Familial chylomicronemia syndrome: case reports of siblings with deletions of the GPIHBP1 gene.

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.

Relationship of bisphenol A substitutes bisphenol F and bisphenol S with adiponectin/leptin ratio among children from the environment and development of children cohort.

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 (ß = 0.160, P= 0.044), higher fat mass (ß = 0.104, P< 0.001), lower adiponectin concentration (ß =- 0.069, P< 0.001), higher leptin concentration (ß = 0.360, P< 0.001), and lower A/L ratio (ß =- 0.428, P< 0.001) compared with the non-detected group. The urinary BPF-detected group had a higher fat mass (ß = 0.074, P< 0.001), lower adiponectin concentration (ß =- 0.069, P< 0.001), higher leptin concentration (ß = 0.360, P< 0.001), and lower A/L ratio (ß =- 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.

Risk Factors for Treatment-Related Amenorrhea in Female Survivors of Childhood and Adolescent Cancer: 10-Year Experiences at Oncofertility Clinic in Korean Tertiary Center.

Purpose: This study investigates the impact of gonadotoxic cancer treatment on treatment-related amenorrhea (TRA) and hormonal status in pediatric and adolescent females who underwent fertility preservation (FP) consultation. Methods: A retrospective review was conducted on 143 females under 21 with cancer referred to the FP clinic at Seoul National University Hospital between 2011 and 2022. We analyzed variables, including age, menarche status, cancer type, and treatment. Subsequently, subjects were evaluated to identify clinical factors affecting TRA at 1-year intervals following the completion of treatment. Upon cancer diagnosis, all patients received FP counseling and underwent semiannual evaluations for menstrual resumption and hormonal status. Results: The median age at diagnosis was 15; menarche was reported in 76.9%. Bone sarcoma (16.1%) and acute lymphoblastic leukemia (14.7%) were predominant. Most consultations (74.8%) occurred pretreatment. After FP consultations, 9.8% of patients underwent oocyte cryopreservation, and 99.3% used gonadotropin-releasing hormone agonists during systemic chemotherapy. One year after treatment completion, TRA was shown in 29.4% of this cohort. Cyclophosphamide-equivalent dose >4000 mg/m2 (adjusted odds ratio [aOR], 2.279; 95% confidence interval [CI]; 1.018-5.105, p = 0.045) and pelvic irradiation (aOR, 16.271; 95% CI, 1.545-171.408; p = 0.020) were independent clinical factors predicting TRA. Conclusion: The study delineates the clinical factors affecting TRA in pediatric and adolescent cancer survivors, revealing the significant impact of specific treatment. The data highlight the critical role of personalized oncofertility consultations in this demographic, offering valuable insights for designing targeted FP strategies at tertiary centers.

Involvement of NOX2-derived ROS in human hepatoma HepG2 cell death induced by Entamoeba histolytica.

Entamoeba histolytica is an enteric tissue-invasive protozoan parasite causing amoebic colitis and liver abscesses in humans. Amoebic contact with host cells activates intracellular signaling pathways that lead to host cell death via generation of caspase-3, calpain, Ca2+ elevation, and reactive oxygen species (ROS). We previously reported that various NADPH oxidases (NOXs) are responsible for ROS-dependent death of various host cells induced by amoeba. In the present study, we investigated the specific NOX isoform involved in ROS-dependent death of hepatocytes induced by amoebas. Co-incubation of hepatoma HepG2 cells with live amoebic trophozoites resulted in remarkably increased DNA fragmentation compared to cells incubated with medium alone. HepG2 cells that adhered to amoebic trophozoites showed strong dichlorodihydrofluorescein diacetate (DCF-DA) fluorescence, suggesting intracellular ROS accumulation within host cells stimulated by amoebic trophozoites. Pretreatment of HepG2 cells with the general NOX inhibitor DPI or NOX2-specific inhibitor GSK 2795039 reduced Entamoeba-induced ROS generation. Similarly, Entamoeba-induced LDH release from HepG2 cells was effectively inhibited by pretreatment with DPI or GSK 2795039. In NOX2-silenced HepG2 cells, Entamoeba-induced LDH release was also significantly inhibited compared with controls. Taken together, the results support an important role of NOX2-derived ROS in hepatocyte death induced by E. histolytica.

Effects of iodine status on thyroid volume and goiter in children living in an iodine-replete area.

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 (<100 µg/L), adequate (100-299 µg/L), mild excess (300-499 µg/L), moderate excess (500-999 µg/L), and severe excess (≥1000 µg/L). Tvol was measured using US, and a goiter on the US (goiter-US) was defined as Tvol greater than 97th percentile value by age- and body surface area (BSA)-specific international references. Results: The median Tvol was 2.4 mL, larger than the international reference value (1.6 mL). The age- and BSA-specific goiter-US rates were 25.9% (n = 59) and 34.6% (n = 79), respectively. The prevalence of excess iodine was 73.7% (n = 168). As iodine status increased from adequate to severe excess, the goiter-US rate significantly increased (P for trend <0.05). The moderate and severe iodine excess groups showed higher risk of goiter-US (adjusted odds ratio (aOR) = 3.1 (95% CI: 1.1-9.2) and aOR = 3.1 (95% CI: 1.2-8.3), respectively; age-specific criteria) than the iodine-adequate group. Conclusions: Excess iodine was prevalent in Korean children, and their Tvol was higher than the international reference values. Goiter rate was associated with iodine excess, which significantly increased in the moderate and severe iodine excess groups. Further studies are warranted to define optimal iodine intake in children.

Surgical indication of pediatric Rathke's cleft cyst based on a 20-year retrospective cohort.

OBJECTIVE: Rathke's cleft cyst (RCC) is the most commonly encountered pituitary incidentaloma in children. Because RCC is not frequently diagnosed in children, there are few reports on pediatric RCCs. The natural course of the disease and appropriate treatments are still obscure. The present study aimed to elucidate the natural history and surgical indications of RCCs in children. METHODS: The authors retrospectively reviewed the clinical presentations, imaging features, ophthalmological evaluations, endocrine evaluations, and surgical outcomes of pediatric RCCs at a single institution from January 2000 to October 2022. Clinical outcomes between the surgery and observation groups were compared. RESULTS: Among 93 patients, there were 41 patients in the surgery group and 52 patients in the observation group. The mean age at diagnosis was 10.9 years, and the mean follow-up period was 5.6 years. Headache fully or partially improved after surgery (86.2%), but the rate of improvement was not different from that of the observation group (70.0%). Ophthalmological abnormalities were effectively improved by surgical treatment (93.3%). Both the improvement and deterioration rates of endocrine abnormalities were significantly higher in the surgery group (p = 0.026 and p < 0.001, respectively), but the deterioration rate (43.9%) was higher than the improvement rate (14.6%). In the surgery group, the recurrence rate was 17.1% and the reoperation rate was 4.9%. Compared with total cyst wall resection, cyst fenestration with partial wall resection was associated with a higher recurrence rate (26.9%, p = 0.035) but a lower rate of endocrine abnormalities (30.8%, p = 0.049). CONCLUSIONS: Pediatric RCCs of ≥ 10 mm in size were analyzed. Ophthalmological abnormalities are the major surgical indications for pediatric RCCs. Headache and partial endocrine abnormalities may be improved with surgery, but they are not absolute indications for surgery. Cyst fenestration with partial wall resection via an endoscopic endonasal approach is the most recommended surgical method. Follow-up is essential to monitor for the occurrence of visual field defects and the recurrence of cysts.

Serum steroid profile captures metabolic phenotypes in adults with classic congenital adrenal hyperplasia.

OBJECTIVES: Adult patients with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency have an increased risk of metabolic diseases. We aimed to investigate whether liquid chromatography-mass spectrometry (LC-MS)-based serum steroid profiling reveals metabolic phenotypes in adults with classic CAH. DESIGN AND METHODS: This study prospectively enrolled 63 adult patients with CAH and 38 healthy volunteers. The levels of the 24 steroids were quantified in the morning serum using LC-MS. Unsupervised clustering algorithms were applied to the serum steroid profiles to identify unique patterns associated with metabolic syndrome. RESULTS: Serum steroid profiles of patients with CAH were clearly delineated from those of healthy controls with a higher degree of interindividual heterogeneity. The unsupervised clustering algorithm divided CAH patients into two clusters based on serum steroid profile. Cluster 2 showed higher serum levels of glucocorticoids and androgens than cluster 1. The prevalence of metabolic syndrome was significantly higher in cluster 2 than in cluster 1 (37.8 % vs. 5.6 %, P = 0.011). Other clinical characteristics, including age, sex, body mass index, CAH subtypes, and glucocorticoid dose, did not differ between the two clusters. The multivariate logistic regression model of selective 15 steroids could discriminate metabolic syndrome in patients with CAH with an area under the receiver operating characteristic curve of 0.832 (95 % confidence interval:0.732-0.933). CONCLUSIONS: Serum steroid profiles can be valuable biomarkers for estimating metabolic risk in adult patients with CAH.

DNA methylation is associated with prenatal exposure to sulfur dioxide and childhood attention-deficit hyperactivity disorder symptoms.

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.

Relationship of iodine excess with thyroid function in 6-year-old children living in an iodine-replete area.

Background: Adequate 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. Methods: A 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. Results: The 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 (ß = - 0.04, p = 0.032 for mild excess; ß = - 0.04, p = 0.042 for severe excess) and T3 levels (ß = - 8.12, p = 0.009 for mild excess; ß = - 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 (ß = 0.04, p = 0.046). Conclusion: Excess 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.

Association between early-childhood exposure to perfluoroalkyl substances and ADHD symptoms: A prospective cohort study.

There is evidence that exposure to perfluoroalkyl substances (PFAS) is associated with attention-deficit/hyperactivity disorder (ADHD) symptoms. Previous studies have focused on prenatal exposure to PFAS, and only few studies have examined the associations of early-childhood exposure, especially at low exposure levels. This study explored the association between early-childhood exposure to PFAS and ADHD symptoms later in childhood. In 521 children, we measured the serum levels of six PFAS in peripheral blood at the ages of 2 and 4 years, including perfluorooctanoate (PFOA), perfluornonanoicacid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonic acid (PFHxS), and perfluorooctane sulfonate (PFOS). The ADHD Rating Scale IV (ARS) was utilized to measure ADHD traits at 8 years of age. We explored the relationship between PFAS and ARS scores using Poisson regression models after adjusting for potential confounders. Levels of exposure to individual PFAS and the summed value were divided into quartiles to examine possible nonlinear relationships. All six PFAS exhibited inverted U-shaped curves. Children in the 2nd and 3rd quartile levels of each PFAS showed higher ARS scores than those in the1st quartile level. Below the 3rd quartile of the summed levels of six PFAS (ΣPFAS), a doubling of the ΣPFAS was associated with an 20.0 % (95 % CI: 9.5 %, 31.5 %) increase in ADHD scores. However, at the age of 4 years, none of the evaluated PFAS exhibited linear or nonlinear associations with the ARS scores. Thus, school-aged children may be vulnerable to the neurotoxic effects of exposure to PFAS at age 2 that contribute to ADHD, particularly at low to mid-levels.

Area-Specific, Hierarchical Nanowrinkling of Two-Dimensional Materials.

This paper describes an approach to generate hierarchical wrinkles in two-dimensional (2D) electronic materials with spatial control over adjacent wavelengths. A rigid fluoropolymer mold was used to pattern a sacrificial polymer skin layer on monolayer graphene, molybdenum disulfide, and hexagonal boron nitride on prestrained thermoplastic sheets. Strain relief and removal of the polymer layer resulted in 2D-material wrinkles whose wavelengths scaled linearly with the local skin thickness. A second generation of wrinkles could be created on top of the first generation by applying a subsequent cycle of polymer skin coating, strain relief, and polymer removal. This area-specific hierarchical wrinkling is general and will facilitate the engineering of the local properties of various 2D materials and their heterostructures.

Relationship Between the Serum FGF21 Level and Growth in Children of Short Stature.

BACKGROUND: This study investigated the relationship between fibroblast growth factor 21 (FGF21) levels and growth in children with growth hormone deficiency (GHD) and idiopathic short stature (ISS), and the effects of the FGF21 level on response to growth hormone (GH) treatment. METHODS: We included 171 pre-pubertal children with a GHD (n = 54), ISS (n = 46), and normal height (n = 71). Fasting FGF21 levels were measured at baseline and every 6 months during GH treatment. Factors associated with growth velocity (GV) after GH therapy were investigated. RESULTS: The FGF21 level was higher in short children than in the controls without significant difference between the GHD and ISS groups. In the GHD group, the FGF21 level was inversely associated with the free fatty acid (FFA) level at baseline (r = -0.28, P = 0.039), however, was positively correlated with the FFA level at 12 months (r = 0.62, P = 0.016). The GV over 12 months of GH therapy was positively associated with the delta insulin-like growth factor 1 level (ß = 0.003, P = 0.020). The baseline log-transformed FGF21 level was inversely associated with GV with marginal significance (ß = -0.64, P = 0.070). CONCLUSION: The FGF21 level was higher in children of short stature, both those with GHD and the ISS, than in children with normal growth. The pretreatment FGF21 level negatively affected the GV of children with GH-treated GHD. These results suggest the existence of a GH/FFA/FGF21 axis in children.

Clinical Manifestations and Outcomes of 20 Korean Hypochondroplasia Patients with the FGFR3 N540K variant.

BACKGROUND: Hypochondroplasia is a skeletal dysplasia caused by activating pathologic variants of FGFR3. The N540K variant accounts for 60-70% of reported cases and is associated with severe manifestations. Here, we analyze the clinical manifestations and outcomes of Korean patients with hypochondroplasia harboring the FGFR3 N540K variant. METHODS: Medical records of 20 unrelated patients with genetically confirmed N540K-related hypochondroplasia were retrospectively reviewed. All individuals were diagnosed with hypochondroplasia by Sanger sequencing for FGFR3, or target-panel sequencing for skeletal dysplasia. The effectiveness of growth hormone therapy was analyzed in 16 patients treated with growth hormones. RESULTS: Among 20 patients (7 men, 13 women), the mean age at first visit was 3.5±1.0 years, and the mean follow-up duration was 6.8±0.6 years. The patients presented with a short stature and/or short limbs. Genu varum, macrocephaly, and developmental delay were observed in 11 (55.0%), 9 (45.0%), and 5 (25.0%) patients, respectively. Of the 12 patients who underwent neuroimaging, five (41.7%) showed abnormal findings (one required operation for obstructive hydrocephalus). Among 16 growth-hormone-treated patients (two were growth-hormone deficient), the increase in height standard deviation scores was significant after a mean 5.4±0.7 years of treatment (+0.6 and+1.8 using growth references for healthy controls and achondroplasia children, respectively). Four patients underwent surgical limb lengthening at a mean age of 8.8±3.3 years. CONCLUSIONS: Neurodevelopmental abnormalities are frequently observed in patients with N540K-related hypochondroplasia. Close monitoring of skeletal manifestations and neurodevelopmental status is necessary for hypochondroplasia.

High intakes of iodine among women during pregnancy and the postpartum period has no adverse effect on thyroid function.

PURPOSE: Given the high consumption of seaweed soup by pregnant and lactating Korean women, concerns have been raised about excessive iodine intake. We evaluated the effects of maternal iodine intake on maternal thyroid function and birth outcomes. We also evaluated iodine intake via seaweed soup during late pregnancy and the early postpartum period. METHODS: A total of 349 pregnant women of the Ideal Breast Milk cohort were recruited in late pregnancy, of whom 302 revisited after delivery. Three-day dietary records were assessed at each visit. Blood was collected for thyroid function test. Obstetrical and birth outcomes were obtained. RESULTS: The median dietary iodine intake was 459 µg/day (interquartile range [IQR] 326.5-647.4 µg/day) during pregnancy. Dietary iodine intake by quartile was not significantly associated with maternal thyroid status, or obstetrical or neonatal outcomes. However, the dietary iodine intake in the early postpartum period was 1759 µg/day (IQR 1026.7-2491.1 µg/day) because of a marked increase in seaweed soup consumption. Of all women, 25.8% consumed seaweed soup more than once over the 3 days of dietary records when pregnant, but the figure rose to 93.4% postpartum. Of postpartum women who consumed seaweed soup daily, the median dietary iodine intakes were 1355, 2394, and 3063 µg/day (soup at one, two, and three-or-four meals). CONCLUSIONS: In these iodine-replete pregnant women, dietary iodine intake during pregnancy showed no effect on maternal thyroid function or birth outcomes. However, iodine intake in the early postpartum period was markedly increased by the frequency of seaweed soup consumption.

The effect of hypothalamic involvement and growth hormone treatment on cardiovascular risk factors during the transition period in patients with childhood-onset craniopharyngioma.

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

Risk factors of postoperative hypoparathyroidism after total thyroidectomy in pediatric patients with thyroid cancer.

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. CONCLUSION: HypoPTH occurred in 43.9% of pediatric thyroid cancer patients after TT in this study. Among them, one-third of patients continued active vitamin D medication for more than 2 years, which was predicted by young age and low preoperative calcium level.

Free, bioavailable 25-hydroxyvitamin D levels and their association with diabetic ketoacidosis in children with type 1 diabetes at diagnosis.

Background: Considering 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. Methods: This 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. Results: Patients 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. Conclusion: Patients 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.

The mediating role of the gut microbiome in the association between ambient air pollution and autistic traits.

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 (PM10) and nitrogen dioxide (NO2) exposure impact autistic traits through the gut microbiome. Using 170 mother-child pairs, PM10 and NO2 exposure levels during pregnancy (1st, 2nd, and 3rd trimesters) and annual residential PM10 levels at age 2, 4, and 6 years were estimated. Autistic traits and gut microbiome were assessed at age 6 years. The associations of PM10 or NO2 exposure, gut microbiome composition, and autistic traits were explored, and mediation analyses of statistically significant findings were also conducted. Exposure to PM10 during 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 NO2 exposure 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 PM10 or NO2 exposure 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). PM10 and possibly NO2 exposure during early pregnancy may affect autistic traits at age 6 years through the alteration of Proteobacteria abundance.

Long-term health outcomes of early menarche in women: an umbrella review.

BACKGROUND: There is limited comprehensive evidence on the potential association between early menarche and subsequent health outcomes. AIM: To evaluate the existing evidence for the association of early menarche with later health outcomes and assesse the strength and validity of the evidence for these associations. DESIGN: Umbrella review. METHODS: We searched PubMed, Web of Science, Embase, CINAHL, Cochrane Database of Systematic Reviews and Google Scholar, and manually screened retrieved references to find systematic reviews and meta-analyses from inception to July 2021. Early menarche was defined by taking into account ethnicity and birth year, and the outcomes were long-term consequences in adulthood. RESULTS: Thirteen reviews encompassing 283 original articles and over 6.8 million participants from 39 countries across 5 continents were included. In categorical outcomes, early menarche was associated with metabolic syndrome (n = 37 543 pooled adjusted relative risk [aRR] 1.56, 95% confidence interval (CI) 1.33, 1.83; high certainty [Hi]), endometrial cancer (n = 874 188, aRR 1.40, 95% CI 1.17, 1.68; Hi), type 2 diabetes mellitus/impaired glucose tolerance (n = 1 185 444, aRR 1.30, 95% CI 1.19, 1.42; Hi), breast cancer (n = 103 574, aRR 1.19, 95% CI 1.06, 1.33; Hi), death from all causes (n = 152 747, aRR 1.11, 95% CI 1.03, 1.19; Hi), obesity (n = 54 006, aRR 1.68, 95% CI 1.53, 1.84; moderate certainty [Mod]), gestational diabetes mellitus (n = 48 535, aRR 1.32, 95% CI 1.09, 1.58; Mod), hypertension (n = 1 682 689, aRR 1.24, 95% CI 1.20, 1.29; Mod), endometriosis (n = 885 390, aRR 1.22, 95% CI 1.09, 1.37; Mod), ovarian cancer (n = 1 022 451, aRR 1.17, 95% CI 1.04, 1.31; Mod) and asthma (n = 22 859, aRR 1.31, 95% CI 1.09, 1.57; low certainty [Lo]). For continuous outcomes, early menarche was associated with increased body mass index (BMI) in adults ≥40 years of age (n = 121 943, adjusted pooled standardized mean difference [aSMD] 0.30, 95% CI 0.28, 0.32; Mod), BMI in adults <40 years of age (n = 124 728, aSMD 0.39, 95% CI 0.36, 0.43; Mod), serum fasting insulin level (n = 17 020, aSMD 0.52, 95% CI 0.48, 0.57; Mod) and homeostatic model assessment of insulin resistance (n = 7925, aSMD 0.27, 95% CI 0.19, 0.35; Mod). CONCLUSION: We found varied levels of evidence for the association between early menarche and the development of subsequent health problems. Our results recommend that physicians should pay attention to these associations, as early menarche can be a potential indicator of metabolic disorders and female-specific cancer and cause death in women.

Case Report and Review of Literature: Autosomal Recessive Hypophosphatemic Rickets Type 2 Caused by a Pathogenic Variant in ENPP1 Gene.

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.