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.

2017 Clinical practice guidelines for dyslipidemia of Korean children and adolescents.

The Committee on Dyslipidemia of Korean Pediatric and Adolescents of the Korean Society of Pediatric Endocrinology has newly developed evidence-based clinical practice guidelines for dyslipidemia in Korean children and adolescents. These guidelines were formulated with the Grading of Recommendations, which include both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. These guidelines are based on the 2011 National Heart, Lung, and Blood Institute Guidelines, which focus on the prevention of cardiovascular disease in children and draw from a comprehensive review of evidence. These guidelines contain the definition of and screening process for dyslipidemia and introduce new dietary methods: the Cardiovascular Health Integrated Lifestyle Diet (CHILD)-1, the CHILD-2-low-density lipoprotein cholesterol, and the CHILD-2-triglyceride. Potential drug therapies for dyslipidemia along with their main effects and doses were also included.

2017 Clinical practice guidelines for dyslipidemia of Korean children and adolescents.

The Committee on Dyslipidemia of Korean Pediatric and Adolescents of the Korean Society of Pediatric Endocrinology has newly developed evidence-based clinical practice guidelines for dyslipidemia in Korean children and adolescents. These guidelines were formulated with the Grading of Recommendations, which include both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. These guidelines are based on the 2011 National Heart, Lung, and Blood Institute Guidelines, which focus on the prevention of cardiovascular disease in children and draw from a comprehensive review of evidence. These guidelines contain the definition of and screening process for dyslipidemia and introduce new dietary methods: the Cardiovascular Health Integrated Lifestyle Diet (CHILD)-1, the CHILD-2-low-density lipoprotein cholesterol, and the CHILD-2-triglyceride. Potential drug therapies for dyslipidemia along with their main effects and doses were also included.

Ease of Use, Preference, and Safety of the Recombinant Human Growth Hormone Disposable Pen Compared with the Reusable Device: A Multicenter, Single-Arm, Open-Label, Switch-Over, Prospective, Phase IV Trial.

PURPOSE: To assess the usability and safety of the disposable pen compared to those of reusable devices in patients receiving recombinant human growth hormone (rhGH) treatment. PATIENTS AND METHODS: This study was a multicenter, single-arm, open-label, switch-over, prospective, Phase IV trial. After screening, eligible patients who were previously treated with rhGH using a reusable device were enrolled to receive treatment with the disposable pen for 8 weeks. The ease of use, preference, and tolerability of the disposable pen compared to those of the reusable device were assessed by the subjects and/or their caregivers using a questionnaire. Adverse events were evaluated by the investigators. RESULTS: Of 116 subjects enrolled in this study, 115 received treatment with the disposable pen and 109 completed the study. The mean age of the subjects was 9.4 years. Compared to the previous reusable device, the disposable pen was assessed as significantly easier to use (mean value 7.88, 95% confidence interval (CI) [7.45-8.30] on a numerical scale ranging from 0 (far less easy) to 10 (far easier)). Furthermore, the percentage of subjects who preferred the disposable pen to the previously used reusable device was 75.7% (95% CI [67.6%-83.8%]). The percentages of subjects who rated pain and discomfort at the injection site as "not at all" were higher after using the disposable pen compared to the reusable device. No specific safety concerns were identified. CONCLUSION: The disposable pen is easier to use than the reusable devices and is preferred by approximately 75% of patients receiving rhGH treatment. Moreover, the disposable pen is safe and acceptable. Therefore, it could be a good alternative to reusable devices. The disposable pen is expected to provide benefits to patients receiving rhGH treatment. CLINICALTRIALSGOV IDENTIFIER: NCT03015909.

Early menarche is associated with non-alcoholic fatty liver disease in adulthood.

BACKGROUND: The aim of this study was to examine the association between early menarche (<12 years) and non-alcoholic fatty liver disease (NAFLD) in premenopausal women and to explore whether it is mediated by adult obesity and insulin resistance. METHODS: We analyzed data of premenopausal women, aged ≥15 years, from the Korea National Health and Nutrition Examination Survey (2007-2009). We divided the women into three groups: early menarche, reference (12.00-15.99 years), and late menarche. The presence of NAFLD was determined using hepatic steatosis index >36.0. RESULTS: Of the 4,387 women evaluated, 673 (15.4%) met the criteria for NAFLD. The prevalence of NAFLD was higher in both women with early and late menarche compared with the reference (early, 23.4%; reference, 14.0%; late, 19.9%, P < 0.001). After adjustment of confounders including age, the OR for NAFLD in early menarche compared with the reference was 3.04 (95%CI: 1.99-4.65). Further adjustment of mediators, such as central obesity or insulin resistance, attenuated the association to 1.91-2.17. There was no association, however, between late menarche and NAFLD after adjustment of confounders. CONCLUSIONS: Early menarche was associated with an increased risk of NAFLD in young and middle-aged premenopausal Korean women.

Behavioral and intelligence outcome in 8- to 16-year-old born small for gestational age.

PURPOSE: We investigated behavioral problems, attention problems, and cognitive function in children and adolescents born small for gestational age (SGA). METHODS: Forty-six SGA children born at term and 46 appropriate for gestational age (AGA) children born at term were compared. Psychiatric symptoms were examined with reference to the Korean-Child Behavior Checklist, Korean-Youth Self Report, and Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS). Cognitive function was estimated using the Wechsler Intelligence Scale. Sociodemographic data were recorded from interviews. RESULTS: SGA children had high scores on delinquent behavior, aggressive behavior, and the externalizing scale, and they also showed a propensity for anxiety and depression. The SGA group had a higher mean ADHD-RS score than the AGA group (10.52±8.10 vs.9.93±7.23), but the difference was not significant. The SGA group had a significantly lower verbal intelligence quotient (IQ) than the AGA group, but the mean scores of both groups were within normal limits. CONCLUSION: This study indicates marked behavioral problems, such as delinquency, aggressiveness, and anxiety and depression, as well as low verbal IQ in the SGA group than in the AGA group. Even in cases in which these symptoms are not severe, early detection and proper treatment can help these children adapt to society.

Ferritin level is associated with metabolic syndrome and elevated alanine aminotransferase in children and adolescents.

BACKGROUND: The aim of the study was to investigate the association among elevated serum ferritin, metabolic syndrome (MetS) and 'elevated alanine aminotransferase (ALT) levels beyond healthy-range limits' in children and adolescents. METHODS: We analyzed data from 4855 subjects (2579 male) aged 10-19 who participated in the Korea National Health and Nutrition Examination Survey (KNHANES) (2007-2012). RESULTS: The prevalence of MetS and 'elevated ALT' tended to increase with an increase in the serum ferritin quartile (p-value for trend: all <0.05). The odds ratios (ORs) for MetS in serum ferritin quartile-Q4 compared to ferritin quartile-Q1 was 1.59 (1.01, 2.55) in females after adjusting for age, body mass index (BMI), and insulin resistance. The ORs for 'elevated ALT' in ferritin quartile-Q4 compared to ferritin quartile-Q1 were 4.45 (2.18, 9.10) in male and 3.10 (1.70, 5.66) in female subjects after adjusting for other covariates. CONCLUSIONS: The independent association between elevated serum ferritin and MetS (or 'elevated ALT') begins in children and adolescents.

Mixed gonadal dysgenesis in 45,X Turner syndrome with SRY gene.

Turner syndrome is the most common chromosomal disorder in girls. Various phenotypic features show depending upon karyotype from normal female through ambiguous genitalia to male. Usually, Turner girls containing 45,X/46,XY mosaicism, or sex-determining region Y (SRY) gene may have mixed gonadal dysgenesis with various external sexual differentiation. We experienced a short statured 45,X Turner girl with normal external genitalia. Because SRY gene was positive, laparoscopic gonadectomy was performed. The dysgenetic gonads revealed bilateral ovotesticular tissues. The authors report a mixed gonadal dysgenesis case found in clinical 45,X Turner patient with positive SRY gene. Screening for SRY gene should be done even the karyotype is 45,X monosomy and external genitalia is normal.

Reference values for bone mineral density according to age with body size adjustment in Korean children and adolescents.

Bone acquisition failure during growth or low bone mineral density (BMD) in childhood and adolescence might increase future osteoporosis risk. To identify these children and adolescents, appropriate reference values are necessary. The robust reference values must be community based as well as sex-, age-, and ethnicity specific. In addition, body size adjustment is necessary because individuals demonstrate different body sizes and different tempos of growth, which affect measured BMD. We aimed to provide reference data with body size adjustment of Korean children and adolescents. We used dual-energy X-ray absorptiometry data of 1,650 subjects (aged 10-20 years; 788 female) from the Korea National Health and Nutrition Examination Survey (2009-2010). The BMD of each region of interest (ROI), including the lumbar spine, total body less head, total body, and femoral neck, were obtained. We calculated the mean and percentiles for each ROI. Because height and weight variations were high and correlated independently with BMD within the same age group, we developed equations to calculate the "predicted BMD Z score." Although 12.8-17.9 % of subjects with short stature showed a low measured BMD Z score depending on the measured site, only 2.6 % of those of short stature had a low adjusted BMD Z score after applying the predicted BMD Z score. We also compared the BMD of children and adolescents of other ethnicities using the same device. This study provided robust reference values for the assessment and monitoring of bone health in Korean children and adolescents. Additionally, it extended the knowledge of bone acquisition in Asian children and adolescents.

Prevalence of insulin resistance and cardiometabolic risk in Korean children and adolescents: a population-based study.

AIMS: We aimed to establish normal reference values of serum insulin and the homeostasis model assessment of insulin resistance (HOMA-IR). We also aimed to verify HOMA-IR "cut-off values" in predicting cardiometabolic risk among Korean children and adolescents. METHODS: Data from 2716 Korean subjects (1421 male and 1295 female, aged 10-20 years) were evaluated. Insulin resistance was defined as HOMA-IR >95th percentile. The odds ratios of cardiometabolic risk were assessed based on the state of insulin resistance. RESULTS: Reference values of insulin and HOMA-IR were determined according to sex and age, based on data obtained from normal-weight subjects with normal fasting glucose levels. HOMA-IR values appeared to peak at the age of 14-15 years in male subjects and at the age of 12-13 years in female subjects. The prevalence of insulin resistance in the subjects was 9.8% (male=10.9%, female=8.6%). The prevalence of insulin resistance in normal-weight, overweight, and obese subjects were 4.7%, 25.6%, and 47.1% respectively. Subjects with insulin resistance had a higher prevalence of metabolic syndrome (odds ratios=18.33; 95% confidence interval, 9.62-34.94) and its components, especially hyperglycemia and hypertriglyceridemia. CONCLUSION: We established reference values of serum insulin and HOMA-IR according to age and sex. Obesity is the most important risk factor for insulin resistance and metabolic syndrome. However, insulin resistance independently increases cardiometabolic risk. This information may be useful for Korean as well as other Asian in planning programs for the prevention of type 2 diabetes.

Estrogen receptor α gene analysis in girls with central precocious puberty.

OBJECTIVE: Estrogen is the final key factor that triggers the onset of puberty. The raised sensitivity of estrogen receptor, which may be caused by an estrogen receptor α (ERα) gene mutation or polymorphism, has been implicated in the etiology of precocious puberty. The aim of this study is to identify ERα gene mutations or polymorphisms in girls with central precocious puberty (CPP). METHODS: A total of 204 Korean girls with CPP were included in this study along with 102 healthy Korean female adults as controls. All coding exons and exon-intron boundaries of the ERα gene were sequenced. The relationship between identified sequence variations and CPP were evaluated via comparison of allele frequencies between the two groups. RESULTS: Eight polymorphisms were identified in the ERα gene. Among the eight polymorphisms in this study, five have been previously reported, whereas the other three were novel polymorphisms. Two of the three novel polymorphisms, p.G145S in exon 1 and p.R555H in exon 8 were only identified in the patient group. The subgroup with p.G145S showed a significantly higher level of peak luteinizing hormone than the subgroup without p.G145S in girls with CPP. CONCLUSION: The scanning and typing of ERα polymorphism has uncovered several potentially meaningful polymorphisms. However, no solid conclusion can be made from this study and further studies are necessary to validate the function of these polymorphisms.

Gender differences in total and regional body composition changes as measured by dual-energy x-ray absorptiometry in Korean children and adolescents.

The objective of this study was to gain normal reference values and to evaluate gender differences in total and regional body composition changes according to age and Tanner stage by dual-energy X-ray absorptiometry in Korean. Four hundred and forty-nine healthy subjects, aged 5-20 yr were enrolled. Until 9 yr of age, males had a higher lean tissue mass and a lower percent body fat (%BF) than the females (12.6% vs 10.0%, p<0.01). These differences were not evident from 10 to 12.9 yr because of early pubertal progression in girls. After 13 yr, a significant sex difference in the body compositions were observed again. In late teens, females have higher %BF than males (25.6% vs 12.3%, p<0.01). However, females have lower android-gynoid percent fat ratio than males at Tanner stages (TSs) 4 and 5 (p<0.01). These differences are because of significant increase of gynoid lean tissue mass after 13 yr in males. The reference data would be useful for future research related to growth and obesity in Korean children and adolescents.

Increased rejection of primary tumors in mice lacking B cells: inhibition of anti-tumor CTL and TH1 cytokine responses by B cells.

We investigated the role of B cells in tumor immunity by studying immune responses of mice genetically lacking B cells to primary tumors. IgM(-/-) B cell-deficient mice (BCDM) exhibited enhanced resistance to 3 histologically diverse syngeneic tumors as compared to the wild-type (WT) mice. EL4 thymoma and MC38 colon carcinoma grew progressively in WT mice, but regressed spontaneously in BCDM whereas growth of B16 melanoma was slowed significantly in BCDM as compared to the WT mice. BCDM exhibited increased T cell infiltration of tumors, higher T(H)1 cytokine response and, in the case of MC38, a higher anti-tumor CTL response. The increased tumor resistance of BCDM did not seem to result from intrinsic changes in their non-B immunocytes because adoptive transfer of WT splenic B cells to BCDM abrogated tumor rejection and resulted in diminished anti-tumor T(H)1 cytokine and CTL responses. Studies involving BCR-transgenic mice indicated that B cells may inhibit anti-tumor T cell responses by antigen-nonspecific mechanisms since neither tumor-specific antibodies nor cognate T:B interactions were necessary for inhibition of tumor immunity by B cells. IFN-gamma secretion in splenocyte:tumor co-cultures of tumor-challenged BCDM was inhibited by WT but not CD40(-/-) B cells indicating that B cells may inhibit anti-tumor T(H)1 cytokine responses in a CD40-dependent manner. Adoptive transfer of CD40(-/-) B cells into BCDM resulted in restored growth of MC38 suggesting additional factors other than CD40 are involved in dampening anti-tumor responses. The effects of B cells on anti-tumor response warrant further study.