Search

The relationship between androgen excess and bone health in patients with congenital adrenal hyperplasia (CAH) with 21-hydroxylase (21-OH) deficiency is not fully understood. This study demonstrated positive correlations between androgen hormones and bone mineral density (BMD) in CAH women with 21-OH deficiency.This study aims to assess BMD and its association with androgen excess in women with CAH.We enrolled 92 women with CAH with 21-OH deficiency and retrospectively reviewed their clinical features, hormone concentrations, body composition, glucocorticoid (GC) dose, and BMD.BMD was not different according to the subtypes of CAH. BMD at the lumbar spine was lower in women with CAH with regular menstruation than those with irregular menstruation (1.081 vs. 1.165 g/cmAndrogen excess may have a protective effect on BMD in women with classic CAH and high cumulative doses of GC.

Phthalates are well-known endocrine-disrupting chemicals. Many detrimental health effects of phthalates were investigated, but studies on the association of phthalates with obesity in children showed inconsistent results. Thus, this systematic review and meta-analysis were performed to clarify whether prenatal and postnatal exposures to phthalates are associated with physical growth disturbances in children. We performed the systematic review and meta-analysis following the PRISMA 2020 statement guidelines, and found 39 studies that met our inclusion criteria, including 22 longitudinal and 17 cross-sectional studies. We observed a significant negative association between the prenatal exposure to DEHP and the body mass index (BMI) z-score of the offspring (β = − 0.05; 95% CI: − 0.10, − 0.001) in the meta-analysis, while no significant association between the prenatal exposure to DEHP and the body fat percentage of the offspring was observed (β = 0.01; 95% CI: − 0.41, 0.44). In the systematic review, studies on the association between phthalates exposure in childhood and obesity were inconsistent. Prenatal exposure to phthalates was found to be associated with decreased BMI z-score in children, but not associated with body fat percentage. Our findings suggest that phthalates disturb the normal muscle growth of children, rather than induce obesity, as previous studies have hypothesized.

Air pollution has been reported to be an environmental risk factor for autism spectrum disorder. However, the gut microbiome's role as a potential mediator has not been investigated. We aimed to clarify whether particulate matter with an aerodynamic diameter ≤10 μm (PMsub10/sub) and nitrogen dioxide (NOsub2/sub) exposure impact autistic traits through the gut microbiome. Using 170 mother-child pairs, PMsub10/suband NOsub2/subexposure levels during pregnancy (1st, 2nd, and 3rd trimesters) and annual residential PMsub10/sublevels at age 2, 4, and 6 years were estimated. Autistic traits and gut microbiome were assessed at age 6 years. The associations of PMsub10/subor NOsub2/subexposure, gut microbiome composition, and autistic traits were explored, and mediation analyses of statistically significant findings were also conducted. Exposure to PMsub10/subduring the 1st trimester of pregnancy was associated with increased autistic traits (10.6% change per interquartile range (IQR) increase, 95% confidence interval [CI]: 1.1, 21.0) and with Proteobacteria relative abundance at age 6 years (66.9% change per IQR increase, 95% CI: 21.3, 129.8). First trimester NOsub2/subexposure was associated with autistic traits (12.1% change, 95% CI: 0.1, 25.5) and Proteobacteria relative abundance at age 6 years (48.1% change, 95% CI: -0.1, 119.6). Proteobacteria relative abundance was related to autistic traits (4.4% change per 2-fold increase, 95% CI: 1.3, 7.5). Relations between PMsub10/subor NOsub2/subexposure during the 1st trimester and autistic traits at age 6 years were partially mediated by Proteobacteria (proportion mediated 23.2%, p = 0.01 and 16.7%, p = 0.06; respectively). PMsub10/suband possibly NOsub2/subexposure during early pregnancy may affect autistic traits at age 6 years through the alteration of Proteobacteria abundance.

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.

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.

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.

Purpose: There is increasing use of modern devices in the management of patients with type 1 diabetes (T1D). We investigated temporal trends for diabetes management and outcomes in Korean pediatric...

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.

Background The GNAS gene on chromosome 20q13.3 is a complex, imprinted locus regulated in a tissue-specific manner. GNAS inactivation disorders are a heterogeneous group of rare disorders caused by mutations and methylation defects. These are divided into pseudohypoparathyroidism (PHP) types 1A and 1B, pseudo-pseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH), depending on the presence or absence of hormone resistance, Albright’s hereditary osteodystrophy (AHO), and ectopic ossification. Methods This study analyzed the clinical characteristics and molecular genetic backgrounds of 18 Korean patients from 16 families with a genetically confirmed GNAS defect. Auxological parameters, AHO phenotypes, types of hormonal resistance, family history, and molecular genetic disturbances were reviewed retrospectively. Results Nine (90%) patients with PHP1A showed resistance to parathyroid hormone (PTH) and all patients showed elevated thyroid-stimulating hormone (TSH) levels at diagnosis. Eight (80%) patients were managed with levothyroxine supplementation. Three of six patients with PHP1B had elevated TSH levels, but none of whom needed levothyroxine medication. AHO features were absent in PHP1B. Patients with PPHP and POH did not show any hormone resistance, and both of them were born as small for gestational age. Among the 11 families with PHP1A, PPHP, and POH, eight different (three novel) mutations in the GNAS gene were identified. Among the six patients with PHP1B, two were sporadic cases and four showed isolated loss of methylation at GNAS A/B:TSS-DMR. Conclusions Clinical and molecular characteristics of Korean patients with GNAS inactivation disorders were described in this study. Also, we reaffirmed heterogeneity of PHP, contributing to further accumulation and expansion of current knowledge of this complex disease.

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, Pl0.001 for TP). Conclusion CAN can be detected in 12.6% of young adult T1DM patients even without other micro- or macrovascular complications. Glycemic control is the main determinant to maintain overall HRV and prevent CAN.

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, Pl0.001) and had lower body weight (mean: 47.0 kg vs. 55.5 kg, P=0.014) than healthy controls, without difference in BMI. CAVI (6.5±0.6 vs. 6.1±0.6, P=0.039) was significantly higher in TS patients compared to healthy controls. Age was positively associated with CAVI (r=0.403, P=0.008) in univariate analysis. After adjusting for age, TS was associated with CAVI (P=0.006). Conclusion Young women with TS showed increased arterial stiffness measured by CAVI compared to healthy women after adjusting for age, suggesting inherent vasculopathy in TS patients.

Because novel cultivars and plant breeders are protected by intellectual property rights internationally, cultivar breeding has become vital. Domestic private seed companies have not focused on the development of novel cultivars of ornamental crops in Korea; therefore, the Rural Development Administration (RDA) has been breeding novel cultivars of ornamental crops, including cymbidium orchids since 1992. In Korea, the area under cultivation and sales of cymbidium were 44 ha and approximately $8 million in 2017. Because cymbidium, one of the major orchids cultivated in Korea, requires a relatively long period for the development of novel cultivars compared with other ornamental crops, RDA breed four cultivars, including ‘Beauty Princess,’ until in 2003 and then had been bred 51 novel cultivars by 2017. In addition, Chisan Agricultural Association Corporation (Chisan AAC) bred 26 novel cultivars, such as ‘Pinklace,’ with the support of RDA from 2008 to 2015. Such cultivars were distributed to farms and sold at wholesale flower markets, such as the aT Flower Marketing Center (aT FMC) of the Korea Agro-Fisheries and Food Trade Corporation, as potted plants or cut flowers. Therefore, farmers have recently acknowledged the improvement of domestic cultivars. An investigation of cymbidium sold as potted plants at the aT FMC from 2009 to 2017 revealed that 21 of 51 RDA cultivars and 7 of 26 Chisan AAC cultivars were sold during 1 to within 5 years. The number of domestic cultivar potted plants sold per year ranged from 2,568 to 5,693 except in 2010 and 2015, which represents 1.5% - 2.1% of all the cymbidium. The prices of domestic cultivars with two, three, and four flower stalks, which accounted for 65.2% - 97.6% of all the cymbidium, were lower at the highest price, higher at average price, and much higher at the lowest price than the prices of foreign cultivars with similar flower stalk numbers. The sales of cymbidium potted plants at other wholesale flower markets, such as Korea flower agriculture corporative, needs to be investigated. Overall, the results of the study suggest that domestic cultivars are not inferior in value compared with foreign cultivars.

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.

Accurate investigations of adrenal hormone levels play a vital role in pediatric endocrinology for the detection of steroid-related disorders. In this study, we developed and validated a simultaneous assay for eight serum steroids, i.e., DHEA, androstenedione, testosterone, progesterone, 17‑hydroxyprogesterone, DHEA‑sulfate, pregnenolone‑sulfate and cholesterol-sulfate, using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Serum samples were prepared by liquid-liquid extraction with methyl t‑butyl ether. Quantitation by LC-MS/MS was performed in multiple reaction monitoring mode with an electrospray ionization source. The run time was 10 min. Analytical performance was evaluated, including imprecision, linearity, ion suppression, carry over and detection capabilities. Serum specimens from 59 children and 120 adults were analyzed to compare the distribution of steroid levels between the groups. All hormones were effectively extracted and separated using our method. The method was essentially free from potential interference and ion suppression. Within-run and between-run imprecision values were20%. The lower limits of quantification varied from 0.025 to 10 ng/mL. The results were generally good and correlated with those obtained using immunoassay techniques. We developed the HPLC-MS/MS method for the simultaneous measurement of free and sulfated steroid hormones. The performance of the developed method was generally acceptable. Thus, this method may provide a novel approach to steroid profiling in children of age before adrenarche.

Background Pyrethroid pesticides are reported to be the most commonly used residential insecticides worldwide. We aimed to investigate the relationship between prenatal and postnatal 3-phenoxybenzoic acid (3-PBA) concentrations, and growth and adiposity parameters in 4-year-old children. Method We obtained data from 578 children who participated in the prospective Environment and Development of Children (EDC) study at around 4 years of age (45–55 months) between August 2008 and July 2011. Anthropometric measurements were obtained at age 4 years. Prenatal and postnatal urinary 3-PBA concentration was measured in maternal urine samples at around 20 weeks of gestation, and in the 4-year-old children, respectively. Result The detection frequency of urinary 3-PBA (geometric mean concentration) was 98–99% (0.98 μg/g Cr) in maternal urine, and almost 99–100% (1.34 μg/g Cr) in 4-year-old children. Prenatal urinary3-PBA concentration was not associated with height, weight, or body mass index (BMI) z-scores at 4 years of age, regardless of sex. Postnatal urinary3-PBA concentration was not related to height z-scores, but was positively associated with weight z-scores with marginal significance among only girls (p = 0.058). Analyzed by sex, there was a significant relationship between postnatal urinary 3-PBA concentration and BMI z-scores (p = 0.015) among girls, after adjusting for covariates. Conclusion Childhood urinary 3-PBA concentration measured at 4 years of age was positively associated with BMI z-scores in 4-year-old girls, but prenatal urinary 3-PBA concentration at midterm pregnancy exhibited no association.

The pathogenic free-living amoeba Naegleria fowleri causes primary amoebic meningoencephalitis, a fatal infection, by penetrating the nasal mucosa and migrating to the brain via the olfactory nerves. N. fowleri can induce host cell death via lytic necrosis. Similar to phosphorylation, O-linked β-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) is involved in various cell-signaling processes, including apoptosis and proliferation, with O-GlcNAc addition and removal regulated by O-GlcNAc transferase and O-GlcNAcase (OGA), respectively. However, the detailed mechanism of host cell death induced by N. fowleri is unknown. In this study, we investigated whether N. fowleri can induce the modulation of O-GlcNAcylated proteins during cell death in Jurkat T cells. Co-incubation with live N. fowleri trophozoites increased DNA fragmentation. In addition, incubation with N. fowleri induced a dramatic reduction in O-GlcNAcylated protein levels in 30 min. Moreover, pretreatment of Jurkat T cells with the OGA inhibitor PUGNAc prevented N. fowleri–induced O-deGlcNAcylation and DNA fragmentation. These results suggest that O-deGlcNAcylation is an important signaling process that occurs during Jurkat T cell death induced by N. fowleri.

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 p p p

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

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 p = 0.036) and perceptional reasoning index (β = 0.456, p = 0.003) of K-WISC-IV were positively correlated with postnatal weight gain in the neonatal intensive care unit. Although cardiometabolic outcomes were comparable in preterm SGA and AGA infants, the growth velocity at different time periods resulted in different cardiometabolic and neurocognitive outcomes. Thus, ensuring an optimal growth velocity at early neonatal period could promote good neurocognitive outcomes, while adequate growth after 1 year could prevent adverse cardiometabolic outcomes in preterm infants.

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.

Epigenetics is known to be involved in regulatory pathways through which greenness exposure influences child development and health. We aimed to investigate the associations between residential surrounding greenness and DNA methylation changes in children, and further assessed the association between DNA methylation and children’s intelligence quotient (IQ) in a prospective cohort study. We identified cytosine-guanine dinucleotide sites (CpGs) associated with cognitive abilities from epigenome- and genome-wide association studies through a systematic literature review for candidate gene analysis. We estimated the residential surrounding greenness at age 2 using a geographic information system. DNA methylation was analyzed from whole blood using the HumanMethylationEPIC array in 59 children at age 2. We analyzed the association between greenness exposure and DNA methylation at age 2 at the selected CpGs using multivariable linear regression. We further investigated the relationship between DNA methylation and children’s IQ. We identified 8743 CpGs associated with cognitive ability based on the literature review. Among these CpGs, we found that 25 CpGs were significantly associated with greenness exposure at age 2, including cg26269038 (Bonferroni-corrected p ≤ 0.05) located in the body of SLC6A3, which encodes a dopamine transporter. DNA methylation at cg26269038 at age 2 was significantly associated with children’s performance IQ at age 6. Exposure to surrounding greenness was associated with cognitive ability-related DNA methylation changes, which was also associated with children’s IQ. Further studies are warranted to clarify the epigenetic pathways linking greenness exposure and neurocognitive function.

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.

Background: Adverse metabolic outcomes later in life have been reported among children or young adults who were born small for gestational age. This study was conducted to examine the impact of preterm birth and subsequent growth after hospital discharge on cardiometabolic risks among early school-aged children. Methods: This case-control study included school-aged children born prematurely (n = 60) and at term (n = 110). Body size, fat mass, blood pressure (BP), glucose, insulin, leptin, adiponectin, and lipid profiles were measured. Weight z-score changes between discharge and early school-age period were also calculated, and factors associated with BP and insulin resistance were analyzed.Results: Early school-aged children who were born preterm had lower fat masses, higher systolic BP and diastolic BP, and higher values of fasting glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR), compared to children born at term. Preterm birth was correlated with HOMA-IR and BPs after adjusting for various factors, including fat mass index and weight z-score changes. Weight z-score changes were associated with HOMA-IR, but not with BPs. Conclusions: Although early school-aged children born prematurely showed lower weight and fat mass, they had higher BPs, fasting glucose, HOMA-IR, and leptin levels. The associations of preterm birth with cardiometabolic factors were independent of weight, fat mass and weight gain velocity.

BACKGROUND: 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 th...

Background The short-stature homeobox-containing gene (SHOX) is one of the major growth genes in humans. The clinical spectrum of SHOX haploinsufficiency ranges from Leri–Weill dyschondrosteosis to idiopathic short stature. Herein, we describe the clinical and genetic characteristics of 23 Korean patients with SHOX deficiency disorders. Methods Medical records of 23 patients (19 females and 4 males) from 15 unrelated families who were genetically confirmed to have SHOX deficiency were retrospectively reviewed. SHOX gene deletions or mutations were determined by sequence analyses using multiplex ligation-dependent probe amplification, chromosomal microarray, and/or Sanger sequencing methods. Results In the 15 families, 9 probands were de novo cases. All 23 patients showed mesomelia. Madelung deformity and tibia vara were observed in 13 (56.5%) and 3 (13.1%) patients, respectively. Genetically, 11 (73.3%) of the 15 families showed SHOX deletions of various sizes, and the other 4 families harboured SHOX sequence variants. Four patients had undergone orthopaedic surgeries (3 for tibia vara and 1 for Madelung deformity). Among 7 patients who had received growth hormone treatment for ≥1 year, 5 showed good responses, with a median first-year change-in-height standard deviation score of +0.6. There were no significant differences in the clinical characteristics of the deletion and point mutation groups. Conclusions A high index of suspicion and the genetic confirmation of SHOX deficiency are helpful for the timely management of the condition and are needed to provide genetic counselling to the family members of the patients.

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 < 0.10) but not at age 6. With one standard deviation increase of methylation at cg19196862 (IGF2R) at age 2 years, the linear mixed model analysis revealed that BMI during ages 2-8 years significantly increased by 0.49 (95% confidence interval; 0.08, 0.90) in girls, but not in boys. The indirect effect of prenatal BPA exposure on early childhood BMI through methylation at cg19196862 (IGF2R) at age 2 years was marginally significant.CONCLUSIONS: Prenatal exposure to BPA may influence differential methylation of IGF2R at age 2. This result indicates that a possible sensitive period of DNA methylation occurs earlier during development, which may affect BMI until later childhood in a sex-specific manner.

Trichomonas vaginalis, a flagellated extracellular protozoan parasite that infects the human genitourinary tract, is usually transmitted by sexual contact. Our previous study showed that the leukotriene B4 (LTB4 ), a T vaginalis-secreted lipid mediator, induces interleukin (IL)-8 production and promotes mast cell degranulation and migration via BLT1 in human. In this study, we investigated whether T vaginalis produces another leukotrienes and whether it causes increased MCP-1 production, mast cell migration and degranulation by activating mast cells. We found that cysteinyl leukotrienes (CysLTs) were contained in T vaginalis-derived secretory product (TvSP) by ELISA. The TvSP-stimulated human mast cell line (HMC-1) exhibited significantly increased monocyte chemoattractant protein-1 (MCP-1) secretion compared to the unstimulated cells. Inhibition of NOX2 activation of cells by treatment of NOX inhibitor or NOX2 siRNA reduced TvSP-stimulated MCP-1 production in HMC-1 cells. It was also confirmed that the receptor for CysLTs is expressed in mast cells. The CysLT receptor (CysLTR) antagonist inhibited TvSP-stimulated MCP-1 production of mast cells, as well as ROS production, migration and degranulation of mast cells, and reduced phospho-NF-kB expression. These results suggest that T vaginalis-secreted CysLTs promote migration, degranulation and MCP-1 production in human mast cells through CysLT receptor-mediated NOX2 activation.

Background Silver-Russell syndrome (SRS) is a pre- or post-natal growth retardation disorder caused by (epi)genetic alterations. We evaluated the molecular basis and clinical value of sequential epigenetic analysis in pediatric patients with SRS. Methods Twenty-eight patients who met≥3 Netchine-Harbison clinical scoring system (NH-CSS) criteria for SRS were enrolled;26 (92.9%) were born small for gestational age, and 25 (89.3%) showed postnatal growth failure. Relative macrocephaly, body asymmetry, and feeding difficulty were noted in 18 (64.3%), 13 (46.4%), and 9 (32.1%) patients, respectively. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) on chromosome 11p15 was performed as the first diagnostic step. Subsequently, bisulfite pyrosequencing (BP) for imprinting center 1 and 2 (IC1 and IC2) at chromosome 11p15, MEST on chromosome 7q32.2, and MEG3 on chromosome 14q32.2 was performed. Results . Seventeen (60.7%) patients exhibited methylation defects, including loss of IC1 methylation (N=14; 11 detected by MS-MLPA and three detected by BP) and maternal uniparental disomy 7 (N=3). The diagnostic yield was comparable between patients who met three or four of the NH-CSS criteria (53.8% vs 50.0%). Patients with methylation defects responded better to growth hormone treatment. Conclusions NH-CSS is a powerful tool for SRS screening. However, in practice, genetic analysis should be considered even in patients with a low NH-CSS score. BP analysis detected additional methylation defects that were missed by MS-MLPA and might be considered as a first-line diagnostic tool for SRS.

Background: Exposure to perfluoroalkyl substances (PFAS) has been suggested to affect thyroid function; however, data on early-life exposure and thyroid function in early childhood are scarce. We i...

Background Previous studies have suggested links between exposure to ambient air pollutants and increased risk of congenital heart defects. However, few studies have investigated the association between other congenital diseases and traffic-related air pollution. In this study, we assessed the relationship between prenatal exposure to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) with congenital diseases in South Korea. Methods Patients with one or more congenital diseases and a control group of patients with non-infective gastroenteritis and colitis with a case:control ratio of 1:3 were obtained from the National Health Insurance Service data for 2008–2013 in South Korea. We estimated the associations of PM2.5 and NO2 exposures with congenital diseases using generalized estimation equations after controlling for covariates. Results Maternal PM2.5 exposure during the first and second trimester showed positive associations with overall congenital diseases, with changes of 14.7% (95% confidence intervals (CI), 9.3%, 20.3%) and 16.2% (95% CI, 11.0%, 21.7%), respectively, per 11.1 μg/m3 and 10.2 μg/m3 increase of PM2.5 interquartile range (IQR). Similarly, NO2 exposure during the first and second trimester was associated with increased numbers of overall congenital anomalies, with 8.2% (95% CI, 4.2%, 12.3%) and 15.6% (95% CI, 9.3%, 22.2%) more cases, respectively, per 10.6 ppb increase of NO2. We found that maternal PM2.5 exposure during the first and second trimesters of pregnancy was significantly associated with increased risk of specific congenital diseases, including subtypes affecting the circulatory, genitourinary, and musculoskeletal system. However, no significant associations were observed during the third trimester. Maternal NO2 exposure across the entire pregnancy was associated with malformations of the musculoskeletal system. Conclusions Our study identified significant links between in utero exposure to PM2.5 and NO2 and certain congenital diseases, and suggests that stricter controls on PM2.5 and NO2 concentrations are required.

Background: Primary goal of growth hormone (GH) treatment for short children is to achieve an adult height in the normal range. Different GH treatment strategies to achieve this goal include titration of GH dose according to serum insulin-like growth factor I (IGF-I) concentrations. However, IGF-I levels do not always correlate well with the growth response. The purpose of this study is to identify the factors affecting IGF-I concentration in each disease and to correct the related factors and then to identify the relationship between IGF-1 and treatment response. Methods: In this study, data of pre-pubertal children with idiopathic growth hormone deficiency (IGHD), organic GHD (OGHD), Turner syndrome (TS), small for gestational age (SGA) who were treated with recombinant human GH more than one year were obtained from the LGS Database. The LGS has been progressing since 2012 and is an open-label, multicenter, prospective, and retrospective observational study. Results: Among 2,021 registered in LGS, the subjects were 366 except for the violation of selection criteria. Among them, IGHD was 252, 16 OGHD, 31 TS, and 67 SGA. The mean age of IGHD was 6.02, and the mean bone age was 4.49 years. OGHD was 7.38, 5.74, TS was 7.13, 6.52, and SGA was 5.61, 4.96 years. The height SDS according to chronologic age was -2.76 in IGHD group, OGHD -2.33, TS -2.9, SGA -2.57. In the IGHD and SGA group, IGF-I level has a positive correlation with weight and BMI (weight; r=0.0071 in IGHD, r=0.0009 in SGA, BMI; r=0.0411 in IGHD, r=0.003 in SGA). IGF-I showed a negative correlation with chronological age in the IGHD group (r=0.0411) and mid-parental height in the SGA group (r=0.0069). There was no significant relationship between pretreatment IGF-I level and growth response. However, in the IGHD group, the growth response was significantly higher when the change in IGF-I SDS value was 1 or more (P=0.0013). Conclusion: This study is the first study using LGS data to identify factors affecting IGF-I levels in Korean children with short stature and the relationship with treatment response. IGF-I levels were positively correlated with body weight in IGHD and SGA groups. There was no significant relationship between pre-treatment IGF-I levels and post-treatment growth response. In conclusion, IGF-I concentrations should be used as a tool for treatment compliance rather than for efficacy determination.

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. Conclusion 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 Mullerian 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.

Objective Pheochromocytoma and paraganglioma (extra-adrenal pheochromocytoma) are rare neuroendocrine tumors that arise from the neuroendocrine cells. Chronic hypoxia is known as a possible cause, and a strong link between cyanotic congenital heart disease and these tumors has been reported. However, reports of phechromocytoma/paraganglioma in Fontan patients were scarce. We herein report seven cases of phechromocytoma/paraganglioma after Fontan operation at a single tertiary center. Methods We retrospectively reviewed medical records and imaging studies who diagnosed as phechromocytoma/paraganglioma after Fontan operation in Seoul National University Children's Hospital. Results Seven patients were identified during follow-up after Fontan operation, and the prevalence was 2.5% among Fontan patients greater than 10 years old on active follow-up. Three patients were diagnosed as phechromocytoma and 4 patients as paraganglioma. Median time interval between Fontan operation and diagnosis of pheochromocytoma/paraganglioma was 21.4 years (range, 10.4-29.7 years). Resting percutaneous oxygen saturation varied from 77% to 94%. All patients underwent complete tumor resection. Phechromocytoma recurred in two patients, of whom one patient died at the age of 18 years due to the tumor progression with multiple metastasis and aggravation of heart failure with profound cyanosis. Pheochromocytoma/paraganglioma developed after hepatocellular carcinoma in two patients. Conclusion Phechromocytoma/paraganglioma could occur in Fontan patients more than expected. Because it is curable by tumor resection during its early phase, early diagnosis and treatment of pheochromocytoma are crucial in Fontan patients not to make hemodynamic deterioration and aggravation of heart failure.

Trichomonas vaginalis is a sexually-transmitted protozoan parasite that causes vaginitis and cervicitis. Although mast cell activation is important for provoking tissue inflammation during infection with parasites, information regarding the signaling mechanisms in mast cell activation and T. vaginalis infection is limited. O-linked N-acetylglucosamine (O-GlcNAc) is a post-translational modification of serine and threonine residues that functions as a critical regulator of intracellular signaling, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). We investigated if O-GlcNAcylation was associated with mast cell activation induced by T. vaginalis-derived secretory products (TvSP). Modified TvSP collected from live trichomonads treated with the 5-lipooxygenase inhibitor AA861 inhibited migration of mast cells. This result suggested that mast cell migration was caused by stimulation of T. vaginalis-secreted leukotrienes. Using the BLT1 antagonist U75302 or BLT1 siRNA, we found that migration of mast cells was evoked via LTB4 receptor (BLT1). Furthermore, TvSP induced protein O-GlcNAcylation and OGT expression in HMC-1 cells, which was prevented by transfection with BLT1 siRNA. TvSP-induced migration, ROS generation, CD63 expression and IL-8 release were significantly suppressed by pretreatment with OGT inhibitor ST045849 or OGT siRNA. These results suggested that BLT1-mediated OGlcNAcylation was important for mast cell activation during trichomoniasis.

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 (l5 years) at radiation exposure (P=0.014 vs. ≥9 years) and HDCT (P=0.042) were significantly predictive for hypothyroidism based on log-rank test. However, sex, type of tumor, and dose of craniospinal irradiation (less vs. more than 23.4 Gy) were not significant predictors. Cox proportional hazard model showed that both younger age (l5 years) at radiation exposure (hazard ratio [HR], 3.1; vs. ≥9 years; P=0.004) and HDCT (HR, 2.4; P=0.010) were significant predictors of hypothyroidism. Conclusion Three-quarters of patients with pediatric medulloblastoma or PNET showed thyroid dysfunction, and over half had permanent thyroid dysfunction. Thus, frequent monitoring of thyroid function is mandatory in all patients treated for medulloblastoma or PNET, especially, in very young patients and/or high-risk patients recommended for HDCT/ASCR.

Background: We investigated iodine status and its association with thyroid function among preschool children residing in iodine-sufficient area. Methods: From the Environment and Development of Children study, 477 children were evaluated for thyroid function and urine iodine concentration (UIC) at age 6 during 2015-2017. After excluding children born with multiple birth and with congenital hypothyroidism or Hashimoto thyroiditis, 439 (231 boys) were included. Subclinical hypothyroidism (SCH) was defined as thyroid stimulating hormone (TSH) levels between 4.9-10 μIU/mL with normal free T4 levels. Iodine status was evaluated by UIC and children were categorized into 4 groups: iodine deficient (UIC < 100 μg/L), adequate (UIC, 100-299 μg/L), mild excessive (UIC, 300-999 μg/L), severe excessive (UIC ≥ 1000 μg/L). Results: Goiter was palpated in 64 (14.6%) with female predominance (26.0% vs. 4.3%, P < 0.001). Serum level of free T4 and T3 was 1.2 ± 0.1 ng/dL and 148.1 ± 18.5 ng/dL, respectively. The median TSH level was 2.3 (0.53-8.59) μIU/mL and the prevalence of SCH was 4.3% without sex-difference. The median UIC level was 606.2 (19.9-16409.7) μg/L, higher in boys (684 vs. 545 μg/L, P = 0.021) than in girls. Iodine was deficient in 19 (4.3%), adequate in 96 (21.9%), mild excessive in 170 (38.7%), and severe excessive in 145 (35.1%). After excluding 19 iodine deficient children, the relationship between iodine status and thyroid function was evaluated by multiple regression analysis after adjusting for age, sex, birth weight, gestational age, body mass index Z-score, and family history. As iodine status increased from adequate, mild excessive to severe excessive group, T3 levels decreased, and TSH levels increased with marginal significance (P for trend < 0.1 for T3 and TSH). When stratified by sex, similar association was found in only girls (P for trend = 0.043 for T3, and 0.062 for TSH) but not in boys, and mild excessive group showed lower free T4 levels (β = -0.05, P = 0.013) and severe excessive group had lower T3 levels (β = -7.04, P = 0.035) than iodine adequate group in only girls, but not in boys. Conclusion: Iodine was deficient in 4.3%, adequate in 21.9%, and excessive in 73.8% among preschool children residing in South Korea. As iodine status increased from adequate to excessive group, TSH levels increased with decreasing free T4 and T3 levels in girls.

Background: We evaluated cardiovascular risk factors at the time of growth hormone (GH) retesting after completion of linear growth in patients with childhood-onset craniopharyngioma (CP). We also investigated the effects of postoperative hypothalamic involvement (HI) and GH discontinuation during transition period on cardiovascular risk factors. Methods: Forty-two CP patients (24 males, mean age 17.7 years) who reached final adult height after GH therapy between 1995 and 2012 from a tertiary center were included. We measured anthropometric data and components of the metabolic syndrome at the time of GH retesting. The period of GH discontinuation was classified as < 6 months vs. ≥ 6 months. The extent of HI was categorized into “no”, “mild”, and “extensive” HI according to Puget grading system. Results: The mean age of initial operation after CP diagnosis was 7.5 ± 3.6 years, and 23 (54.8%) patients showed extensive HI. All patients were treated with GH during childhood for median 5.8 years (range 2.4-8.2years). Duration of GH discontinuation was median 1.5 years (range 0.5-3.2 years), and 32 (76.2%) had GH discontinuation ≥ 6 months. At the time of GH retesting, 13 (31.0%) were obese, and the proportion of patients with impaired fasting glucose (≥ 100 mg/dL), high triglycerides (≥ 150 mg/dL), low high-density lipoprotein (HDL) cholesterol (male, < 40 mg/dL; female, < 50 mg/dL), and hypertension (systolic blood pressure ≥ 130mmHg or diastolic blood pressure ≥ 85mmHg) was 5 (11.9%), 18 (42.9%), 24 (57.1%), and 5 (11.9%), respectively. When multivariate-adjusted models were constructed including age, sex, postoperative duration, extent of HI, duration of GH discontinuation, and family history of cardiovascular disease, the extent of HI was significantly predictive for increased body mass index z-score (β = 1.27, P = 0.017), fasting insulin levels (β = 7.1, P = 0.049), HOMA-IR (β = 1.61, P = 0.020), and decreased HDL cholesterol levels (β = -9.9, P = 0.012). GH discontinuation more than 6 months was significantly associated with decreased HDL cholesterol levels (β = -10.23, P = 0.026). Conclusion: In this study, impaired fasting glucose or hypertension accounted for one-tenth, and dyslipidemia was detected in more than half of childhood-onset CP patients with GH deficiency at the time of GH retesting. The more extensive HI and the longer duration of GH discontinuation were associated with increased risk of metabolic disturbance during the transition period.

Introduction: Adiposity rebound (AR) refers to the increase in body mass index (BMI) that follows the BMI nadir in childhood. Earlier AR increases the likelihood of being overweight/obese and may lead to early pubertal advancement, especially in girls. We aimed to evaluate the longitudinal changes in anthropometrics, bone age (BA), and breast development in relation to AR timing in girls. Methods: This study included girls (n = 349) of the Environment and Development of Children (EDC) cohort, a prospective cohort of healthy children started in 2012 with biennial visits to study the effects of environmental exposures on physical and neurobehavioral development. The BMI trajectories of girls with 3 or more measurements between 2 and 8 years of age (n = 242) were visually inspected to determine AR timing. After excluding preterm and multiple births, 204 girls were included and categorized according to the age at AR: group 1 (

Objectives Vitamin 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. Methods A 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. Results The 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. Conclusions In 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.

Purpose We investigated the clinical course of infants with congenital heart disease (CHD) who experienced thyroid dysfunction within 100 days of birth. Methods We performed retrospective medical reviews of 54 CHD patients (24 male patients) who underwent a thyroid function test (TFT) between January 2007 and July 2016. Data were collected on birth history, diagnosis of CHD, underlying chromosomal or genetic abnormalities, medication history, surgery, ventilator care, and exposure to iodine contrast media (ICM). Results of neonatal screening tests (NSTs) and TFTs were reviewed. Results A total of 36 patients (29 transient, 7 permanent) showed thyroid dysfunction. Among the seven patients with permanent hypothyroidism, three had an underlying syndrome, three showed abnormal NST results, and one was admitted to the intensive care unit for macroglossia and feeding cyanosis. We found that infants with transient thyroid dysfunction had a lower birth weight and were more commonly exposed to thyroid disrupting medication and/or ICM. However, these risk factors were not significant. A total of 8 patients with a history of ICM exposure showed thyroid dysfunction. Excluding 3 patients with elevated thyroid stimulating hormone before ICM exposure, 5 patients recovered from transient thyroid dysfunction. Conclusions We observed thyroid dysfunction in two-thirds of CHD infants (53.7% transient, 13.0% permanent) who had risk factors and received TFT screening within 100 days, despite normal NSTs. Further studies with larger sample sizes are required to revise the criteria for TFT screening in CHD infants.