Hye Rim Chung

Iodine and thyroid function

Severe iodine deficiency causes hypothyroidism that results in impaired somatic growth and motor development in children. Mild and moderate iodine deficiencies cause multifocal autonomous growth of thyroid, which results in thyrotoxicosis. On the other hand, iodine excess is associated with the development of hypothyroidism and thyroid autoimmunity. In areas of iodine deficiency, a sudden increase in iodine intake is associated with transient hyperthyroidism. Recent studies demonstrated that long-term thyroid function of subjects who experienced both iodine deficiency and iodine excess during childhood tended to be abnormal despite optimization of their current iodine intake. Iodine status in the Korean Peninsula is very unique because people in the Republic of Korea have been shown to have predominantly excessive iodine levels, whereas the Democratic Peoples Republic of Korea is known to be an iodine-deficient area. Further research is warranted to verify the optimal ranges of iodine intake and to clarify the effects of iodine intake on thyroid disorders in the Korean Peninsula.

Clinical characterization and identification of two novel mutations of the GNAS gene in patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism

Objective  Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are rare disorders resulting from genetic and epigenetic aberrations in the GNAS locus.

High allele frequency of the p.Q258X mutation and identification of a novel mis-splicing mutation in the STAR gene in Korean patients with congenital lipoid adrenal hyperplasia.

OBJECTIVE Steroidogenic acute regulatory (STAR) protein plays a crucial role in steroidogenesis, and mutations in the STAR gene cause congenital lipoid adrenal hyperplasia (CLAH). This study investigated the STAR mutation spectrum and functionally analyzed a novel STAR mutation in Korean patients with CLAH. METHODS Mutation analysis of STAR was carried out in 25 unrelated Korean CLAH patients. A region of STAR comprising exons 4-7 was cloned from human genomic DNA into an expression vector, followed by site-directed mutagenesis and transient expression in COS7 cells. The splicing pattern was analyzed by in vitro transcription, and each transcript was functionally characterized by measuring pregnenolone production in COS7 cells cotransfected with the cholesterol side chain cleavage system. RESULTS Mutation p.Q258X was identified in 46 of 50 alleles (92%); mutation c.653C>T was detected in two alleles (4%); and mutations p.R182H and c.745-6_810del were found in one allele (2%). Reverse transcriptase-PCR products amplified from a patient heterozygous for compound c.653C>T and c.745-6_810del mutation revealed multiple alternatively spliced mRNAs. In vitro expression analysis of a minigene consisting of exons 4-7 containing the c.653C>T yielded two transcripts in which exon 6 or exons 5 and 6 were skipped. The encoded proteins exhibited defective pregnenolone-producing ability. The c.745-6_810del mutation led to full and partial intron retention. CONCLUSIONS p.Q258X is the most common STAR mutation in Korea. A previously reported c.653C>T variant was found to cause aberrant splicing at the mRNA level, resulting in perturbation of STAR function. The c.745-6_810del mutation also resulted in aberrant splicing.

Adrenal and thyroid function in the fetus and preterm infant

Adrenal and thyroid hormones are essential for the regulation of intrauterine homeostasis, and for the timely differentiation and maturation of fetal organs. These hormones play complex roles during fetal life, and are believed to underlie the cellular communication that coordinates maternal-fetal interactions. They serve to modulate the functional adaptation for extrauterine life during the perinatal period. The pathophysiology of systemic vasopressor-resistant hypotension is associated with low levels of circulating cortisol, a result of immaturity of hypothalamic-pituitary-adrenal axis in preterm infants under stress. Over the past few decades, studies in preterm infants have shown abnormal clinical findings that suggest adrenal or thyroid dysfunction, yet the criteria used to diagnose adrenal insufficiency in preterm infants continue to be arbitrary. In addition, although hypothyroidism is frequently observed in extremely low gestational age infants, the benefits of thyroid hormone replacement therapy remain controversial. Screening methods for congenital hypothyroidism or congenital adrenal hyperplasia in the preterm neonate are inconclusive. Thus, further understanding of fetal and perinatal adrenal and thyroid function will provide an insight into the management of adrenal and thyroid function in the preterm infant.

Independent relationships of obesity and insulin resistance with serum proinsulin level in prepubertal children with normal glucose tolerance.

Lee YA, Yoo JH, Kim JH, Lee SH, Kim JH, Lim HH, Kang MJ, Chung HR, Lee SY, Shin CH, Yang SW. Independent relationships of obesity and insulin resistance with serum proinsulin level in prepubertal children with normal glucose tolerance.

Clinical and laboratory characteristics of neonatal hypocalcemia

Purpose To describe the clinical characteristics of full-term neonates with hypocalcemia and to suggest factors associated with neonatal hypocalcemia Methods The medical records of full-term neonates with hypocalcemia were reviewed. Hypocalcemia was defined as an ionized calcium (iCa) concentration of <4 mg/dL. Parathyroid hormone (PTH) insufficiency was defined as a serum PTH level of <60 pg/mL or a serum phosphorus level higher than the serum calcium level in the presence of hypocalcemia. Results Fifty-three neonates were enrolled. The median age at diagnosis of hypocalcemia was 3 days. In all the neonates, formula feeding predominance was observed. Thirty-eight neonates (69.8%) were compatible with PTH insufficiency. The number of formula-fed neonates was significantly higher than that of breast-fed patients among neonates with PTH insufficiency (P=0.017). Intact PTH was negatively correlated with serum phosphorus levels. Twelve out of 14 neonates (85.7%) had 25-hydroxy vitamin D (25OHD) levels <20 ng/mL and 9 neonates (64.3%) had 25OHD levels <10 ng/mL. Twenty-one neonates had hypocalcemic tetany. The serum calcium and iCa concentrations of neonates with tetany were 4.2-8.3 mg/dL and 1.85-3.88 mg/dL, respectively. Three neonates showed symptomatic hypocalcemia with calcium levels over 7.5 mg/dL. Among the 16 neonates who underwent electroencephalography (EEG), 12 had abnormalities, which normalized after 1-2 months. Conclusion Formula milk feeding, PTH insufficiency and low serum vitamin D concentration are associated with the development of neonatal hypocalcemia. Symptoms such as tetany and QT interval prolongation can develop in relatively mild hypocalcemia. Moreover, transient neonatal hypocalcemia can cause transient EEG abnormalities.

DNA methylation profiles in sibling pairs discordant for intrauterine exposure to maternal gestational diabetes

ABSTRACT Intrauterine exposure to hyperglycemia is reported to confer increased metabolic risk in later life, supporting the ‘developmental origins of health and disease’ hypothesis. Epigenetic alterations are suggested as one of the possible underlying mechanisms. In this study, we compared pairwise DNA methylation differences between siblings whose intrauterine exposure to maternal gestational diabetes (GDM) were discordant. Methylation of peripheral blood DNA of 18 sibling pairs was measured using Infinium HumanMethylation450 BeadChip assays. Of the 465,447 CpG sites analyzed, 12 showed differential methylation (false discovery rate <0.15), including markers within genes associated with monogenic diabetes (HNF4A) or obesity (RREB1). The overall methylation at HNF4A showed inverse correlations with mRNA expression levels, though non significant. In a gene set enrichment analysis, metabolism and signal transduction pathways were enriched. In conclusion, we found DNA methylation markers associated with intrauterine exposure to maternal GDM, including those within genes previously implicated in diabetes or obesity.

Blood glucose levels within 7 days after birth in preterm infants according to gestational age

Purpose This study investigated blood glucose levels in preterm babies according to gestational age (GA). Methods Subjects were 141 preterm infants with a GA<34 weeks. Data on blood glucose levels, GA, body weight, glucose infusion rate, and other contributing factors in the first 7 days after birth were analyzed. Hypoglycemia was defined as a blood glucose level of <40 mg/dL up to 24 hours after birth and as <50 mg/dL thereafter. Hyperglycemia was defined as a blood glucose level >180 mg/dL. Results During the 7 days after birth, hypo- and hyperglycemia occurred in 29 (29 of 141, 20.6%) and 42 (42 of 141, 29.8%) neonates, respectively. During the first 2 hours, 18 neonates (12.8%) exhibited hypoglycemia, and only 2 (2 of 141, 1.4%) developed hyperglycemia. From 6 to 24 hours, hypo- and hyperglycemia were observed in 0 and 9 (9 of 141, 6.4%) neonates, respectively. Infants small for their GA (SGA) were at risk for hypoglycemia both within 24 hours (odds ratio [OR], 2.718; P=0.045) and during days 2 to 7 (OR, 4.454; P=0.006), and hyperglycemia during days 2 to 7 (OR, 3.200; P=0.005). Low 1-minite Apgar score was risk factor for both hypo- and hyperglycemia during days 2 to 7 (OR, 0.756; P=0.035 for hypoglycemia and OR, 0.789; P=0.016 for hyperglycemia). Both hypo- and hyperglycemia within 24 hours were less common in those who started feeding (OR, 0.294; P=0.013 for hypoglycemia and OR, 0.162; P=0.011 for hyperglycemia). Conclusion Careful blood glucose level monitoring is required in preterm infants, especially SGA infants or those with low Apgar score. Early feeding could be beneficial for maintaining euglycemia.

The association of variable number of tandem repeats of the insulin gene with susceptibility to type 1 diabetes among Korean subjects.

There is ethnic variation in the variable number of tandem repeats of the insulin gene (INS VNTR), one of the susceptibility loci for developing type 1 diabetes (T1D). We evaluated the influence of the genotypes and subdivisions of INS VNTR on the development of T1D in Korean subjects.

Factors Associated with the Presence and Severity of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Korean Children and Adolescents

The aim of this study was to identify the risk factors for presence and severity of diabetic ketoacidosis (DKA) at the onset of type 1 diabetes mellitus (T1DM) in Korean children and adolescents. A retrospective chart review of children and adolescents newly diagnosed with T1DM was conducted in seven secondary and tertiary centers in Korea. Eligible subjects were < 20 years of age and had records on the presence or absence of DKA at the time of T1DM diagnosis. DKA severity was categorized as mild, moderate, or severe. Data were collected on age, height, body weight, pubertal status, family history of diabetes, delayed diagnosis, preceding infections, health insurance status, and parental education level. A total of 361 patients (male 46.3%) with T1DM were included. Overall, 177 (49.0%) patients presented with DKA at T1DM diagnosis. Risk factors predicting DKA at T1DM diagnosis were age ≥ 12 years, lower serum C-peptide levels, presence of a preceding infection, and delayed diagnosis. Low parental education level and preceding infection increased the severity of DKA. These results suggest that alertness of the physician and public awareness of diabetes symptoms are needed to decrease the incidence and severity of DKA at T1DM diagnosis.