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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.

Abstract Recent advancements in next-generation sequencing (NGS) technologies have created new opportunities for comprehensive screening of multiple parasite species. In this study, we cloned the 18 S rDNA V9 region of 11 species of intestinal parasites into plasmids. Equal amounts and concentrations of these 11 plasmids were pooled, and amplicon NGS targeting the 18 S rDNA V9 region was performed using the Illumina iSeq 100 platform. A total of 434,849 reads were identified, and all 11 parasite species were detected, although the number of output reads for each parasite varied. The read count ratio, in descending order, was as follows: Clonorchis sinensis, 17.2%; Entamoeba histolytica, 16.7%; Dibothriocephalus latus, 14.4%; Trichuris trichiura, 10.8%; Fasciola hepatica, 8.7%; Necator americanus, 8.5%; Paragonimus westermani, 8.5%; Taenia saginata, 7.1%; Giardia intestinalis, 5.0%; Ascaris lumbricoides, 1.7%; and Enterobius vermicularis, 0.9%. We found that the DNA secondary structures showed a negative association with the number of output reads. Additionally, variations in the amplicon PCR annealing temperature affected the relative abundance of output reads for each parasite. These findings can be applied to improve parasite detection methodologies and ultimately enhance efforts to control and prevent intestinal parasitic infections.

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.

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.

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.

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.

Mitotane is an adrenolytic drug that exhibits therapeutic effects within a narrow target range (14–20 μg/dL). Various complications develop if the upper limit is exceeded. We present the case of a 5-year-old girl with breast development, acne, and pubic hair who was diagnosed with an adrenal mass that was subsequently excised. The pathological finding was adrenocortical carcinoma with a high risk of malignancy, and adjuvant therapy (combined mitotane and radiation therapy) was recommended. Mitotane was initiated at a low dose to allow monitoring of the therapeutic drug level, and high-dose hydrocortisone was also administered. However, the patient exhibited elevated adrenocorticotropic hormone levels and vague symptoms such as general weakness and difficulty concentrating. It was important to determine if these symptoms were signs of the neurological complications that develop when mitotane level is elevated. Encephalopathy progression and pubertal signs appeared 6 months after diagnosis, induced by high mitotane level. The mitotane decreased to subtherapeutic level several months after its discontinuation, at which time endocrinopathy (central hypothyroidism, hypercholesterolemia, and secondary central precocious puberty) developed. The case shows that low-dose mitotane can trigger neurological and endocrinological complications in a pediatric patient, indicating that the drug dose should be individualized with frequent monitoring of the therapeutic level.

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.

The Committee on Pediatric Bone Health of the Korean Society of Pediatric Endocrinology has newly developed evidence-based clinical practice guidelines for optimizing bone health in Korean children and adolescents. These guidelines present recommendations based on the Grading of Recommendations, which includes the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. These guidelines include processes of bone acquisition, definition, and evaluation of low bone mineral density (BMD), causes of osteoporosis, methods for optimizing bone health, and pharmacological treatments for enhancing BMD in children and adolescents. While these guidelines provide current evidence-based recommendations, further research is required to strengthen these guidelines.

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

Background Previous studies on the epidemiology and complications of congenital adrenal hyperplasia (CAH) were conducted in Western countries and in children/adolescents. We aimed to explore the epidemiology of CAH, as well as the risk of comorbidities and mortality, in a Korean nationwide case-control study. Methods CAH patients (n=2,840) were included between 2002 and 2017 from the National Health Insurance Service database and the Rare Intractable Disease program. CAH patients were compared, at a 1:10 ratio, with age-, sex-, and index year-matched controls (n=28,400). Results The point prevalence of CAH patients in Korea was 1 in 18,745 persons in 2017. The annual incidence rate declined between 2003 and 2017 from 3.25 to 0.41 per 100,000 persons. CAH patients were at elevated risk for cardiovascular disease (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.4 to 1.9), stroke (OR, 1.7; 95% CI, 1.3 to 2.0), diabetes mellitus (OR, 2.8; 95% CI, 2.6 to 3.1), dyslipidemia (OR, 2.4; 95% CI, 2.2 to 2.6), and psychiatric disorders (OR, 1.5; 95% CI, 1.3 to 1.6). Fracture risk increased in CAH patients aged over 40 years (OR, 1.4; 95% CI, 1.1 to 1.7). CAH patients were at higher risk of mortality than controls (hazard ratio, 1.6; 95% CI, 1.3 to 2.0). Conclusion Our nationwide study showed a recent decline in the incidence of CAH and an elevated risk for cardiovascular, metabolic, skeletal, and psychiatric disorders in CAH patients. Lifelong management for comorbidity risk is a crucial component of treating CAH patients.

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.

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.

Background The effect of intrauterine hyperglycemia on fat mass and regional fat proportion of the offspring of mothers with gestational diabetes mellitus (OGDM) remains to be determined. Methods The body composition of OGDM (n=25) and offspring of normoglycemic mothers (n=49) was compared using dualenergy X-ray absorptiometry at age 5 years. The relationship between maternal glucose concentration during a 100 g oral glucose tolerance test (OGTT) and regional fat mass or proportion was analyzed after adjusting for maternal prepregnancy body mass index (BMI). Results BMI was comparable between OGDM and control (median, 16.0 kg/m2 vs. 16.1 kg/m2). Total, truncal, and leg fat mass were higher in OGDM compared with control (3,769 g vs. 2,245 g, P=0.004; 1,289 g vs. 870 g, P=0.017; 1,638 g vs. 961 g, P=0.002, respectively), whereas total lean mass was lower in OGDM (15,688 g vs. 16,941 g, P=0.001). Among OGDM, total and truncal fat mass were correlated with fasting and 3-hour glucose concentrations of maternal 100 g OGTT during pregnancy (total fat mass, r=0.49, P=0.018 [fasting], r=0.473, P=0.023 [3-hour]; truncal fat mass, r=0.571, P=0.004 [fasting], r=0.558, P=0.006 [3-hour]), but there was no correlation between OGDM leg fat mass and maternal OGTT during pregnancy. Regional fat indices were not correlated with concurrent maternal 75 g OGTT values. Conclusion Intrauterine hyperglycemia is associated with increased fat mass, especially truncal fat, in OGDM aged 5 years.

Abstract Background Adverse metabolic outcomes later in life have been reported among children or young adults who were born as preterm infants. This study was conducted to examine the impact of very preterm/very low birth weight (VP/VLBW) birth and subsequent growth after hospital discharge on cardiometabolic outcomes such as insulin resistance, fasting glucose, and systolic and diastolic blood pressure (BP) among children at 6–8 years of age. Methods This retrospective cohort study included children aged 6–8 years and compared those who were born at

Abstract We evaluated trajectories of glycated hemoglobin (HbA1c) levels and body mass index z-scores (BMIz) for 5 years after diagnosis among Korean children and adolescents with type 1 diabetes (T1D) or type 2 diabetes (T2D) using the common data model. From the de-identified database of three hospitals, 889 patients

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.

Abstract Prematurity, size at birth, and postnatal growth are important factors that determine cardiometabolic and neurodevelopmental outcomes later in life. In the present study, we aimed to investigate the associations between the size at birth and growth velocity after birth with cardiometabolic and neurodevelopmental outcomes in preterm infants. Fifty-six preterm infants born at

Objectives Bisphenol A (BPA) is used in the electrical, mechanical, medical, and food industries. Previous studies have suggested that BPA is an endocrine disruptor. Regulation of BPA has led to increased use of bisphenol F (BPF) and bisphenol S (BPS). However, few studies have investigated the associations of BPF and BPS with thyroid dysfunction in children. Our study investigated the associations of prenatal BPA and early childhood BPA, BPF, and BPS exposure with thyroid function in 6-year-old children. Methods Prenatal BPA concentrations were measured during the second trimester of pregnancy in an established prospective birth cohort. We measured urinary BPA, BPF, and BPS concentrations and thyroid hormone levels (thyroid-stimulating hormone, total T3, and free T4) in 6-year-old children (n=574). We examined the associations between urinary bisphenol concentrations and percentage change of thyroid hormone concentrations using multivariate linear regression. We also compared thyroid hormone levels by dividing the cohort according to BPA, BPF, and BPS concentrations. Results The associations between prenatal BPA and total T3 levels were statistically significant in all models, except for girls when using a crude model. The associations between urinary BPA and BPS concentrations and levels of all thyroid hormones were not statistically significant. However, we observed that lower free T4 levels (−1.94%; 95% confidence interval, −3.82 to −0.03) were associated with higher urinary BPF concentrations in girls only. Conclusions Our findings identified significant associations between prenatal BPA exposure and total T3 levels in all children and between BPF exposure and free T4 levels in girls only.

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,

Purpose Despite the prevalent use of insulin pump therapy worldwide, few studies have been conducted among young patients with type 1 diabetes (T1D) in Korea. We investigated the durability and effectiveness of insulin pump therapy among Korean pediatric and young adult patients with T1D. Methods This study included 54 patients with T1D diagnosed at pediatric ages (range, 1.1–14.1 years) who initiated insulin pump therapy during 2016–2019 at Seoul National University Children's Hospital and Seoul National University Bundang Hospital. Clinical and biochemical data, including anthropometric measurements, insulin dose, and glycated hemoglobin (HbA1c) levels were obtained from T1D diagnosis to last follow-up. Results Forty-four patients (81.5%) continued insulin pump therapy with a median pump use duration of 2.9 years (range, 0.2–3.5 years); 10 discontinued the therapy within 12 months (

Objectives Prenatal cadmium (Cd) exposure may be associated with attention-deficit/hyperactivity disorder (ADHD) in children. Therefore, the objective of this study was to examine the relationship between Cd exposure during gestation and ADHD at 6 years of age. Methods As part of an ongoing cohort study (the Environment and Development of Children study), 479 mother-child pairs from Seoul, Korea were included for analysis between 2008 and 2011. The whole blood concentration of Cd was analyzed using atomic absorption spectrophotometry. The parents were surveyed about ADHD behaviors in their children at age 6. Multivariable linear regression models were used to investigate the relationship between prenatal exposure to Cd and ADHD at 6 years of age. Results Increased prenatal Cd concentrations were associated with increased scores for ADHD for girls, but not for boys, at age 6. A 2-fold increase in the prenatal Cd level was significantly associated with a 22.3% (95% confidence interval, 11.6 to 34.1) increase in ADHD in girls at 6 years of age, as indicated by the linear regression model. Conclusions Our results identified significant associations between prenatal Cd exposure and ADHD scores in 6-year-old girls.

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.

There is a lack of studies regarding the long-term outcomes of Asian adults with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. We hypothesized that adults with CAH are at higher metabolic risk than their age-, and sex-matched controls. We further investigated the long-term health outcome-related factors in adults with CAH. We compared metabolic risk between adults with CAH (71 men, 93 women) and age-, and sex-matched controls (190 men, 261 women) from the Korean National Health and Nutrition Examination Survey data. The presence of obesity, testicular adrenal rest tumors (TARTs), and menstrual irregularity was assessed. Hormone status and treatment regimens were compared according to the presence of adverse outcomes. The median age was 27.0 y and 28.0 y for men and women, respectively. Adults with CAH had a higher waist circumference (88.0 vs. 82.3 cm in men, and 83.5 vs. 72.3 cm in women), and blood pressure (125.0 vs. 113.0 mmHg in men, and 120.0 vs. 104.0 mmHg in women) than age- and sex-matched controls (P

Per- or polyfluoroalkyl substances (PFAS), a family of synthetic polyfluorinated compounds, are widely used in consumer products. Ubiquitous exposures to PFAS, in consideration of their persistence, bioaccumulation potential, and toxicities have led to concerns regarding possible harmful effects during critical periods of development in early-life and long-term consequences on health. The potential effects of PFAS depend on various factors including the type of PFAS and the timing and level of exposure. We performed a systematic review of the epidemiologic literature to assess the effects of early-life PFAS exposure on prenatal and postnatal growth, adiposity, and puberty in children and adolescents. For birth size, most studies indicated that prenatal PFAS exposure, in particular long-chain PFAS, may impair fetal growth, albeit some reports of null associations with maternal PFAS. For growth within 2 years of age, prenatal PFAS exposure showed no associations with height and either null or negative associations with weight. However, postnatal PFAS exposures were inversely related to height and weight at 2 years in a cross-sectional study. For postnatal adiposity, prenatal PFAS may mostly have negative associations with body mass index in the first 2 years of life, but positive relationships with adiposity in childhood and adolescence, although some studies showed null associations. For puberty, the evidence for associations between early-life PFAS exposure and pubertal development or sex hormone levels were limited and inconclusive. From experimental studies, plausible mechanisms through which PFAS may affect early-life growth and puberty include PFAS-induced activation of peroxisome proliferator-activated receptor, alterations of thyroid or steroid hormone synthesis and metabolism, and their weak estrogenic or anti-androgenic properties. Although the published literature suggests possible effects of PFAS exposures on early-life growth, adiposity, and puberty, current human evidence is limited in establishing PFAS-induced effects on early-life physical development. Further investigation is warranted to clarify PFAS-induced effects on growth and physical development in consideration of the critical time-window of exposure, concomitant exposure to chemical mixtures including various PFAS types, and possible non-monotonic dose-response relationship for growth and adiposity trajectories.

Purpose Patients with Turner syndrome (TS) have increased risk of morbidities and mortality related to cardiovascular complications. Cardio-ankle vascular index (CAVI) is a novel method of evaluating arterial stiffness independent of changes in blood pressure. We compared arterial stiffness using CAVI between TS patients and healthy control subjects. Methods Nineteen young women with TS (mean, 26.8 years; range, 20.0–35.1 years) and 23 healthy women matched for age and body mass index (BMI) were recruited for CAVI measurements at Seoul National University Hospital between 2010 and 2013. Anthropometric parameters, fasting blood testing and measurements of CAVI were compared between the 2 groups. Results TS patients were significantly shorter (mean: 150.1 cm vs. 160.7 cm, P

Purpose The aim of this study was to evaluate the prevalence and risk factors for cardiac autonomic neuropathy (CAN) in nonobese nonobese young type 1 diabetes mellitus (T1DM) patients without micro- or macrovascular complications. Methods CAN was assessed in 95 patients with T1DM, aged 18–29 years, using standard cardiovascular reflex tests – heart rate response to deep breathing, standing, and the Valsalva maneuver and blood pressure response to standing. Furthermore, power spectral analyses of overall heart rate variability (HRV), standard deviation of NN intervals (SDNN), and total power (TP) were tested with DiCAN. CAN was defined as abnormal results for at least 1 of the 4 cardiovascular reflex tests. Results The prevalence of CAN was 12.6%. The frequency of one and 2 abnormal reflex tests was 10.5% and 2.1%, respectively. No significant differences were observed in age, sex, mean hemoglobin A1c (HbA1c) level, and duration of diabetes with respect to presence of CAN. Patients with CAN exhibited lower overall HRV parameters (SDNN and TP) compared with those without CAN even though there was no statistical significance. In multivariable analyses, higher mean HbA1c level was significantly associated with lower overall HRV (β=-44.42, P=0.002 for SDNN and β=-2.82, P

Over the last decades, the onset of puberty in girls has occurred earlier, but the tempo of pubertal progression has been relatively slower, resulting in a younger age at puberty onset without a change in age at menarche. Sufficient energy availability and adiposity contribute to early pubertal development, and environmental factors, such as endocrine-disrupting chemicals (EDCs), may affect not only the control of energy balance, but also puberty and reproduction. EDCs are hormonally active substances that can perturb puberty by acting both peripherally on target organs, such as adipose tissue or adrenal glands, and/or centrally on the hypothalamic-pituitary-gonadal (HPG) axis. Depending on whether the exposure takes place earlier during fetal and neonatal life or later during early childhood, EDCs can lead to different outcomes through different mechanisms. Evidence of associations between exposures to EDCs and altered pubertal timing makes it reasonable to support their relationship. However, human epidemiologic data are limited or inconsistent and cannot provide sufficient evidence for a causal relationship between EDC exposure and changes in pubertal timing. Further investigation is warranted to determine the overall or different effects of EDCs exposure during prenatal or childhood windows on pubertal milestones and to reveal the underlying mechanisms, including epigenetic marks, whereby early-life exposure to EDCs affect the HPG-peripheral tissue axis.

BackgroundGlycosylated hemoglobin (HbA1c) has been recommended as a diagnostic test for prediabetes and diabetes. Here, we evaluated the level of agreement between diagnoses based on fasting plasma glucose (FPG) versus HbA1c levels and determined optimal HbA1c cutoff values for these diseases in youth and young adults.MethodsThe study included 7,332 subjects (n=4,129, aged 10 to 19 years in youth group; and n=3,203 aged 20 to 29 years in young adult group) from the 2011 to 2016 Korea National Health and Nutrition Examination Survey. Prediabetes and diabetes were defined as 100 to 125 mg/dL (impaired fasting glucose [IFG]) and ≥126 mg/dL for FPG (diabetes mellitus [DM] by FPG [DMFPG]), and 5.7% to 6.4% and ≥6.5% for HbA1c, respectively.ResultsIn the youth group, 32.5% with IFG had an HbA1c level of 5.7% to 6.4%, and 72.2% with DMFPG had an HbA1c ≥6.5%. In the young adult group, 27.5% with IFG had an HbA1c level of 5.7% to 6.4%, and 66.6% with DMFPG had an HbA1c ≥6.5%. Kappa coefficients for agreement between the FPG and HbA1c results were 0.12 for the youth group and 0.19 for the young adult group. In receiver operating characteristic curve analysis, the optimal HbA1c cutoff for IFG and DMFPG were 5.6% and 5.9% in youths and 5.5% and 5.8% in young adults, respectively.ConclusionUsefulness of HbA1c for diagnosis of IFG and DMFPG in Koreans aged

BackgroundAutonomic nervous system dysfunction is implicated in the development of hypothalamic obesity. We investigated the relationship between hypothalamic involvement (HI), central obesity, and cardiac autonomic dysfunction by assessing heart rate variability (HRV) indices in patients with childhood-onset craniopharyngioma.MethodsA cross-sectional study of 48 patients (28 males, 10-30 years old) with hypothalamic damage after childhood-onset craniopharyngioma was performed. Postoperative HI was graded as mild (n = 19) or extensive (n = 29) on magnetic resonance imaging. Anthropometry, body composition and HRV indices including the standard deviation of all normal R-R intervals (SDNN) and total power (TP) as overall variability markers, root-mean square differences of successive R-R intervals (RMSSD) and high frequency (HF) as parasympathetic modulation markers, and low frequency (LF) as a sympathetic/sympathovagal modulation marker were measured.ResultsPatients with extensive HI had increased means of body mass index, waist circumference, and fat mass than those with mild HI (P < 0.05, for all). Centrally obese patients had a lower mean HF, a parasympathetic modulation marker, than centrally non-obese patients (P < 0.05). The extensive HI group had lower means of overall variability (SDNN and TP), parasympathetic modulation (HF), and sympathetic/sympathovagal modulation (LF) than the mild HI group (P < 0.05, for all). The interaction effect of HI and central obesity on HRV indices was not significant. In models adjusted for age, sex, and family history of cardiometabolic disease, the means of the overall variability indices (P < 0.05 for both SDNN and TP) and a sympathetic/sympathovagal modulation index (P < 0.05 for LF) were lower with extensive HI, without differences according to central obesity.ConclusionsThe reduced HRV indices with extensive HI suggests that hypothalamic damage may contribute to cardiac autonomic dysfunction, underscoring the importance of minimizing hypothalamic damage in patients with childhood-onset craniopharyngioma.

Low-iodine diet (LID) is a crucial preparation for radioactive iodine (RAI) treatment or scan in thyroid cancer. The aim of this study is to analyze the influence of thyroid stimulating hormone (TSH) stimulation protocols and other clinical factors on LID adequacy. Thyroid cancer patients who underwent LID for RAI scan or treatment were retrospectively analyzed. Patients were guided to have LID for 2 weeks before RAI administration and urine iodine/creatinine ratio (UICR, μg/g Cr) was measured. TSH stimulation was conducted using either thyroid hormone withdrawal (THW) or recombinant human TSH (rhTSH) injection. Adequacy of LID was classified by UICR as 'excellent (< 50)', 'adequate (50-100)', 'inadequate (101-250)' and 'poor (> 250)'. A total of 1715 UICR measurements from 1054 patients were analyzed. UICR was significantly higher in case of rhTSH use than THW (72.4 ± 48.1 vs. 29.9 ± 45.8 μg/g Cr, P < 0.001). In patients who underwent LID twice using both TSH stimulation protocols alternately, UICR was higher in case of rhTSH than THW regardless of the order of method. Among clinical factors, female, old-age, and the first LID were significant factors to show higher UICR. Although the adequacy of LID was 'adequate' or 'excellent' in most patients, multivariate analysis demonstrated that THW method, male, young age, and prior LID-experience were significant determinants for achieving 'excellent' adequacy of LID. In conclusion, UICR was higher and the proportion of 'excellent' LID adequacy was lower with rhTSH than with THW. UICR was higher also in women, old-age, and LID-naïve patients. Further researches are required to suggest effective methods to reduce body iodine pool in case of rhTSH use and to validate the efficacy of such methods on outcomes of RAI treatment.

ObjectivesVitamin D is essential for bone health. Not only total but also free 25-hydroxyvitamin D (25OHD) may contribute to bone mass. We sought to determine which vitamin D measure best reflected clinical and bone parameters in healthy children.MethodsA cross-sectional study including 146 healthy children (71 boys, 9.5 ± 1.9 years) conducted at a tertiary medical center. We used a multiplex liquid chromatography-tandem mass spectrometry-based assay to simultaneously measure vitamin D metabolites. The bioavailable and free 25OHD (25OHDBioA and 25OHDFree) levels were calculated using the genotype-specific or genotype-constant affinity coefficients of vitamin D-binding proteins (yielding spe-25OHDBioA, spe-25OHDFree and con-25OHDBioA, con-25OHDFree respectively). The 25OHDFree level was directly measured (m-25OHDFree). Bone mineral content (BMC) and bone mineral density (BMD) were assessed via dual-energy X-ray absorptiometry.ResultsThe total 25OHD (25OHDTotal), the two forms of 25OHDBioA, the three forms of 25OHDFree, and 24,25-dihydroxyvitamin D3 levels correlated with parathyroid hormone level (all p < 0.01). Serum 25OHDTotal and m-25OHDFree levels were influenced by age, pubertal status, season, body mass index (BMI), daylight hours, and vitamin D intake (all p < 0.05). The con-25OHDBioA and con-25OHDFree levels better reflected pubertal status and daylight hours than did the spe-25OHDBioA and spe-25OHDFree levels (both p < 0.01). The association between the 25OHDTotal level and bone parameters varied according to the BMI (interaction p < 0.05). In 109 normal-weight children, the con-25OHDBioA and con-25OHDFree levels correlated with total body BMC and BMD (both p < 0.05), whereas the 25OHDTotal and 24,25-dihydroxyvitamin D3 levels were associated with total body BMC (both p < 0.05). No such association was found in overweight or obese children.ConclusionsIn healthy children, total, bioavailable, and free 25OHD levels comparably reflected lifestyle factors. In normal-weight children, the con-25OHDBioA and con-25OHDFree, but not m-25OHDFree levels, reflected bone mass, as did the 25OHDTotal level.

Objectives: Epigenetic mechanisms have been suggested to play a role in the link between in utero exposure to bisphenol A (BPA) and pediatric obesity; however, there is little evidence regarding this mechanism in humans. We obtained data on obesity-associated CpG sites from a previous epigenome-wide association study, and then examined whether methylation at those CpG sites was influenced by prenatal BPA exposure. We then evaluated the relationship between CpG methylation status and body mass index (BMI) in a prospective children’s cohort at ages 2, 4, 6, and 8 years. Methods: Methylation profiles of 59 children were longitudinally analyzed at ages 2 and 6 years using the Infinium Human Methylation BeadChip. A total of 594 CpG sites known to be BMI or obesity-associated sites were tested for an association with prenatal BPA levels, categorized into low and high exposure groups based on the 80th percentile of maternal BPA levels (2.68 μg/g creatinine), followed by an analysis of the association between DNA methylation and BMI from ages 2–8. Results: There was a significant increase in the methylation levels of cg19196862 (IGF2R) in the high BPA group at age 2 years (p = 0.00030, false discovery rate corrected p

Background: Limited studies have investigated the association between prenatal and early childhood phthalate exposures and thyroid function among children. Objectives: To investigate the association between early life phthalate exposure and thyroid function among school-age children, considering both prenatal and early childhood exposures, using longitudinal data from an established prospective cohort. Methods: We measured urinary phthalate metabolite levels during pregnancy and at 2, 4, and 6 years of age and conducted thyroid function tests at 6 years of age. We assessed the associations between phthalate metabolite levels and thyroid function using linear regression and Bayesian kernel machine regression (BKMR) models (n = 492). Results: In linear regression models, a doubling of urinary mono-n-butyl phthalate (MnBP) levels, measured during pregnancy and at 4 years of age, was associated with lower thyroid-stimulating hormone (TSH) levels at 6 years of age (−5.0%, 95% confidence interval [CI]: −8.8%, −1.0% and −5.7%, 95% CI: −9.7%, −1.5%, respectively). A similar association was found between mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) levels at 4 years of age and TSH levels at 6 years of age (−5.5%, 95% CI: −9.7%, −1.1%). Urinary mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) (2.3%, 95% CI: 0.1%, 4.5%) and MEOHP levels at 2 years of age (2.2%, 95% CI: 0.1%, 4.4%) and mono-2-ethyl-5-carboxypentyl phthalate (1.4%, 95% CI: 0.1%, 2.7%) and mono-benzyl phthalate levels at 6 years of age (1.1%, 95% CI: 0.4%, 1.9%) were associated with higher triiodothyronine (T3) levels at 6 years of age. Urinary MnBP during pregnancy, MEHHP, MEOHP, and MnBP at 4 years of age were also associated with lower free thyroxine (fT4) × TSH. In BKMR models, urinary MnBP levels during pregnancy were associated with lower TSH levels and fT4 × TSH (both posterior inclusion probabilities: 0.99). Conclusions: Our findings suggest that early life phthalate exposure influences subsequent thyroid function. However, the results should be interpreted cautiously, because a single spot urine sample was used to quantify the phthalate exposures at each time point.

Purpose The hemoglobin glycation index (HGI) represents the degree of nonenzymatic glycation and has been positively associated with cardiometabolic risk factors (CMRFs) and cardiovascular disease in adults. This study aimed to investigate the association between HGI, components of metabolic syndrome (MS), and alanine aminotransferase (ALT) in a pediatric nondiabetic population. Methods Data from 3,885 subjects aged 10–18 years from the Korea National Health and Nutrition Examination Survey (2011–2016) were included. HGI was defined as subtraction of predicted glycated hemoglobin (HbA1c) from measured HbA1c. Participants were divided into 3 groups according to HGI tertile. Components of MS (abdominal obesity, fasting glucose, triglycerides, high-density lipoprotein cholesterol, and blood pressure), and proportion of MS, CMRF clustering (≥2 of MS components), and elevated ALT were compared among the groups. Results Body mass index (BMI) z-score, obesity, total cholesterol, ALT, abdominal obesity, elevated triglycerides, and CMRF clustering showed increasing HGI trends from lower-to-higher tertiles. Multiple logistic regression analysis showed the upper HGI tertile was associated with elevated triglycerides (odds ratio, 1.65; 95% confidence interval, 1.18–2.30). Multiple linear regression analysis showed HGI level was significantly associated with BMI z-score, HbA1c, triglycerides, and ALT. When stratified by sex, age group, and BMI category, overweight/obese subjects showed linear HGI trends for presence of CMRF clustering and ALT elevation. Conclusions HGI was associated with CMRFs in a Korean pediatric population. High HGI might be an independent risk factor for CMRF clustering and ALT elevation in overweight/obese youth. Further studies are required to establish the clinical relevance of HGI for cardiometabolic health in youth.

Androgen insensitivity syndrome (AIS) is a rare genetic disease caused by various abnormalities in the androgen receptor (AR). The AR is an essential steroid hormone receptor that plays a critical role in male sexual differentiation and development and preservation of the male phenotype. Mutations in the AR gene on the X chromosome cause malfunction of the AR so that a 46,XY karyotype male has some physical characteristics of a woman or a full female phenotype. Depending on the phenotype, AIS can be classified as complete, partial or mild. Here, we report 2 cases of complete AIS in young children who showed complete sex reversal from male to female as a result of AR mutations. They had palpable inguinal masses and normal female external genitalia, a blind-end vagina and absent Müllerian duct derivatives. They were both 46,XY karyotype and AR gene analysis demonstrated pathologic mutations in both. Because AIS is inherited in an X-linked recessive manner, we performed genetic analysis of the female family members of each patient and found the same mutation in the mothers of both patients and in the female sibling of case 2. Gonadectomy was performed in both patients to avoid the risk of malignancy in the undescended testicles, and estrogen replacement therapy is planned for their adolescence. Individuals with complete AIS are usually raised as females and need appropriate care.

BackgroundIodine is an intrinsic element of thyroid hormone, which is essential for childhood growth and development. The Ideal Breast Milk (IBM) cohort study aims to evaluate the effects of maternal iodine status during pregnancy and lactation on maternal thyroid function, offspring growth and development, and offspring thyroid function.MethodsThe IBM cohort study recruited pregnant women from Seoul National University Hospital between June 2016 and August 2017, followed by enrollment of their offspring after delivery. For the maternal participants, iodine status is evaluated by urinary iodine concentration (UIC) and dietary records in the third trimester and at 3 to 4 weeks and 12 to 15 months postpartum. For the child participants, cord blood sampling and UIC measurements are performed at birth. At 3 to 4 weeks of age, UIC and breastmilk iodine concentrations are measured. At 12 to 15 months of age, growth and development are assessed and measurements of UIC, a thyroid function test, and ultrasonography are performed.ResultsA total of 198 pregnant women in their third trimester were recruited. Their mean age was 35.1±3.5 years, and 78 (39.4%) of them were pregnant with twins. Thirty-three (16.7%) of them had a previous history of thyroid disease.ConclusionKorea is an iodine-replete area. In particular, lactating women in Korea are commonly exposed to excess iodine due to the traditional practice of consuming brown seaweed soup postpartum. The study of the IBM cohort is expected to contribute to developing guidelines for optimal iodine nutrition in pregnant or lactating women.

Purpose We investigated the clinical characteristics of patients who developed thyroid dysfunction and evaluated the risk factors for hypothyroidism following radiotherapy and chemotherapy in pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). Methods The medical records of 66 patients (42 males) treated for medulloblastoma (n=56) or PNET (n=10) in childhood between January 2000 and December 2014 at Seoul National University Children’s Hospital were retrospectively reviewed. A total of 21 patients (18 high-risk medulloblastoma and 3 PNET) underwent high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) Results During the median 7.6 years of follow-up, 49 patients (74%) developed transient (n=12) or permanent (n=37) hypothyroidism at a median 3.8 years of follow-up (2.9–4.6 years). Younger age (

Abstract The present study aimed to describe the distribution of and to investigate the factors associated with glycated haemoglobin (HbA1c) values in Korean youth (10–19 years old) and young adults (20–29 years old). Data from the Korea Health and Nutrition Examination Survey (2011–2015) were used. A total of 6,418 participants (male 3,140 [53.2%]) aged 10–29 years were included in the analysis. Percentiles of HbA1c were calculated and HbA1c values were compared according to age, sex, and associated factors. The mean HbA1c values (% [mmol/mol]) were 5.42 ± 0.01 (35.7 ± 0.1) for youths and 5.32 ± 0.01 (34.7 ± 0.1) for young adults (P

Childhood obesity could contribute to adulthood obesity, leading to adverse health outcomes in adults. However, the mechanisms for how obesity is developed are still unclear. To determine the epigenome-wide and genome-wide expression changes related with childhood obesity, we compared microRNome and transcriptome levels as well as leptin protein levels in whole bloods of 12 obese and 24 normal children aged 6 years. miR-328-3p, miR-1301-3p, miR-4685-3p, and miR-6803-3p were negatively associated with all obesity indicators. The four miRNAs were also associated with 3948 mRNAs, and separate 475 mRNAs (185 among 3948 mRNAs) were associated with all obesity indicators. The 2533 mRNAs (64.2%) among the 3948 mRNAs and 286 mRNAs (60.2%) among the 475 mRNAs were confirmed as targets of the four miRNAs in public databases through miRWalk 2.0. Leptin protein was associated with miR-6803-3p negatively and all obesity indicators positively. Using DAVID bioinformatics resources 6.8, top three pathways for obesity-related gene set were metabolic pathways, pathways in cancer, and PI3K-Akt signaling pathway. The top three obesity-related disease classes were metabolic, cardiovascular, and chemdependency. Our results support that childhood obesity could be developed through miRNAs-related epigenetic mechanism and, further, these obesity-related epigenetic changes could control the pathways related with the development of various diseases.