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Purpose Few data on the clinical course after levothyroxine (L-T4) discontinuation in pediatric patients with Hashimoto thyroiditis (HT) are available. We investigated outcomes and predictors for successful withdrawal from L-T4 among children with HT. Methods Among 168 patients diagnosed with HT between January 2000 and March 2021 at Seoul National University Children’s Hospital and in whom L-T4 therapy was initiated during childhood, we attempted to discontinue this therapy in 47, 3 boys and 44 girls. L-T4 was restarted when patients developed overt or subclinical hypothyroidism (thyroid-stimulating hormone [TSH] levels≥10 mIU/L) after L-T4 discontinuation. Results Median age at discontinuation was 15.4 years (12.7–18.4 years) with a median duration of L-T4 therapy of 47 months (20.3–80.3 months). During the median 30 months of follow-up (10.6–61.0 months) after L-T4 discontinuation, 33 (70.2%) developed thyroid dysfunction. Among these patients, 17 were eventually restarted on L-T4. TSH levels over 50 mIU/L at L-T4 initiation (hazard ratio, HR 3.5, P=0.002), age under 12 years at L-T4 discontinuation (HR 11.1, P=0.0001), and TSH levels higher than the upper 50% of normal (above 2.25 mIU/L in the present study) at L-T4 discontinuation (HR 2.7, P=0.014) were significantly predictive for overt hypothyroidism or subclinical hypothyroidism after L-T4 discontinuation. In addition, age under 12 years at L-T4 discontinuation was only predictive factor for restarting L-T4 medication (HR 4.3, P=0.012). Conclusions L-T4 discontinuation in pediatric patients with HT resulted in thyroid dysfunction in 70.2% of cases; 36.2% of patients who attempted discontinuation required resumption of L-T4. Older age and lower TSH levels at L-T4 discontinuation were advantageous for successful withdrawal.

Objective: This study aimed to assess selenium status in South Korean pregnant women and its impact on maternal thyroid function and pregnancy outcomes. Methods: ‘Ideal Breast Milk (IBM) Cohort Study’ included 367 pregnant women out of 442 participants and categorized into three groups based on plasma selenium levels: deficient (< 70 μg/L), suboptimal (70–99 μg/L), and optimal (≥ 100 μg/L). During the second or third trimester, various blood parameters, including selenium, thyroid-stimulating hormone, free T4, free T3, and anti-thyroid peroxidase antibody levels, were measured. Thyroid parenchymal echogenicity was assessed as another surrogate marker for thyroid autoimmunity using ultrasonography. Results: The median plasma selenium was 98.8 (range: 46.7–206.4) μg/L, and 30 individuals (8%) were categorized as deficient, while 164 (45%) were classified in the suboptimal group. Selenium deficiency was associated with markers of autoimmune thyroiditis, including positive anti-thyroid peroxidase antibody results (13.3 (deficient) vs 4.6 (optimal) %, P = 0.031) and thyroid parenchymal heterogeneity on ultrasound (33.3 (deficient) vs 14.6 (suboptimal) vs 17.3 (optimal) %, P = 0.042), independently of gestational age. The incidence of severe preeclampsia was higher in the group not taking selenium supplements, particularly among those with twin pregnancies, compared to the group taking selenium supplements (0 (selenium supplement) vs 9.0 (no supplement) %, P = 0.015). Conclusion: Pregnant women experience mild selenium deficiency, which can lead to significant health issues including maternal thyroid autoimmunity and obstetrical complications during pregnancy. Guidelines for appropriate selenium intake according to the stage of pregnancy and the number of fetuses are needed.

ObjectiveHepatopulmonary syndrome (HPS) is a rare complication of metabolic associated fatty liver disease (MAFLD) occurring subsequent to hypopituitarism, often developing after resection of hypothalamic or pituitary tumors. The aim of this study is to report an illustrative case of an HPS patient who was successfully treated with growth hormone replacement therapy, without liver transplantation which is conventionally regarded as the only treatment option. Additionally, we conducted a comprehensive review of published case reports of HPS in the pediatric population.MethodsWe systematically searched literature databases to identify case reports and case series of HPS associated with hypopituitarism diagnosed in childhood. The search included MEDLINE/PubMed, Scopus, Embase, and Google Scholar from 1990 to 2023. The review process adhered to the PRISMA checklist for comprehensive reporting and methodological transparency.ResultsAn 18-year-old female, who had been followed up for MAFLD after craniopharyngioma resection, presented with cyanosis and progressive dyspnea. She was diagnosed with severe degree of HPS. The patient began treatment with recombinant human growth hormone, leading to a significant improvement in respiratory symptoms within 3 months, and normalization of lung shunt ratio after 6 months of therapy. In our systematic review, nine patients from nine studies across six countries were identified. The median age at diagnosis of hypopituitarism was 10.5 years (range 1–16 years), and HPS was diagnosed at a median interval of 7 years later (range 0–26 years). Half of the patients had not received growth hormone therapy after being diagnosed with hypopituitarism, which subsequently led to the diagnosis of HPS. Three patients underwent liver transplantation, but non-alcoholic steatohepatitis recurred in all cases. Six patients were successfully treated with growth hormone replacement therapy without undergoing liver transplantation.ConclusionsHPS can occur in pediatric patients with MAFLD who have undergone resection of the tumor in the hypothalamus or pituitary gland. Our findings suggest that growth hormone replacement therapy can be a possible alternative to liver transplantation for HPS patients. However, further investigations need to be performed to validate the efficacy of growth hormone treatment in different causes of HPS cases.

Background: This study investigated the association of prenatal and early childhood exposure to air pollution with epigenetic age acceleration (EAA) at six years of age using the Environment and Development of Children Cohort (EDC Cohort) Materials & methods: Air pollution, including particulate matter [< 2.5 µm (PM2.5) and < 10 µm (PM10) in an aerodynamic diameter], nitrogen dioxide (NO2), ozone (O3), carbon monoxide (CO), and sulfur dioxide (SO2) were estimated based on the residential address for two periods: 1) during the whole pregnancy, and 2) for one year before the follow-up in children at six years of age. The methylation levels in whole blood at six years of age were measured, and the methylation clocks, including Horvath’s clock, Horvath’s skin and blood clock, PedBE, and Wu’s clock, were estimated. Multivariate linear regression models were constructed to analyze the association between EAA and air pollutants. Results: A total of 76 children in EDC cohort were enrolled in this study. During the whole pregnancy, interquartile range (IQR) increases in exposure to PM2.5 (4.56 μg/m3) and CO (0.156 ppm) were associated with 0.406 years and 0.799 years of EAA (Horvath’s clock), respectively. An IQR increase in PM2.5 (4.76 μg/m3) for one year before the child was six years of age was associated with 0.509 years of EAA (Horvath’s clock) and 0.289 years of EAA (Wu’s clock). PM10 (4.30 μg/m3) and O3 (0.003 ppm) exposure in the period were also associated with EAA in Horvath’s clock (0.280 years) and EAA in Horvath’s skin and blood clock (0.163 years), respectively. Conclusion: We found that prenatal and childhood exposure to ambient air pollutants is associated with EAA among children. The results suggest that air pollution could induce excess biological aging even in prenatal and early life.

Abstract Background Familial chylomicronemia syndrome (FCS) is a rare monogenic form of severe hypertriglyceridemia, caused by mutations in genes involved in triglyceride metabolism. Herein, we report the case of a Korean family with familial chylomicronemia syndrome caused by compound heterozygous deletions of glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). Case presentation A 4-year-old boy was referred for the evaluation of severe hypertriglyceridemia (3734 mg/dL) that was incidentally detected 4 months prior. His elder brother also demonstrated an elevated triglyceride level of 2133 mg/dL at the age of 9. Lipoprotein electrophoresis revealed the presence of chylomicrons, an increase in the proportion of pre-beta lipoproteins, and low serum lipoprotein lipase levels. The patient’s parents and first elder brother had stable lipid profiles. For suspected FCS, genetic testing was performed using the next-generation sequencing-based analysis of 31 lipid metabolism-associated genes, which revealed no pathogenic variants. However, copy number variant screening using sequencing depth information suggested large heterozygous deletion encompassing all the coding exons of GPIHBP1. A real-time quantitative polymerase chain reaction was performed to validate the deletion site. The results showed that the siblings had two heterozygous copy number variants consisting of the whole gene and an exon 4 deletion, each inherited from their parents. During the follow-up period of 17 months, the patient did not develop pancreatitis, following dietary intervention. Conclusion These siblings’ case of familial chylomicronemia syndrome caused by rare GPIHBP1 deletions highlight the implementation of copy number variants—beyond next-generation sequencing—as an important consideration in diagnosis. Accurate genetic diagnosis is necessary to establish the etiology of severe hypertriglyceridemia, which increases the risk of pancreatitis.

Purpose The association between appendicular skeletal muscle mass (ASM) and cardiometabolic risk has been emphasized. We estimated reference values of the percentage of ASM (PASM) and investigated their association with metabolic syndrome (MS) in Korean adolescents. Methods Data from the Korea National Health and Nutrition Examination Survey performed between 2009 and 2011 were used. Tables and graphs of reference PASM were generated using 1,522 subjects, 807 of whom were boys aged 10 to 18. The relationship between PASM and each component of MS in adolescents was further analyzed in 1,174 subjects, 613 of whom were boys. Moreover, the pediatric simple MS score (PsiMS), the homeostasis model assessment of insulin resistance (HOMA-IR), and the triglyceride-glucose (TyG) index were analyzed. Multivariate linear and logistic regressions adjusting for age, sex, household income, and daily energy intake were performed. Results In boys, PASM increased with age; the trend was different in girls, in whom PASM declined with age. PsiMS, HOMA-IR, and TyG index showed inverse associations with PASM (PsiMS, β=-0.105, P

Objective: Adequate iodine intake is essential for growing children, and thyroid volume (Tvol) is considered as an indicator of iodine status. We investigated Tvol and goiter using ultrasonography (US) and their association with iodine status in 228 6-year-old children living in Korea. Methods: Iodine status was assessed using urine iodine concentration (UIC) and categorized as deficient (

Background: Bisphenol A (BPA) is known as an obesogenic endocrine disruptor. Bisphenol S (BPS) and F (BPF) are substitutes that have recently replaced BPA. Objectives: To investigate the relationships of urinary bisphenols (BPA, BPS and BPF) with adiposity measurements (obesity, BMI z-score, and fat mass), serum adipokine levels (adiponectin and leptin), and adiponectin/leptin ratio (A/L ratio) in 6- and 8-year-old children. Methods: A total of 561 children who participated in the Environment and Development of Children cohort (482 and 516 children visited at age 6 and 8, respectively) at Seoul National University Children’s Hospital during 2015–2019 were included. Urinary BPA levels were log-transformed. BPS levels were categorized into three groups (non-detected, lower-half, and higher-half of detected), and BPF levels were classified into two groups (non-detected and detected). Results: The urinary BPS higher-half group had a higher BMI z-score (β = 0.160, P = 0.044), higher fat mass (β = 0.104, P < 0.001), lower adiponectin concentration (β =- 0.069, P < 0.001), higher leptin concentration (β = 0.360, P < 0.001), and lower A/L ratio (β =- 0.428, P < 0.001) compared with the non-detected group. The urinary BPF-detected group had a higher fat mass (β = 0.074, P < 0.001), lower adiponectin concentration (β =- 0.069, P < 0.001), higher leptin concentration (β = 0.360, P < 0.001), and lower A/L ratio (β =- 0.428, P < 0.001) compared with the non-detected group. The BPA levels showed no consistent associations with outcomes, except for isolated associations of BPA at age 6 with a higher BMI z-score at age 6 (P = 0.016) and leptin at age 8 (P = 0.021). Conclusions: Increased exposure to BPS and BPF is associated with higher fat mass and leptin concentration, lower serum adiponectin, and lower A/L ratio in children. These findings suggest potential adverse effects of BPA substitutes on adiposity and adipokines. No consistent association of BPA exposure with outcomes could be partly explained by the decreasing BPA levels over time.

Abstract Epigenetic influence plays a role in the association between exposure to air pollution and attention deficit hyperactivity disorder (ADHD); however, research regarding sulfur dioxide (SO2) is scarce. Herein, we investigate the associations between prenatal SO2 exposure and ADHD rating scale (ARS) at ages 4, 6 and 8 years repeatedly in a mother–child cohort (n = 329). Whole blood samples were obtained at ages 2 and 6 years, and genome-wide DNA methylation (DNAm) was analyzed for 51 children using the Illumina Infinium HumanMethylation BeadChip. We analyzed the associations between prenatal SO2 exposure and DNAm levels at ages 2 and 6, and further investigated the association between the DNAm and ARS at ages 4, 6 and 8. Prenatal SO2 exposure was associated with ADHD symptoms. From candidate gene analysis, DNAm levels at the 6 CpGs at age 2 were associated with prenatal SO2 exposure levels. Of the 6 CpGs, cg07583420 (INS-IGF2) was persistently linked with ARS at ages 4, 6 and 8. Epigenome-wide analysis showed that DNAm at 6733 CpG sites were associated with prenatal SO2 exposure, of which 58 CpGs involved in Notch signalling pathway were further associated with ARS at age 4, 6 and 8 years, persistently. DNAm at age 6 was not associated with prenatal SO2 exposure. Changes in DNAm levels associated with prenatal SO2 exposure during early childhood are associated with increases in ARS in later childhood.

Autoantibodies against glutamic acid decarboxylase (GADA), tyrosine phosphatase-related islet antigen 2 (IA2A), insulin (INSA), and islet cells (ICA) are critical for determining the type of diabetes and management strategy in new-onset diabetes mellitus (NODM), but there have been few reports of all diabetes-associated autoantibody (DAA) in Korea. We retrospectively analyzed 193 patients with NODM aged 0 to 18 years who were followed at two tertiary centers in Korea (2017 to 2021). Patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) were 93 (48.2%) and 100 (51.8%), respectively. In T1DM patients, the DAA positivity rate was 94.6%; prevalence of GADA, IA2A, INSA, and ICA was 71.0%, 71.0%, 31.2%, and 10.8%, respectively; and IA2A added 10.7% point autoantibody positivity (83.9% for GADA+INSA+ICA and 94.6% for GADA+INSA+ICA+IA2A). Among the patients with T2DM, 12 (12.0%) were positive for DAA, and all were positive for INSA. These findings suggest that DAA at diagnosis, especially GADA and IA2A, is useful for classifying diabetes in Korean children and adolescents.

Purpose Hypothalamic damage may increase the risk of adulthood obesity and cardiovascular disease in patients with craniopharyngioma. We evaluated the effects of hypothalamic involvement (HI) and growth hormone (GH) discontinuation on cardiovascular risk factors during the transition period in patients with childhood-onset craniopharyngioma. Methods Thirty-three patients (17 males, 16 females) underwent retesting for adult GH deficiency (GHD) between 2005 and 2020 at Seoul National University Children's Hospital. Postoperative HI was graded by Puget's criteria and data regarding GH replacement were collected. At retesting, body mass index (BMI), fasting blood glucose, insulin, high-density lipoprotein cholesterol (HDL-C), triglycerides, and blood pressure were assessed. Results The mean age of commencement and discontinuation of GH replacement for childhood GHD was 10.0±3.6 and 15.3±3.1 years, respectively. The mean age at retesting for adult GHD was 17.7±2.5 years. When patients were categorized by post-GH discontinuation duration, those with durations >6 months (n=27) showed lower HDL-C levels than those with

Purpose Hypoparathyroidism (hypoPTH) is the most common complication following thyroidectomy. We investigated the frequency and risk factors of hypoPTH after total thyroidectomy (TT) in pediatric patients with thyroid cancer. Methods This retrospective study included 98 patients younger than 20 years who were diagnosed with thyroid cancer after T T during 1990–2018 and followed for more than 2 years at Seoul National University Hospital. HypoPTH was defined as receiving active vitamin D (1-hydroxycholecalciferol or 1,25-dihydroxycholecalciferol) after surgery. Results The study included 27 boys (27.6%) and 71 girls (72.4%). The mean age at diagnosis was 14.9±3.7 years. HypoPTH occurred in 43 patients (43.9%). Twenty-one patients (21.4%) discontinued active vitamin D less than 6 months after surgery, while 14 (14.3%) continued active vitamin D for more than 2 years. Tumor multifocality (odds ratio [OR], 3.7 vs. single tumor; P=0.013) and preoperative calcium level (OR, 0.2; P=0.028) were independent predictors of hypoPTH immediately after TT. In addition, age (OR, 0.8; P=0.011) and preoperative calcium level (OR, 0.04; P=0.014) significantly decreased the risk for persistent hypoPTH requiring active vitamin D for more than 2 years. Conclusions HypoPTH occurred in 43.9% of pediatric thyroid cancer patients after TT in this study. Among them, one-third of patients continued active vitamin D medication for more than 2 years, which was predicted by young age and low preoperative calcium level.

Background Discontinuing growth hormone (GH) treatment during the transition to adulthood has been associated with adverse health outcomes in patients with childhood-onset growth hormone deficiency (CO-GHD). This study investigated the metabolic changes associated with interrupting GH treatment in adolescents with CO-GHD during the transition period. Methods This study included 187 patients with CO-GHD who were confirmed to have adult GHD and were treated at six academic centers in Korea. Data on clinical parameters, including anthropometric measurements, metabolic profiles, and bone mineral density (BMD) at the end of childhood GH treatment, were collected at the time of re-evaluation for GHD and 1 year after treatment resumption. Results Most patients (n=182, 97.3%) had organic GHD. The median age at treatment discontinuation and re-evaluation was 15.6 and 18.7 years, respectively. The median duration of treatment interruption was 2.8 years. During treatment discontinuation, body mass index Z-scores and total cholesterol, low-density lipoprotein, and non-high-density lipoprotein (HDL) cholesterol levels increased, whereas fasting glucose levels decreased. One year after GH treatment resumption, fasting glucose levels, HDL cholesterol levels, and femoral neck BMD increased significantly. Longer GH interruption (>2 years, 60.4%) resulted in worse lipid profiles at re-evaluation. The duration of interruption was positively correlated with fasting glucose and non-HDL cholesterol levels after adjusting for covariates. Conclusion GH treatment interruption during the transition period resulted in worse metabolic parameters, and a longer interruption period was correlated with poorer outcomes. GH treatment should be resumed early in patients with CO-GHD during the transition period.

Purpose The effects of circadian blood pressure (BP) alterations on the development and progression of microvascular complications in type 1 diabetes mellitus (T1DM) patients are unknown. We evaluated the effects of circadian BP alterations with development of microvascular complications during follow-up with patients with childhood-onset T1DM. Methods We investigated the medical records of 81 pediatric patients with T1DM who underwent 24-hour ambulatory BP monitoring (ABPM) between January 2009 and February 2010. Results Mean age at diagnosis and ABPM evaluation was 8.0±3.9 and 15.6±2.4 years, respectively. Hypertension (daytime, nighttime, and 24-hour mean hypertension) data were available in 42 patients. During the 8 years of follow-up after ABPM, microvascular complications occurred in 8 patients (diabetic retinopathy [DR] alone in 5, microalbuminuria alone in 2, and both in 1), of whom 7 had nondipper BP. Nighttime diastolic BP, nighttime mean arterial pressure, and glycated hemoglobin A (HbA1c) level were higher in patients with DR than in those without DR (P

BackgroundAdequate iodine intake is essential for growing children, as both deficient and excessive iodine status can result in thyroid dysfunction. We investigated the iodine status and its association with thyroid function in 6-year-old children from South Korea.MethodsA total of 439 children aged 6 (231 boys and 208 girls) were investigated from the Environment and Development of Children cohort study. The thyroid function test included free thyroxine (FT4), total triiodothyronine (T3), and thyroid-stimulating hormone (TSH). Urine iodine status was evaluated using urine iodine concentration (UIC) in morning spot urine and categorized into iodine deficient (< 100 μg/L), adequate (100–199 μg/L), more than adequate (200–299 μg/L), mild excessive (300–999 μg/L), and severe excessive (≥ 1000 μg/L) groups. The estimated 24-hour urinary iodine excretion (24h-UIE) was also calculated.ResultsThe median TSH level was 2.3 μIU/mL, with subclinical hypothyroidism detected in 4.3% of patients without sex differences. The median UIC was 606.2 μg/L, with higher levels in boys (684 μg/L vs. 545 μg/L, p = 0.021) than girls. Iodine status was categorized as deficient (n = 19, 4.3%), adequate (n = 42, 9.6%), more than adequate (n = 54, 12.3%), mild excessive (n = 170, 38.7%), or severe excessive (n = 154, 35.1%). After adjusting for age, sex, birth weight, gestational age, body mass index z-score, and family history, both the mild and severe excess groups showed lower FT4 (β = − 0.04, p = 0.032 for mild excess; β = − 0.04, p = 0.042 for severe excess) and T3 levels (β = − 8.12, p = 0.009 for mild excess; β = − 9.08, p = 0.004 for severe excess) compared to the adequate group. Log-transformed estimated 24h-UIE showed a positive association with log-transformed TSH levels (β = 0.04, p = 0.046).ConclusionExcess iodine was prevalent (73.8%) in 6-year-old Korean children. Excess iodine was associated with a decrease in FT4 or T3 levels and an increase in TSH levels. The longitudinal effects of iodine excess on later thyroid function and health outcomes require further investigation.

Abstract 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).

The year 2021 is the centennial of insulin discovery. The discovery of insulin changes diabetes mellitus from a death sentence to a manageable disease. It became a historical turning point in the lives of people with diabetes. Since the first use of insulin in a patient in 1922, insulin and its analogs have been remarkable in saving the lives of people with diabetes. As insulin began to be used as a drug, it was introduced to, and used in Korea until now. This review briefly summarizes the history of insulin treatment in Korean children and adolescents with diabetes.

BackgroundConsidering the roles of 25-hydroxyvitamin D (25OHD) in glucose homeostasis and immune modulation, vitamin D deficiency may be related to the development of type 1 diabetes (T1DM) and diabetic ketoacidosis (DKA). We evaluated the total, free, bioavailable 25OHD levels and vitamin D binding protein (VDBP) levels and genotypes between T1DM patients and controls.MethodsThis retrospective, cross-sectional study included 84 children with T1DM (38 boys and 46 girls, 8.0 ± 3.6 years) and 1:1 age- and sex-matched healthy controls. A multiplex liquid chromatography-tandem mass spectrometry-based assay was used to simultaneously measure vitamin D metabolites.ResultsPatients with T1DM had lower levels of total 25OHD (16.3 ± 5.1 vs. 19.9 ± 6.5 ng/mL, P< 0.001) and VDBP (146.0 ± 27.8 vs. 224.9 ± 36.1 µg/mL, P = 0.001), but higher free 25OHD (8.0 ± 2.5 vs. 6.5 ± 2.3 pg/mL, P< 0.001) than controls. Patients who presented with DKA had lower levels of 25OHD in the total (15.0 ± 4.6 vs. 17.6 ± 5.2 ng/mL, P = 0.020), free (7.5 ± 2.6 vs. 8.4 ± 2.4 pg/mL, P = 0.059), and bioavailable (2.3 ± 0.9 vs. 2.8 ± 0.8 ng/mL, P = 0.014) forms than those without DKA at the T1DM diagnosis. The lower the total, free, and bioavailable 25OHD levels at diagnosis, the lower the pH and HCO3-. The proportions of the VDBP genotypes did not differ between the patients and controls.ConclusionPatients with T1DM had higher levels of free 25OHD than healthy children, despite lower levels of total 25OHD. However, patients with DKA exhibited lower levels of bioavailable 25OHD than those without DKA at the T1DM diagnosis. The lower the concentrations of free and bioavailable 25OHD, the more severe the acidosis at the initial T1DM presentation.

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a rare form of hereditary rickets, which is characterized by defective bone mineralization and renal phosphate wasting due to a loss-of-function variant in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene. Although pathogenic variant of ENPP1 has been known to manifest other phenotypes including arterial calcification, hearing loss, ossification of posterior longitudinal ligament, or pseudoxanthoma elasticum, there have been few reports including systematic examination in individuals diagnosed with ARHR2 to date. Herein, we report a case of ARHR2 with a bi-allelic pathogenic variant of ENPP1, in which the patient presented with gait abnormalities with severe genu varum at 26 months of age. Targeted gene panel sequencing was performed to investigate the genetic cause of rickets, and a homozygous nonsense variant in ENPP1, c.783C>G (p.Tyr261*), was identified. The patient was treated with oral phosphate and active vitamin D supplements and underwent corrective osteotomy for varus deformity. His phenotype was limited to rickets. A periodic systematic evaluation is needed to identify any comorbidities in ARHR2 patients since ENPP1 variants may present phenotypes other than rickets and symptoms may evolve or change over time.

ObjectivesThe objective of this study is to investigate whether body mass index (BMI) changes are associated with fasting glucose and insulin resistance (IR) in early childhood.MethodsFrom the Environment and Development of Children (EDC) cohort, 334 children who visited at ages 2 and 4 were included in this study. Height and weight were measured at ages 2 and 4, and fasting glucose and insulin were assessed at age 4. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated as insulin (μIU/ml) × glucose (mg/dl)/405. The BMI Z-score [BMI (Z)] quartiles for each age group were defined as Q4, ≥75th percentile; Q2–3, 25th to 75th percentile; and Q1,

Background: Bisphenol A (BPA) has been linked to attention-deficit/hyperactivity disorder (ADHD) symptoms, but the neurotoxic effects of bisphenol substitutes such as bisphenol F (BPF) and S (BPS) have not been well investigated. We investigated the associations between BPA, BPF, and BPS with ADHD symptoms at multiple time points in children. Methods: The levels of BPA (at ages 4, 6, and 8), BPF (at ages 6 and 8), and BPS (at ages 6 and 8) were measured in 619 children. Because of the low detection frequency of BPF and BPS levels, participants were divided into categories (97%), whereas BPF and BPS were less frequently detected (age 6: 17.5% for BPF and 42.0% for BPS; age 8: 51.6% for BPF and 73.3% for BPS). Doubling in BPA levels was associated with increased ARS scores by 4.7% (95% confidence intervals [CI]: 0.5, 9.2) at age 6. The association was greater with BPA levels higher than 3.0 μg/g creatinine (24.2% [95% CI: 15.5, 33.6] increase). The BPF ≥ LOD group had 10.8% (95% CI: 1.2, 21.4) higher ARS scores than the BPF

Background: Pyrethroid insecticides are commonly used in residential settings, and their use has increased rapidly. Although research has been scarce, they have been reported to be associated with impaired neurodevelopment. Moreover, susceptible exposure windows and the long-term effects of pyrethroids have not been investigated. We examined the association between pyrethroid exposure and attention-deficit/hyperactivity disorder (ADHD) symptoms over time, with exposure windows spanning from the prenatal period to school-age. Methods: Using 524 mother–child pairs, we measured urinary concentrations of 3-phenoxybenzoic acid (3-PBA), a major pyrethroid metabolite, and asked parents to fill-out the ADHD Rating Scale IV (ARS). We used Poisson regression to identify the susceptible periods of pyrethroid exposure, by correlating various 3-PBA exposure windows (prenatal, ages 2, 4, 6 and 8) with ADHD symptoms at ages 6 and 8. Results: Doubling of prenatal and age 2 3-PBA concentrations was associated with increased ADHD symptoms at age 6 (2.7% change, 95% confidence interval [CI]: 0.3, 5.2; 5.2% change [95% CI: 0.5, 10.2], respectively). The 3-PBA concentrations at age 4 and age 6 were linked with ADHD symptoms at age 8 (2.7% change [95% CI: 0.3, 5.3]; 3.3% change [95% CI: 0.2, 6.4], respectively). There were no clear sex-specific patterns in association. Discussion: Both prenatal and early-childhood exposure to 3-PBA were found to be associated with ADHD symptoms. Exposure during pregnancy, and at ages 2 to 6 were found to be susceptible periods for pyrethroid neurotoxicity at ages 6 and 8.

Background Hyperuricemia has a suspected relationship with hypertension, metabolic syndrome, kidney disease, and cardiovascular disease. Endocrine disruptors may affect uric acid metabolism; however, few epidemiologic studies have been performed in children regarding newly developed bisphenol A (BPA) substitutes. We evaluated the associations between BPA, bisphenol S (BPS), and bisphenol F (BPF) exposure and serum uric acid concentrations in 6-year-old Korean children. Methods From the Environment and Development of Children cohort study, six-year-old children (N = 489; 251 boys) who underwent an examination during 2015–2017 were included. Anthropometry, questionnaires, and biological samples were evaluated. BPA, BPS, and BPF levels were measured from spot urine samples, and log-transformed or categorized into groups for analysis. We constructed linear regression models adjusting for age, sex, urinary creatinine levels, body mass index z-scores, and estimated glomerular filtration rates. Results Mean serum uric level was 4.2 mg dL-1 (0.8 SD) without sex-differences. Among the three bisphenols, higher BPS exposure was associated with increased serum uric acid concentrations (P-value for trend = 0.002). When BPS levels were categorized into three groups (non-detection < 0.02 μg L-1 vs. medium BPS; 0.02–0.05 μg L-1 vs. high BPS ≥ 0.05 μg L-1), the high BPS group showed higher serum uric acid concentrations (by 0.26 mg dL-1, P = 0.003) than the non-detection group after adjusting for covariates, which was significant in boys but not girls. Discussions Urinary BPS levels was positively associated with serum uric acid concentrations in 6-year-old children, and the association was more pronounced in boys. Considering the increasing use of BPS and concerning effect of hyperuricemia on health outcomes, their positive relationship should be investigated further.

Background: Phthalates are synthetic chemicals with endocrine-disrupting properties. They are reportedly associated with various neurotoxic outcomes. Studies on exposure to phthalates and children’s autistic traits have shown inconsistent results with respect to sex and susceptible time periods. We investigated the association of phthalate exposure during the prenatal period and childhood with autistic traits over time using a birth cohort in South Korea. Methods: Five phthalate metabolites were measured during mid-term pregnancy and children's follow-up at ages of 4, 6, and 8 years among a total of 547 mother–child pairs. The social communication questionnaire (SCQ) was used to assess autistic traits of children at each time point. The relationship between phthalate metabolites and SCQ scores were analyzed by exposure windows and sex. Results: A 2.7 fold increase in di-(2-ethylhexyl) phthalate metabolite levels, mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) during pregnancy was associated with increased SCQ scores at 4 years by 8.5% (95% confidence intervals [CI]: 1.9%, 15.5%) and 7.4% (95% CI: 0.3%, 15.0%), respectively, but not at the age of 6 or 8 years. Moreover, MEHHP levels at ages of 4 and 8 years were associated with increased SCQ scores at 8 years by 9.9% (95% CI: 1.8%, 18.6%) and 9.6% (95% CI: 1.3%, 18.6%), respectively. Boys showed stronger associations between phthalate exposure and SCQ scores than girls. Conclusion: The study suggested different susceptible time windows of phthalate exposure: exposure during pregnancy is associated with autistic traits in young children, whereas exposure during early childhood years leads to autistic traits in school-aged children, particularly boys.

Background: Humans are exposed to a mixture of metals during their lifetime; however, evidence of neurotoxicity of such mixtures in critical time windows is still insufficient. We aimed to elucidate the associations of four metals mixture across multiple time points with children’s intelligence quotient (IQ) in a prospective cohort study. Methods: Prenatal exposure and exposure at age 4 and 6 years to four types of blood metals, namely lead, mercury, cadmium, and manganese were quantified in 502 pregnant women and their children who participated in the Environment and Development Cohort study. Children’ s IQ scores were assessed using the Wechsler Intelligence Scale at age 6. Bayesian kernel machine regression (BKMR), quantile g-computation models, and elastic net (ENET) models were used to assess the associations of their blood metals mixture with IQ scores. Results: Multivariate linear regression models indicated that postnatal blood manganese exposure at the age of 4 years was significantly negatively associated with children’s IQ [β = − 5.99, 95% confidence interval (CI): −11.37 to − 0.61]. In the multi-chemical BKMR and quantile g-computation model, statistically significant inverse associations were found between the mixture of prenatal and postnatal metals and children’s IQ score (Difference in children’ IQ per quartile increase: −2.83; 95% CI: −5.28, −0.38). Interestingly, we found that manganese levels at both age of 4 and 6 years were contributing factors to children’s IQ in the mixture models, namely, BKMR, quantile g-computation, and ENET models. Conclusions: Multi-pollutant mixtures of prenatal and postnatal exposures to four metals affected child IQ at 6 years of age. We found a relationship between manganese exposure at both age 4, and 6 years and children’s IQ. Additional studies are warranted to confirm these associations and to control the exposure to different metals during pregnancy and preschool childhood.

As the direction and strategies of new ventures depend on the top management team (TMT)’s stability and continuous efforts, we investigate the relationship between executive turnover and research and development (R&D) investment investment. Furthermore, we assess the moderating role of the founder chief executive officer (CEO)’s prior experiences to show that founders’ experiential knowledge mitigates the adverse side effects of executives’ departure. Our empirical analysis utilizes a large pool of firm-level survey datasets comprising 1897 Korean founder-led ventures. The empirical results show that executive turnover reduces R&D intensity, suggesting that new ventures’ longer-term investments may be affected by the instability of the management team. We also show that the negative effects of executive turnover weaken when the founder CEO has a longer prior work experience, prior business group experience, and founding experience. Our findings show that the founder CEO’s entrepreneurship based on valuable prior experiential knowledge mitigates the negative impact of organizational instability. While the TMT factor is essential for a new venture’s survival, our findings show that the manner in which leaders act should also be considered separately.

Purpose: Hypothalamic damage may increase the risk of adulthood obesity and cardiovascular disease in patients with craniopharyngioma. We evaluated the effects of hypothalamic involvement (HI) and growth hormone (GH) discontinuation on cardiovascular risk factors during the transition period in patients with childhood-onset craniopharyngioma. Methods: Thirty-three patients (17 males, 16 females) underwent retesting for adult GH deficiency (GHD) between 2005 and 2020 at Seoul National University Children's Hospital. Postoperative HI was graded by Puget's criteria and data regarding GH replacement were collected. At retesting, body mass index (BMI), fasting blood glucose, insulin, high-density lipoprotein cholesterol (HDL-C), triglycerides, and blood pressure were assessed. Results: The mean age of commencement and discontinuation of GH replacement for childhood GHD was 10.0±3.6 and 15.3±3.1 years, respectively. The mean age at retesting for adult GHD was 17.7±2.5 years. When patients were categorized by post-GH discontinuation duration, those with durations >6 months (n=27) showed lower HDL-C levels than those with <6 months (P=0.037). Patients with extensive HI (n=16) had higher BMI z-scores than did those with no HI or mild HI (P=0.020). Both the extent of HI and longer post-GH discontinuation duration were significantly predictive for decreased HDL-C levels (P<0.05, for both). Conclusion: The extent of HI and GH discontinuation duration during the transition period can increase cardiovascular risks in patients with childhood-onset craniopharyngioma. [ABSTRACT FROM AUTHOR]

Purpose: Hypoparathyroidism (hypoPTH) is the most common complication following thyroidectomy. We investigated the frequency and risk factors of hypoPTH after total thyroidectomy (TT) in pediatric patients with thyroid cancer. Methods: This retrospective study included 98 patients younger than 20 years who were diagnosed with thyroid cancer after TT during 1990–2018 and followed for more than 2 years at Seoul National University Hospital. HypoPTH was defined as receiving active vitamin D (1-hydroxycholecalciferol or 1,25-dihydroxycholecalciferol) after surgery. Results: The study included 27 boys (27.6%) and 71 girls (72.4%). The mean age at diagnosis was 14.9±3.7 years. HypoPTH occurred in 43 patients (43.9%). Twentyone patients (21.4%) discontinued active vitamin D less than 6 months after surgery, while 14 (14.3%) continued active vitamin D for more than 2 years. Tumor multifocality (odds ratio [OR], 3.7 vs. single tumor; P=0.013) and preoperative calcium level (OR, 0.2; P=0.028) were independent predictors of hypoPTH immediately after TT. In addition, age (OR, 0.8; P=0.011) and preoperative calcium level (OR, 0.04; P=0.014) significantly decreased the risk for persistent hypoPTH requiring active vitamin D for more than 2 years. Conclusion: HypoPTH occurred in 43.9% of pediatric thyroid cancer patients after TT in this study. Among them, one-third of patients continued active vitamin D medication for more than 2 years, which was predicted by young age and low preoperative calcium level. [ABSTRACT FROM AUTHOR]