm/year in the comparator group. The lower bound of 95% two-sided confidence interval for group difference in the change of annualized HV (- 1.02) satisfied the non-inferiority margin (- 1.5). The change in height standard deviation score (HtSDS) at 52-week was 0.70 ± 0.23 for the DA-3002 group and 0.66 ± 0.39 for the comparator group, showing no significant (p = 0.685) difference between the two groups. The change of skeletal maturity defined as change in bone age/change in chronological age between the two groups was not significantly different (1.25 ± 0.58 for the DA-3002 group and 1.47 ± 0.45 for the comparator group, p = 0.134). Changes from baseline in serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after 52 weeks of treatment did not differ significantly between the two groups (p = 0.565 and p = 0.388, respectively) either. The occurrence of adverse events was not statistically different between groups. CONCLUSIONS: This study demonstrates that the efficacy and safety of GH treatment with DA-3002 in children with TS are comparable with those of the comparator. It is expected to analysis the long-term effect of DA-3002 on the increase of final adult height in children with TS and possible late-onset complications in the future. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov. ClinicalTrials.gov identifier: NCT01813630 (19/03/2013).

Clinical Validation of a Deep Learning-Based Hybrid (Greulich-Pyle and Modified Tanner-Whitehouse) Method for Bone Age Assessment.

OBJECTIVE: To evaluate the accuracy and clinical efficacy of a hybrid Greulich-Pyle (GP) and modified Tanner-Whitehouse (TW) artificial intelligence (AI) model for bone age assessment. MATERIALS AND METHODS: A deep learning-based model was trained on an open dataset of multiple ethnicities. A total of 102 hand radiographs (51 male and 51 female; mean age ± standard deviation = 10.95 ± 2.37 years) from a single institution were selected for external validation. Three human experts performed bone age assessments based on the GP atlas to develop a reference standard. Two study radiologists performed bone age assessments with and without AI model assistance in two separate sessions, for which the reading time was recorded. The performance of the AI software was assessed by comparing the mean absolute difference between the AI-calculated bone age and the reference standard. The reading time was compared between reading with and without AI using a paired t test. Furthermore, the reliability between the two study radiologists' bone age assessments was assessed using intraclass correlation coefficients (ICCs), and the results were compared between reading with and without AI. RESULTS: The bone ages assessed by the experts and the AI model were not significantly different (11.39 ± 2.74 years and 11.35 ± 2.76 years, respectively, p = 0.31). The mean absolute difference was 0.39 years (95% confidence interval, 0.33-0.45 years) between the automated AI assessment and the reference standard. The mean reading time of the two study radiologists was reduced from 54.29 to 35.37 seconds with AI model assistance (p < 0.001). The ICC of the two study radiologists slightly increased with AI model assistance (from 0.945 to 0.990). CONCLUSION: The proposed AI model was accurate for assessing bone age. Furthermore, this model appeared to enhance the clinical efficacy by reducing the reading time and improving the inter-observer reliability.

Efficacy and safety of the recombinant human growth hormone in short children born small for gestational age: A randomized, multicentre, comparative phase III trial.

OBJECTIVE: Growth hormone (GH) treatment is known to be effective in increasing stature in children with a short stature born small for gestational age (SGA). This multicentre, randomized, open-label, comparative, phase III study aimed to evaluate the efficacy and safety of Growtropin-II (recombinant human GH) and to demonstrate that the growth-promoting effect of Growtropin-II is not inferior to that of Genotropin in children with SGA (NCT ID: NCT02770157). METHODS: Seventy five children who met the inclusion criteria were randomized into 3 groups in a ratio of 2:2:1 (the study group [Growtropin-II, n = 30], control group [Genotropin, n = 30], and 26-week non-treatment group [n = 15]). The study and control groups received subcutaneous injections of Growtropin-II and Genotropin, respectively for 52 weeks, whereas the non-treatment group underwent a non-treatment observation period during weeks 0 to 26 and a dosing period during weeks 27 to 52 and additional dosing till week 78 only in re-consenting children. RESULTS: No significant differences in demographic and baseline characteristics between the groups were observed. The mean ± standard deviation change difference in annualized height velocity (aHV) (study group - control group) was 0.65 ±2.12 cm/year (95% confidence interval [CI], -0.53 to 1.83), whereas the lower limit for the 2-sided 95% CI was -0.53 cm/year. Regarding safety, treatment-emergent adverse events (TEAEs) occurred in 53.33% children in the study group and 43.33% children in the control group; the difference in the incidence of TEAEs between the 2 treatment groups was not statistically significant (P  = .4383). A total of 17 serious adverse events (SAEs) occurred in 13.33% children in the treatment groups, and no significant difference in incidence between groups (P  = .7065) was seen. Two cases of adverse drug reaction (ADR) occurred in 2 children (3.33%): 1 ADR (injection site swelling or pain) occurred in 1 child (3.33%) each in the study and control groups. CONCLUSIONS: This study demonstrates that the change in aHV from the baseline till 52 weeks with Growtropin-II treatment is non-inferior to that with Genotropin treatment in children with short stature born SGA. Growtropin-II is well-tolerated, and its safety profile is comparable with that of Genotropin over a 1-year course of treatment.

Efficacy of Triptorelin 3-Month Depot Compared to 1-Month Depot for the Treatment of Korean Girls with Central Precocious Puberty in Single Tertiary Center.

BACKGROUND: Triptorelin depot is largely used to treat central precocious puberty (CPP) in children, and a 3-month depot has been introduced. However, data about the 3-month gonadotropin-releasing hormone use for treatment of CPP in Korean girls are not available. This study was conducted to compare the efficacy of a triptorelin 11.25 mg 3-month depot with that of a 3.75 mg 1-month depot in suppressing pubertal development for the treatment of CPP. METHODS: A retrospective study, including 106 girls with CPP treated with triptorelin, was conducted. Fifty patients were treated with a triptorelin 3-month depot, and 56 were treated with a triptorelin 1-month depot. Serum luteinizing hormone (LH), follicle-stimulating hormone, and estradiol levels were analysed every 6 months after the visit. The height and bone age of each patient was evaluated at the beginning of treatment, after 6 months, and one year after therapy. RESULTS: The baseline characteristics of the girls treated with a 3-month depot were similar to those of the girls treated with a 1-month depot. A suppressed levels of LH to the triptorelin injection (serum LH < 2.5 IU/L) at 6 months was seen in 90.0% and 98.2% of the girls treated with the 3-month and 1-month depots, respectively (P = 0.160). After 1 year of treatment, a suppressed levels of LH was seen in 93.5% and 100% of the girls treated with the 3-month and 1-month depots, respectively (P = 0.226). Height velocity showed no significant difference between the two groups. Degree of bone age advancement decreased from 1.22 ± 0.07 and 1.22 ± 0.08 years at baseline (P = 0.914) to 1.16 ± 0.07 and 1.17 ± 0.08 in the girls treated with the 3-month and 1-month depots after 1 year, respectively (P = 0.481). CONCLUSION: This study showed that the efficacy of long-acting triptorelin 3-month was comparable to 1-month depot regarding hormonal suppression and inhibition of bone maturation. The triptorelin 11.25 mg 3-month depot is an effective treatment for girls with CPP.

The role of growth hormone device optimization in patient-reported outcomes: real-world evidence from South Korea.

BACKGROUND: Growth hormone (GH) treatment preference and adherence are affected by delivery device convenience, injection-site pain, confidence in correct dose administration, and device satisfaction. This survey investigated if switching device to NordiFlex® improved treatment experience in pediatric patients in South Korea. DESIGN AND METHODS: Patients aged 4-≤18 years were surveyed. Participants were NordiFlex® users who previously used NordiLet®/other devices. Participants compared preference, self-reported adherence, satisfaction, perceived ease of use, and device subjective benefits (across four domains: ease of use, self-efficacy, minimal disruption of daily life, positive feelings about injections) of NordiFlex® vs. previous device. RESULTS: Ninety-four patients were enrolled, of which 91.5% previously used NordiLet®. Significantly more patients preferred, and were more satisfied with NordiFlex® vs. previous device; mean score: 0.65 (95% confidence interval [CI]:0.41;0.88) and 0.61 (95% CI:0.36;0.85), respectively. Participants reported greater perceived ease of use (0.49 [95% CI:0.26;0.72]) and fewer missed injections (0.20 [95% CI:0.06;0.34], with NordiFlex® vs. previous device. Bivariate analysis showed significant associations between preference for NordiFlex® and higher scores on self-efficacy, ease of use, minimal disruption of daily life, and positive feelings about injection (all p < 0.001). CONCLUSION: These results suggest that improvements in device features could be associated with improved treatment experience.

Serum Levels of Thyroid Stimulating Hormone and Luteinizing Hormone Are Decreased in Girls with Central Precocious Puberty after 12-Month GnRH Agonist Treatment.

Puberty is the transitional period from childhood to adult that leads to growth spurt, sexual maturation and attainment of reproductive capacity. Precocious puberty is defined when secondary sexual characteristics develop before the age of eight for girls and nine for boys. Central precocious puberty (CPP) is diagnosed when the process is driven by premature activation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion. Many factors promote CPP, and the thyroid function is thought to be one of them. In our previous study, thyroid stimulating hormone (TSH) was higher in the CPP group than that of the participants without CPP. This elevation of TSH in CPP is said to be associated with pubertal luteinizing hormone (LH) elevation. The aim of this study was to evaluate the causal relationship between TSH and LH in CPP patients. A total of 221 girls diagnosed with CPP and treated with GnRH agonists were included. All participants except one showed LH suppression (peak LH < 3 IU/L), and serum levels of follicle stimulating hormone (FSH) were also lower after the treatment. These results indicate that puberty has slowed down and that the patients were successfully treated for CPP. As for thyroid hormones, TSH was significantly lower and free thyroxine (fT4) levels were higher after 12 months of GnRH agonist treatment compared with baseline. With GnRH agonist treatment, the serum levels of LH and TSH were decreased, suggesting that the increase in serum TSH levels is associated with premature LH elevation in girls with CPP.

Prevalence of idiopathic scoliosis in girls with central precocious puberty: effect of a gonadotropin-releasing hormone agonist.

PURPOSE: Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis and occurs in children between 10 to 18 years old, during periods of growth spurts and puberty changes. In patients with central precocious puberty (CPP), due to early growth spurt, AIS is expected to develop before 10 years of age. Both AIS and CPP are more common in girls than in boys. The aim of this study was to determine the prevalence of AIS in girls with CPP and to evaluate the effect of treatment with gonadotropin-releasing hormone (GnRH) agonists on progression of scoliosis in these patients. METHODS: We retrospectively reviewed medical records of 553 girls, 338 with CPP and 215 without CPP. Scoliosis angle was measured on the standing frontal radiograph of each patient according to the Cobb method. Patients with a Cobb angle of 10° or more were diagnosed with scoliosis. For girls with CPP, followup spine radiographs were collected 1 year after treatment with GnRH agonists. Progression of scoliosis before and after treatment was compared in terms of Cobb angle changes. RESULTS: AIS was more prevalent in girls that were affected by CPP compared to controls without CPP (11.5% vs. 6.0%, CPP girls vs. non-CPP girls, respectively, P=0.031). The peak serum luteinizing hormone level positively correlated with Cobb angle (R2=0.015, P=0.023) in the CPP group. No progression of scoliosis was observed in CPP girls after one year of GnRH agonist treatment. Additionally, the prevalence of scoliosis decreased in CPP girls after 1 year of the treatment. CONCLUSION: We report that the prevalence of AIS is higher in girls with CPP than in non-CPP patients. A regular follow-up schedule for spine radiographs should be considered to reduce the risk of progression. Furthermore, GnRH agonist treatment for CPP may have a suppressive effect on progression of AIS.

Efficacy and Safety Evaluation of Human Growth Hormone Therapy in Patients with Idiopathic Short Stature in Korea - A Randomised Controlled Trial.

BACKGROUND: This trial evaluated the efficacy and safety of growth hormone (GH) therapy (Norditropin®; Novo Nordisk, Bagsværd, Denmark) in paediatric patients with idiopathic short stature (ISS) in Korea. METHODS: This was an open-label, parallel-group, multicentre, interventional trial (ClinicalTrials.gov identifier: NCT01778023). Pre-pubertal patients (mean age 6.2 years; height, 107.1 cm) were randomised 2:1 to 12 months' GH treatment (0.469 mg/kg/week; group A, n=36) or 6 months untreated followed by 6 months' GH treatment (group B, n=18). Safety analysis was based on adverse events (AEs) in all GH-treated patients. RESULTS: After 6 months, height velocity (Ht-V), change in both height standard deviation score (Ht-SDS) and insulin-like growth factor 1 (mean difference [95% confidence interval {CI}]: 5.15 cm/year [4.09, 6.21]; 0.57 [0.43, 0.71]; 164.56 ng/mL [112.04, 217.08], respectively; all p<0.0001) were greater in group A than in group B. Mean difference in Ht-V for 0-6 months versus 6-12 months was 2.80 cm/year (95% CI 1.55, 4.04) for group A and -4.60 cm/year (95% CI -6.12, -3.09; both p<0.0001) for group B. No unexpected AEs were reported. CONCLUSIONS: During the first 6 months, height was significantly increased in GH-treated patients versus untreated patients with ISS. Safety of GH was consistent with the known safety profile.

Role of NPR2 mutation in idiopathic short stature: Identification of two novel mutations.

BACKGROUND: C-type natriuretic peptide (CNP, NPPC) and its receptor, natriuretic peptide receptor-B (NPR-B, NPR2), are critical for endochondral ossification. A monoallelic NPR2 mutation has been suggested to mildly impair long bone growth. This study was performed to identify the NPR2 mutations in Korean patients with idiopathic short stature (ISS). METHODS: One hundred and sixteen subjects with nonsyndromic ISS were enrolled in this study, and the NPPC and NPR2 were sequenced. In silico prediction and in vitro functional analysis, using a cell-based assay, were performed to confirm their protein derangement. RESULTS: Mean age at diagnosis of ISS was 8.0 years, and the height z-score was -2.65. Three pathogenic variants (R921Q, R495C, and Y598N) and one benign variant (R787W) of the NPR2 were identified, while no novel sequence variant of the NPPC was found in all subjects. Two novel pathogenic mutants (R495C and Y598N) were predicted as highly pathogenic by several computational methods. In vitro study involving stimulation with CNP, R495C-, and Y598N-transfected cells showed decreased cGMP production compared to wild type-transfected cells. CONCLUSION: Heterozygous NPR2 mutations were found in 2.6% of ISS Korean subjects. This prevalence and the dominant-negative effect of mutant NPR-B on growth signals imply that it is one of genetic causes of ISS.

Idiopathic Short Stature Phenotypes among Korean Children: Cluster Analysis.

Idiopathic short stature (ISS) is a heterogeneous group and their responsiveness to growth hormone treatment varies among individuals. The aim of this study was to identify homogeneous phenotypes to better assess response before the initiation of treatment. We focused on person-centered approaches using a latent profile analysis. Clinical data of 218 children (127 boys and 91 girls) aged 4-15 years were obtained from the "LG Growth Study" which is a non-interventional Korean multicenter registry for growth hormone treatment. Growth hormone dose, first-year difference in height standard deviation score (Δheight SDS), mid-parental height SDS, and initial bone age were inputted into the model. The distribution of scatter plot was clearly distinguished at the chronological age of 8.83 years, Δheight SDS of 0.82 and mean GH dose of 0.36 mg/kg/week. The latent profile analysis revealed three distinct phenotypes names as follows: younger good responder (n = 56), older good responder (n = 111), and older poor responder (n = 51) groups. Despite more than twice the mean growth hormone dose, the older poor responder group showed the least improvement in the mean Δheight SDS. The pretreatment height velocity and peak growth hormone level were lower for the older poor responder group compared with those of the older good responder group. The statistically optimal cutoff point for predicting poor response was 3.41 cm/year for pretreatment height velocity and 9.18 ng/mL for peak growth hormone level. This study offers a new multidimensional approach to enable personalized growth hormone treatment optimization according to ISS phenotypes.

Serum osteocalcin levels in overweight children.

PURPOSE: Bone plays a role in glucose metabolism through the release of uncarboxylated osteocalcin into the systemic circulation. The identified novel roles for osteocalcin include increasing insulin secretion and sensitivity, energy expenditure, reduction of fat mass, and mitochondrial proliferation and functional enhancement. This study aimed to determine serum osteocalcin levels in overweight children and to investigate the relationships of osteocalcin with glucose metabolism and insulin sensitivity. METHODS: After overnight fasting, serum osteocalcin levels were measured in overweight (n=50) children between 6.0 and 12.9 years of age and nonoverweight controls (n=60). Height, weight, fasting serum glucose, insulin, alkaline phosphatase, total cholesterol, and 25 hydroxy vitamin D3 (25(OH)VitD3) were also measured in all subjects. RESULTS: There were significant differences in serum osteocalcin levels between the overweight and control groups (64.00±20.44 vs. 89.56±28.63, P<0.001). Serum osteocalcin levels were inversely correlated with body mass index (BMI) (r=-0.283, P=0.003), weight standard deviation score (SDS) (r=-0.222, P=0.020), BMI SDS (r=-0.297, P=0.002), insulin (r=-0.313, P=0.001), and homeostasis model assessment of insulin resistance (HOMA-IR) index (r=-0.268, P=0.005). In the subsequent multiple regression analyses, BMI, HOMA-IR, and age were determined to be independent predicting factors for serum osteocalcin. CONCLUSION: Our findings showed associations of serum osteocalcin with glucose metabolism and insulin sensitivity in overweight children, but we could not establish a causal relationship.

Thyroid function in girls with central precocious puberty.

PURPOSE: Obesity is a well-known risk factor for central precocious puberty (CPP). Recently, elevated thyroid stimulating hormone (TSH) was reported in obese youth. However, few data regarding the relationship between CPP and TSH are available. The aim of this study was to evaluate thyroid function in girls with CPP and the relationship between CPP and serum TSH concentration. METHODS: This was a retrospective cross-sectional study. A total of 1,247 girls aged between 6.0 and 8.9 years who had undergone a gonadotropin-releasing hormone (GnRH) stimulation test to determine the presence of puberty were studied. Subjects were classified into CPP (n=554) and non-CPP (n=693) groups according to the results of the GnRH stimulation test. Characteristics and laboratory data of the CPP and non-CPP groups were compared and correlations between those characteristics and laboratory data and TSH concentration were evaluated. Serum TSH concentration in the CPP group was higher than that of the non-CPP group (3.19±1.55 mIU/L vs. 2.58±1.34 mIU/L, P<0.001). RESULTS: Serum free thyroxine (fT4) concentration in the CPP group was notably lower than that of the non-CPP group (1.38±0.14 ng/dL vs. 1.44±0.18 ng/dL, P<0.001). Across all subjects, 149 girls (11.9%) had hyperthyrotropinemia. The prevalence of hyperthyrotropinemia was higher in the CPP group compared to the non-CPP group (15.7% vs. 8.9%, P<0.001). TSH concentrations were positively correlated with age, height, weight, BMI, bone age, bone age advance, insulin-like growth factor 1 (IGF-1), IGF-1 standard deviation score, basal luteinizing hormone (LH), peak LH and basal follicle-stimulation hormone. TSH concentrations were negatively correlated with fT4. Multiple linear regression analysis showed that age (ß=0.548, P<0.001) and peak LH (ß=0.019, P=0.008) were independently associated with serum TSH concentration. CONCLUSION: Hyperthyrotropinemia in girls with CPP tends to be associated with pubertal LH elevation. In conclusion, pubertal onset may be associated with thyroid function.