Height outcomes in Korean children with idiopathic short stature receiving growth hormone treatment.

Objectives: Growth hormone (GH) therapy's capacity to increase height velocity and height at the end of the study in children with idiopathic short stature (ISS) is controversial. We aimed to investigate the height standard deviation score (SDS) and height velocity of patients with ISS in Korea who received GH treatment. Methods: We retrospectively reviewed and performed linear mixed model and survival analyses on data from 12 tertiary hospitals in Korea, including subjects diagnosed with ISS from January 2009 to September 2019, treated with GH therapy for more than 6 months, and who were at a pre-pubertal state at the time of diagnosis. Results: We included 578 children (330 boys and 248 girls). The mean daily dose of GH in this study was 0.051 mg/kg, which was lower than the approved dose in Korea of 0.062 - 0.067 mg/kg. Height SDS was higher in patients who started treatment before the age of 6 years. The probability of reaching the target SDS (-1 SDS) from the beginning of treatment to 2-3 years after its start was higher in children starting treatment before the age of 6 years. The hazard ratio to reach the target SDS (-1 SDS) when using automatic pen or electronic devices was 1.727 times higher than that when using the needle and syringe device. Conclusion: ISS patients should start GH treatment at an early age, and even lower-than-recommended drug doses may be effective. The selection of automatic pen or electronic device can have a positive effect on reaching the target height SDS.

Clinical practice guidelines for optimizing bone health in Korean children and adolescents.

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

Growth and Bone Mineral Density Changes in Ovariectomized Rats Treated with Estrogen Receptor Alpha or Beta Agonists.

BACKGROUND: Estrogen controls the pubertal growth spurt, growth plate closure, and accretion of bone mineral density (BMD) of long bones after biding estrogen receptor (ER). There are two subtypes of ER, ERα and ERß. If each ER subtype has different effects, we may control those actions by manipulating the estrogen binding intensity to each ER subtype and increase the final adult height without markedly reducing BMD or impairing reproductive functions. The purpose of our study was to compare these effects of ERα and ERß on long bones in ovariectomized rats. METHODS: Thirty female rats were ovariectomized and randomly divided into 3 groups. The control, propylpyrazole triol (PPT), and 2,3-bis (4-hydroxyphenyl) propionitrile (DPN) groups were subcutaneously injected for 5 weeks with sesame oil, PPT as an ERα agonist, and DPN as an ERß agonist, respectively. The crown-lump length and body weight were measured weekly. BMD, serum levels of growth hormone (GH) and estradiol were checked before and after 5 weeks of injections. Pituitary GH1 expression levels were determined with quantitative real-time polymerase chain reaction, the proximal tibias were dissected, decalcified and stained with hematoxylin-eosin, and the thicknesses of epiphyseal plates including proliferative and hypertrophic zones were measured in 20-evenly divided sites after 5 weeks of injections. Comparisons for auxological data, serum hormone and pituitary GH1 expression levels, BMD, and epiphyseal plate thicknesses among 3 groups before and after injections were conducted. RESULTS: There was no significant difference in body lengths among 3 groups. The body weights were significantly lower, but, serum GH, pituitary GH1 expression levels, and BMDs were higher in PPT group than the other 2 groups after 5 weeks of injections. There was no significant difference in the thicknesses of the total epiphyseal plate, proliferative, and hypertrophic zone among 3 groups. CONCLUSION: ERα is more involved in pituitary GH secretion and bone mineral deposition than ERß. Weight gain might be prevented with the ERα agonist.

Near final height in Korean children referred for evaluation of short stature: clinical utility and analytical validity of height prediction methods.

PURPOSE: Predicted adult height (PAH) is often crucial to decision-making about treatment with human growth hormone (GH) or gonadotropin-releasing hormone agonist in children with short stature. This study compares final adult height (FAH) with different methods used to determine PAH and assesses the clinical utility and analytical validity of height prediction for children not treated with GH. METHODS: Clinical findings were retrospectively analyzed, and the heights of 44 children (22 males and 22 females) who visited our clinic between August 2006 and June 2017 and reached near final adult height (NFAH) were evaluated. Children treated with GH were excluded. We compared measured NFAH to PAH using the Bayley-Pinneau (BP), Tanner-Whitehouse Mark 2, and Roche-Wainer-Thissen (RWT) methods. RESULTS: Pearson correlation between all 3 prediction methods and NFAH showed high positive correlations in males and females (P<0.05). The average difference between PAH and NFAH for the BP method (0.4±3.9 cm) was significantly lower than those for the RWT and TW 2 methods in females (P=0.000, analysis of variance). Furthermore, only PAH by the BP method in females was very close to measured NFAH (paired t-test). A Bland-Altman plot verified that 95% of the differences between the PAH and NFAH exist between limits of agreement (mean±1.96 standard deviation). CONCLUSIONS: The BP method is more useful to predict NFAH in females than other methods. Careful attention is still required when using such tools because PAH can be inaccurate. Therefore, a more accurate FAH prediction model for Korean children is needed.

Percentile Distributions of Birth Weight according to Gestational Ages in Korea (2010-2012).

The Pediatric Growth Chart (2007) is used as a standard reference to evaluate weight and height percentiles of Korean children and adolescents. Although several previous studies provided a useful reference range of newborn birth weight (BW) by gestational age (GA), the BW reference analyzed by sex and plurality is not currently available. Therefore, we aimed to establish a national reference range of neonatal BW percentiles considering GA, sex, and plurality of newborns in Korea. The raw data of all newborns (470,171 in 2010, 471,265 in 2011, and 484,550 in 2012) were analyzed. Using the Korean Statistical Information Service data (2010-2012), smoothed percentile curves (3(rd)-97(th)) by GA were created using the lambda-mu-sigma method after exclusion and the data were distinguished by all live births, singleton births, and multiple births. In the entire cohort, male newborns were heavier than female newborns and singletons were heavier than twins. As GA increased, the difference in BW between singleton and multiples increased. Compared to the previous data published 10 years ago in Korea, the BW of newborns 22-23 gestational weeks old was increased, whereas that of others was smaller. Other countries' data were also compared and showed differences in BW of both singleton and multiple newborns. We expect this updated data to be utilized as a reference to improve clinical assessments of newborn growth.

Pubertal growth and epiphyseal fusion.

The complex networks of nutritional, cellular, paracrine, and endocrine factors are closely related with pubertal growth and epiphyseal fusion. Important influencing factors include chondrocyte differentiation capacity, multiple molecular pathways active in the growth plate, and growth hormone-insulin-like growth factor-I axis activation and epiphyseal fusion through estrogen and its receptors. However, the exact mechanisms of these phenomena are still unclear. A better understanding of the detailed processes involved in the pubertal growth spurt and growth plate closure in longitudinal bone growth will help us develop methods to efficiently promote pubertal growth and delay epiphyseal fusion with fewer adverse effects.

Comparison of growth and pubertal progression in wild type female rats with different bedding types.

PURPOSE: Endocrine-disrupting chemicals interfere with the endocrine system and therefore affect growth and pubertal progression. The study aim was to compare the growth and pubertal progression in wild-type female rats with different bedding types. METHODS: Twenty 5-week-old female wild-type Sprague Dawley rats were randomly assigned to two groups with different bedding types: one group received wood shaving bedding, while a second group received corncob bedding. We determined crown-rump length and body weight as anthropometric measurements and assessed the serum growth hormone (GH) and estradiol levels. The gh1 mRNA expression levels were compared using quantitative real time transcription polymerase chain reaction. The estrous cycle was evaluated by vaginal smear. RESULTS: The anthropometric measurements were not significantly different between the two groups. The mean relative expression of the gh1 gene was lower in the corncob bedding group than that in the wood shaving group (P=0.768). Meanwhile serum GH and estradiol were increased in the wood shaving bedding group; however this difference was not statistically significant. The time to first estrus and the length of the estrous cycle were increased in the corncob bedding group; the proportion of normal estrous cycles was also decreased. These findings indicate irregularities in the estrous cycle. CONCLUSION: Endocrine-disrupting chemicals in corncob bedding might be associated with time to first estrus and length of the estrous cycle. Therefore, the type of bedding should be considered as a factor affecting pubertal progression in rodents.

New Korean reference for birth weight by gestational age and sex: data from the Korean Statistical Information Service (2008-2012).

PURPOSE: To construct new Korean reference curves for birth weight by sex and gestational age using contemporary Korean birth weight data and to compare them with the Lubchenco and the 2010 United States (US) intrauterine growth curves. METHODS: Data of 2,336,727 newborns by the Korean Statistical Information Service (2008-2012) were used. Smoothed percentile curves were created by the Lambda Mu Sigma method using subsample of singleton. The new Korean reference curves were compared with the Lubchenco and the 2010 US intrauterine growth curves. RESULTS: Reference of the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles birth weight by gestational age were made using 2,249,804 (male, 1,159,070) singleton newborns with gestational age 23-43 weeks. Separate birth weight curves were constructed for male and female. The Korean reference curves are similar to the 2010 US intrauterine growth curves. However, the cutoff values for small for gestational age (<10th percentile) of the new Korean curves differed from those of the Lubchenco curves for each gestational age. The Lubchenco curves underestimated the percentage of infants who were born small for gestational age. CONCLUSION: The new Korean reference curves for birth weight show a different pattern from the Lubchenco curves, which were made from white neonates more than 60 years ago. Further research on short-term and long-term health outcomes of small for gestational age babies based on the new Korean reference data is needed.

Intrathyroidal thymic tissue mimicking a malignant thyroid nodule in a 4-year-old child.

Intrathyroidal thymic tissue is rare and may be confused with a malignant thyroid nodule because of hyperechoic dots mimicking calcifications. We report the case of a thyroid nodule with malignant ultrasonographic findings in a 4-year-old child, which was confirmed cytologically as ectopic thymic tissue. The sonographic findings of ectopic thymus were similar to those of the thymus; therefore, clinicians should be familiar with ultrasonography findings of normal thymic tissue.

Association of polymorphisms in the vitamin D receptor promoter with idiopathic short stature.

The genetic alterations of vitamin D receptor (VDR) are related with the growth of long bone. There were a lot of reports regarding an association of polymorphisms in the VDR promoter with many disorders, but not with idiopathic short stature (ISS). We investigated the association of them with ISS. A total of 50 subjects, including 29 ISS patients and 21 healthy controls with their heights within the normal range was recruited. We selected two single nucleotide polymorphisms (SNPs) from VDR promoter (rs11568820 at the Cdx-2 binding site upstream of exon 1e and rs4516035 at -1012 upstream of exon 1a) as candidates, respectively. In genotype analysis, the frequency of A/A genotype at the Cdx-2 binding site locus (rs11568820) upstream of exon 1e of VDR was decreased to 6.9% in ISS patients (28.6% in controls) (P = 0.027). The genetic variation at the Cdx-2 binding site of VDR promoter can be a contributing factor of growth of height.

Dexibuprofen for fever in children with upper respiratory tract infection.

BACKGROUND: The aim of this study was to investigate the safety and efficacy of dexibuprofen compared to ibuprofen. METHODS: This double-blind, double-dummy study enrolled patients from January 2008 to May 2009 presenting at one of five tertiary care centers in Seoul, Korea with febrile illness who were then given one of three active treatments: one dose of dexibuprofen 2.5 or 5 mg/kg (DEX 1); dexibuprofen 3.5 or 7 mg/kg (DEX 2); or ibuprofen 5 or 10 mg/kg (control) syrup. Those with a temperature <38.5°C were given the lower dose. Temperature was measured every hour for 4 h. Primary study outcome was mean change in temperature 4 h after one dose. RESULTS: A total of 264 children (aged 6 months-14 years) with febrile illness due to upper respiratory tract infection were consecutively sampled and screened, with 260 randomized. No patients withdrew due to adverse effects. Mean temperature change after 4 h (mean ± SD: DEX 1, 0.99 ± 0.84°C; DEX 2, 1.12 ± 0.92°C; control, 1.38 ± 0.84°C) differed only between DEX 1 and controls (P = 0.007, 95% confidence interval [CI]: -0.61 to -0.15). When groups were subdivided according to initial temperature, there were no significant differences in mean temperature change after 4 h between DEX 2 subgroups (<38.5°C, 0.88 ± 0.86°C; ≥38.5°C, 1.46 ± 0.90°C) and controls (1.07 ± 0.84°C and 1.72 ± 0.91°C, respectively), but there was a significant difference between DEX 1 (≥38.5°C, 1.25 ± 0.76°C) and controls (P = 0.0222, 95%CI: -0.80 to -0.13). There were no significant differences in adverse events among groups. CONCLUSION: Dexibuprofen (3.5 or 7 mg/kg) is as effective and tolerable as ibuprofen for fever caused by upper respiratory tract infection in children.

Estrogen receptor α polymorphism in boys with constitutional delay of growth and puberty.

PURPOSE: There were a lot of reports regarding associations of polymorphisms in the estrogen receptor α (ESR1). with many disorders. But, those with constitutional delay of growth and puberty (CDGP) are not known. Our aim is to find out any association between CDGP and ESR1. METHODS: In a total of 27 subjects, we compared 7 CDGP patients with 20 healthy controls with their heights and sexual maturity rates were within normal range. We selected three single nucleotide polymorphisms from intron 1 of ESR1 (rs3778609, rs12665044, and rs827421) as candidates, respectively. RESULTS: In genotype analyses, the frequency of G/G genotype at rs827421 in intron 1 of ESR1 was increased in CDGP boys (P=0.03). CONCLUSION: The genetic variation of ESR1 can be a contributing factor of tempo of growth and puberty.

Two cases of female hydrocele of the canal of nuck.

The processus vaginalis within the inguinal canal forms the canal of Nuck, which is a homolog of the processus vaginalis in women. Incomplete obliteration of the processus vaginalis causes indirect inguinal hernia or hydrocele of the canal of Nuck, a very rare condition in women. Here, we report 2 cases of hydrocele of the canal of Nuck that were diagnosed with ultrasonography in both cases and magnetic resonance imaging in 1 case to confirm the sonographic diagnosis. High ligation and hydrocelectomy were conducted in both patients. In 1 patient, 14 months later, the occurrence of contralateral inguinal hernia was suspected, but did not require surgery. The other patient had a history of surgery for left inguinal hernia 11 months before the occurrence of right hydrocele of the canal of Nuck. In both cases, the occurrence of an inguinal hernia on the contralateral side was noted.

Polymorphisms of methylenetetrahydrofolate reductase are not a risk factor for Kawasaki disease in the Korean population.

PURPOSE: Hyperhomocysteinemia is known as a risk factor for atherosclerosis. Preclinical arteriosclerosis is noted and premature atherosclerosis is known to be accelerated in Kawasaki disease (KD) patients. Genetic polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene result in elevated plasma homocysteine concentrations and are known to be associated with the development of coronary artery disease. Our hypothesis is that single nucleotide polymorphisms (SNPs) of the MTHFR gene are related to the development of KD and coronary artery lesions (CALs). METHODS: For this study, we selected 3 candidate single nucleotide polymorphisms (SNPs) (rs2274976, rs1801131, and rs1801133) of MTHFR. These SNPs are located on chromosome 1p36.3. We included 101 KD patients and 306 healthy adults as controls in this study. CALs were seen in 38 patients. Genotypes of the selected SNPs were determined by direct sequencing and analyzed with SNPAlyze. RESULTS: The genetic distribution and allelic frequency of the 3 MTHFR SNPs (rs2274976, rs1801131, and rs1801133) were not significantly different in patients with KD compared to the control group (P=0.71, 0.17, and 0.96, respectively). There was no difference in the genetic distribution of the MTHFR SNPs between the normal control group and the CAL group (P=0.43, 0.39, 0.52 respectively). CONCLUSION: The genetic distribution of the MTHFR SNPs (rs2274976, rs1801131, and rs1801133) was not different in the KD group compared to the control group. In addition, the genetic distribution of these SNPs was not different in the CAL group compared to the control group in the Korean population.

Decreasing trends of neonatal and infant mortality rates in Korea: compared with Japan, USA, and OECD nations.

Neonatal mortality rate (NMR) and infant mortality rate (IMR) are two of the most important indices reflecting the level of public health of a country. In this review, we investigated changes in NMR and IMR in Korea and compared the results with those of Japan, USA, and OECD nations. During the past 20 yr, NMR and IMR have lowered remarkably from 6.6 and 9.9 in 1993 to 1.7 and 3.2 in 2009, respectively, in Korea. It is an impressive finding that Korean IMR (3.2 in 2009) is lower than the average of OECD nations (4.7 in 2008), and USA (6.3 in 2009), although higher than Japanese IMR (2.8 in 2009). The proportion of NMR among the IMR calculation decreased from 66.7% in 1993 to 53.1% in 2009. The reason the value of Korea was higher than Japan but lower than USA was speculated to be an aspect of the health care service system. Several suggestions in perinatal, neonatal and infantile health care such as establishment of perinatal care center, research network system, regionalization, and new policies for care of pre-term and high risk pregnancy, are elucidated to achieve further improvement on NMR and IMR in Korea.

Novel compound heterozygous mutations in the vitamin D receptor gene in a Korean girl with hereditary vitamin D resistant rickets.

Hereditary vitamin D resistant rickets (HVDRR) is a rare genetic disorder caused by a mutation of vitamin D receptor (VDR) gene. A number of cases had been reported in many countries but not in Korea. We examined a three-year old Korean girl who had the typical clinical features of HVDRR including rickets, hypocalcemia, hypophosphatemia, elevated serum calcitriol level and secondary hyperparathyroidism. The girl and her father were both heterozygous for the 719C-to-T(I146T)---> c.437C > T(p.T1461) [corrected] mutation in exon 4, whereas she and her mother were both heterozygous for 754C-to-T (R154C)---> c.472 > T(p.R158C) [corrected] mutation in exon 5 of the VDR gene. In this familial study, we concluded that the girl had compound heterozygous mutations in her VDR gene which caused HVDRR. This is the first report of a unique mutation in the VDR gene in Korea.

Recent trends in neonatal mortality in very low birth weight Korean infants: in comparison with Japan and the USA.

With regard to the outcome of intensive neonatal care, one of the most important concerns in neonatology is the mortality rate of very low birth weight infants (VLBWI; birth weight < 1,500 g) and extremely low birth weight infants (ELBWI; birth weight < 1,000 g). The present study was conducted to analyze and compare the mortality of VLBWI and ELBWI and neonatal care among Korean, Japanese, and American newborns. In Korea, the survival rates of VLBWI have increased significantly; they were 31.8% in the early 1960s, 65.8% in the early 1990s, 77.5% in 2002, 84.7% in 2007, and 85.7% in 2009. The survival rates of ELBWI have also increased; they were 8.2% in the early 1960s, 37.4% in the early 1990s, 56.1% in 2002, 67.7% in 2007, and 71.8% in 2009. The survival rates of VLBWI and ELBWI have significantly improved over the past 50 yr in Korea. However, the Korean survival rates of VLBWI and ELBWI are still lower than for similar groups in Japan and the USA. To achieve better outcomes that reach the level of these countries, the organization of perinatal care centers, nationwide neonatal perinatal research networks, and regionalization are needed in Korea.

Multiple births conceived by assisted reproductive technology in Korea.

PURPOSE: The recent trends of multiple births (MBs) conceived by assisted reproductive technology (ART) in Korea were analyzed as well as the relationship with maternal age, especially advanced maternal age. METHODS: Data were obtained from the Korean Statistical Information Service and annual ART reports from the ART committee of the Korean Society of Obstetrics and Gynecology. RESULTS: MBs increased from the early 1990s; there was a 275% increase by 2008. The number of total live births was 448,153 and MBs accounted for 10,767; the MB rate was 24.0% in 2006. Among 2,326 deliveries conceived by ART, multiple deliveries accounted for 786 (33.8%). The total number of live births with ART was 3,125 and 1,585 (50.7%) of them were MBs. During 2006, 14.7% of the entire MBs in Korea were associated with ART. The proportion of women of advanced maternal age was much higher in the ART group than in the total live birth group. CONCLUSION: MBs in women of advanced maternal age have been increasing in Korea with the use of ART. The results of this study showed that ART was a significant factor associated with the increase in MBs in Korea.

Recent trends in the incidence of multiple births and its consequences on perinatal problems in Korea.

The aim of this study was to survey multiple birth data and to analyze the recent trends of multiple births and its consequences on perinatal problems in Korea from 1991 to 2008. Data were obtained from the Korean Statistical Information Service. The total number of multiple births showed increasing trends. The multiple birth rate was maintained within less than 10.0 for the decade from 1981 to 1990. However, it increased gradually to reach 27.5 in 2008. The maternal age for multiple births was higher than for total live births. The mean birth weight of the total live births was 3.23 kg; for the multiple births it was 2.40 kg in 2008. The incidence of low birth weight infants (LBWI) among total live births was 3.8% in 2000 and 4.9% in 2008. For multiple births it was 49.2% and 53.0% during the same years. The incidence of preterm births among total live births was 3.8% in 2000 and 5.5% in 2008; for the multiple births it was 38.3% and 51.5% during the same years. The incidence of multiple births and its consequences on perinatal problems (preterm, LBWI, and advanced-maternal age) have been increased steadily over the last two decades in Korea.