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The year 2021 is the centennial of insulin discovery. The discovery of insulin changes diabetes mellitus from a death sentence to a manageable disease. It became a historical turning point in the lives of people with diabetes. Since the first use of insulin in a patient in 1922, insulin and its analogs have been remarkable in saving the lives of people with diabetes. As insulin began to be used as a drug, it was introduced to, and used in Korea until now. This review briefly summarizes the history of insulin treatment in Korean children and adolescents with diabetes. [ABSTRACT FROM AUTHOR]

Myhre syndrome (MS) is a rare autosomal-dominant disorder characterized by short stature, intellectual disability, skeletal anomalies, restricted joint mobility, distinctive facial dysmorphism, and deafness. Early diagnosis of MS is difficult because its features progress and become noticeable at school age. Recently, the SMAD4 gene was identified as the major gene responsible for MS. Herein, we report the first Korean case of MS after identification of a SMAD4 mutation by clinical exome sequencing. The patient was born small for gestational age, and she had the typical clinical features of MS, including short stature, characteristic facial appearance, developmental delay, and selective mutism. She was diagnosed with central precocious puberty. Because of the patient's precocious puberty and short stature, we administered combined recombinant human growth hormone and gonadotropin-releasing hormone agonist treatments, which resulted in improved height. While there have been 79 cases of MS reported worldwide, to our knowledge, this is the first case of genetically-confirmed MS in Korea. [ABSTRACT FROM AUTHOR]

Purpose: Gonadotropin-releasing hormone agonist (GnRHa) has been the mainstay of central precocious puberty (CPP) treatment for decades, but few reports have compared the efficacy of 1-month and 3-month depot GnRHa formulations. This study investigates the short-term efficacy of 1-month and 3-month GnRHa depots in girls with CPP. Methods: Overall, 150 girls with CPP were included in a retrospective review of medical records. Subjects in group 1 (n=105) were treated with 1-month GnRHa depots for ≥12 months, and those in group 2 (n=45) were treated with 1-month GnRHa depots for 6 months followed by 3-month GnRHa depots for ≥6 months. Anthropometric and biochemical data were compared between the groups at 3-time points (after 0, 6, and 12 months of GnRHa treatment). Results: Demographic and clinical characteristics did not differ between the groups at baseline or after 6 months of GnRHa treatment. After 12 months of GnRHa treatment, patients in the both groups showed no difference in bone age (BA), chronological age (CA), BA--CA difference, height standard deviation score (SDS) for CA and BA, or body mass index SDS for CA and BA. The sexual maturity rate of the breast was prepubertal at 12 months in most of subjects. GnRH-stimulated luteinizing hormone (LH) level was suppressed during GnRHa treatment in both groups at 6 and 12 months, although the LH level in group 2 was higher than that in group 1. Conclusion: Treating CPP with a 3-month GnRHa depot showed short-term efficacy comparable to that with a 1-month depot in anthropometric parameters and pubertal suppression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Despite the prevalent use of insulin pump therapy worldwide, few studies have been conducted among young patients with type 1 diabetes (T1D) in Korea. We investigated the durability and effectiveness of insulin pump therapy among Korean pediatric and young adult patients with T1D. Methods: This study included 54 patients with T1D diagnosed at pediatric ages (range, 1.1--14.1 years) who initiated insulin pump therapy during 2016--2019 at Seoul National University Children's Hospital and Seoul National University Bundang Hospital. Clinical and biochemical data, including anthropometric measurements, insulin dose, and glycated hemoglobin (HbA1c) levels were obtained from T1D diagnosis to last follow-up. Results: Forty-four patients (81.5%) continued insulin pump therapy with a median pump use duration of 2.9 years (range, 0.2--3.5 years); 10 discontinued the therapy within 12 months (<1 month, n=6; 1--6 months, n=1; and 6--12 months, n=3) due to physical interferences or financial problems. Older age (≥10 years of age) and longer diabetes duration (≥2 years) at the initiation of pump therapy were associated with discontinuation (P<0.05 for both). For patients continuing pump therapy, HbA1c levels significantly decreased after 1 year of therapy (from 8.9% to 8.1%, P<0.001) without changes in the body mass index z-scores or insulin dose. Although 4 patients experienced diabetic ketoacidosis, all recovered without complications. Conclusion: Insulin pump therapy was effective in improving glycemic control in T1D patients during 12 months of treatment. Early initiation of insulin pump therapy after T1D diagnosis was helpful for continuing therapy. [ABSTRACT FROM AUTHOR]

Isolated hypogonadotropic hypogonadism (IHH) is a rare genetic disorder that is clinically and genetically heterogeneous. It is characterized by absent or incomplete pubertal development owing to an isolated defect in the production, secretion, or action of gonadotropin-releasing hormone. The incidence of IHH is estimated at 1:30,000 in males and 1:125,000 in females. Although the vast majority of IHH cases are sporadic, some X-linked recessive, autosomal dominant, and autosomal recessive modes of inheritance have been described. IHH can be classified into Kallmann syndrome with anosmia and normosmic IHH. Here, we report dizygotic twin sisters with normosmic IHH who showed short stature and absence of puberty as a result of a variant of the FGFR1 gene. They had a normal sense of smell, and brain magnetic resonance imaging (MRI) showed well-defined olfactory bulbs. The older sister and the twins' mother had cleft palate, while the younger sister did not. The mother had menarche at the age of 16 years after hormonal replacement owing to delayed puberty. Molecular analysis of the FGFR1 gene identified a missense variant c.874C>G (p.His292Asp) in the twins and their mother. Herein, we described the clinical heterogeneity observed in the 2 affected twins who carry an identical variant in the FGFR1 gene. Further studies of the effects of modifier genes and epigenetic factors on the expression of FGFR1, as well as the various clinical manifestations of its mutations, are warranted. [ABSTRACT FROM AUTHOR]

Purpose: The hemoglobin glycation index (HGI) represents the degree of nonenzymatic glycation and has been positively associated with cardiometabolic risk factors (CMRFs) and cardiovascular disease in adults. This study aimed to investigate the association between HGI, components of metabolic syndrome (MS), and alanine aminotransferase (ALT) in a pediatric nondiabetic population. Methods: Data from 3,885 subjects aged 10-18 years from the Korea National Health and Nutrition Examination Survey (2011-2016) were included. HGI was defined as subtraction of predicted glycated hemoglobin (HbA1c) from measured HbA1c. Participants were divided into 3 groups according to HGI tertile. Components of MS (abdominal obesity, fasting glucose, triglycerides, high-density lipoprotein cholesterol, and blood pressure), and proportion of MS, CMRF clustering (≥2 of MS components), and elevated ALT were compared among the groups. Results: Body mass index (BMI) z-score, obesity, total cholesterol, ALT, abdominal obesity, elevated triglycerides, and CMRF clustering showed increasing HGI trends from lower-to-higher tertiles. Multiple logistic regression analysis showed the upper HGI tertile was associated with elevated triglycerides (odds ratio, 1.65; 95% confidence interval, 1.18-2.30). Multiple linear regression analysis showed HGI level was significantly associated with BMI z-score, HbA1c, triglycerides, and ALT. When stratified by sex, age group, and BMI category, overweight/obese subjects showed linear HGI trends for presence of CMRF clustering and ALT elevation. Conclusion: HGI was associated with CMRFs in a Korean pediatric population. High HGI might be an independent risk factor for CMRF clustering and ALT elevation in overweight/obese youth. Further studies are required to establish the clinical relevance of HGI for cardiometabolic health in youth. [ABSTRACT FROM AUTHOR]

Purpose: Regarding recombinant human growth hormone (rhGH) use in the pediatric population, no long-term follow-up data are available for Korean patients. To fill in the gap of knowledge, a registry study (LG Growth Study) was initiated to assess the safety and effectiveness of four types of rhGH products in real-life settings. Methods: A total of 4,000 children will be registered and prospectively followed up at 6-month intervals until 2 years after epiphyseal closure to collect data on treatment and adverse events, with primary interest in malignancies and growth outcomes. Results: As of 22 March 2017, approximately 50% (2,024) of the target number of patients have been included in the analysis set: growth hormone deficiency, 1,297 (64.1%); idiopathic short stature, 315 (15.6%); small for gestational age, 206 (10.2%); Turner syndrome, 197 (9.7%); and chronic renal failure, 9 (0.4%). At baseline, median age (years) was 8 (interquartile range [IQR], 5-11); 52% (1,048) were boys; and the majority were at Tanner stage I (83% based on breast/external genitalia, 97% on pubic hair). Median height standard deviation score was -2.26 (IQR, -2.69 to -2.0), and median bone age delay (years) was -1.46 (IQR, -2.26 to -0.78). Conclusion: This registry study will provide the opportunity to assess the risk of malignancies as well as the general safety data in Korean pediatric patients receiving rhGH. In addition, the long-term effectiveness of rhGH and comparative data between different disease entities will provide practical insight on the standard rhGH treatment. [ABSTRACT FROM AUTHOR]

Purpose: Gonadotropin-releasing hormone agonist (GnRHa) is used as a therapeutic agent for central precocious puberty (CPP); however, increased obesity may subsequently occur. This study compared body mass index (BMI) and insulin resistance during the first year of GnRHa treatment for CPP. Methods: Patient group included 83 girls (aged 7.0-8.9 years) with developed breasts and a peak luteinizing hormone level of =5 IU/L after GnRH stimulation. Control group included 48 prepubertal girls. BMI and insulin resistance-related indices (homeostasis model assessment of insulin resistance [HOMA-IR] and quantitative insulin sensitivity check index [QUICKI]) were used to compare the groups before treatment, and among the patient group before and after GnRHa treatment. Results: No statistical difference in BMI z-score was detected between the 2 groups before treatment. Fasting insulin and HOMA-IR were increased in the patient group; fasting glucose-to-insulin ratio and QUICKI were increased in the control group (all P<0.001). In normal-weight subjects in the patient group, BMI z-score was significantly increased during GnRHa treatment (-0.1±0.7 vs. 0.1±0.8, P<0.001), whereas HOMA-IR and QUICKI exhibited no differences. In overweight subjects in the patient group; BMI z-score and HOMA-IR were not significantly different, whereas QUICKI was significantly decreased during GnRHa treatment (0.35±0.03 vs. 0.33±0.02, P=0.044). Conclusion: Girls with CPP exhibited increased insulin resistance compared to the control group. During GnRHa treatment, normal-weight individuals showed increased BMI z-scores without increased insulin resistance; the overweight group demonstrated increased insulin resistance without significantly altered BMI z-scores. Long-term follow-up of BMI and insulin resistance changes in patients with CPP is required. [ABSTRACT FROM AUTHOR]

Purpose: Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is classified as Kallmann syndrome (KS) with anosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). This study was undertaken to investigate the clinical, endocrinological, and molecular characteristics in Korean patients with KS and nIHH. Methods: Twenty-six patients from 25 unrelated families were included. Their clinical, endocrinological, and radiological indings were analyzed retrospectively. Mutation analysis of the GNRH1, GNRHR, KISS1, KISS1R, PROK2, PROKR2, TAC3, TACR3, FGF8, FGFR1, and KAL1 genes was performed in all patients. CHD7 and SOX10 were analyzed in patients with CHARGE (Coloboma, Heart defects, choanae Atresia, Growth retardation, Genitourinary abnormality, Ear abnormality) features or deafness. Results: Of the 26 patients, 16 had KS and 10 had nIHH. At diagnosis, mean chronologic age was 18.1 years in males and 18.0 years in females; height SDS were -0.67±1.35 in males, -1.12±1.86 in females; testis volume was 2.0±1.3 mL; and Tanner stage was 1.5. There were associated anomalies in some of the KS patients: hearing loss (n=6) and congenital heart disease (n=4). Absence or hypoplasia of the olfactory bulb/sulci was found in 84.62% of patients with KS. Molecular defects in KAL1, SOX10, and CHD7 were identiied in 5 patients from 4 families (16.0%, 4/25 pedigrees). After sex hormone replacement therapy, there were improvement in sexual characteristics and the sexual function. Conclusion: This study described the clinical, endocrinological, and molecular genetic features in IGD patients in Korea. Although the mutation screening was performed in 10 genes that cause IGD, molecular defects were identified in relatively small proportions of the cohort. [ABSTRACT FROM AUTHOR]

Purpose: Whether parental origin of the intact X chromosome and/or the presence of Y chromosome sequences (Yseq) play a role in three-year height response to growth hormone (GH) were investigated. Methods: Paternal (Xp) or maternal (Xm) origin of X chromosome was assessed by microsatellite marker analysis and the presence of hidden Yseq was analyzed. The first-, second-, and third-year GH response was measured as a change in height z-score (Z_Ht) in Turner syndrome (TS) patients with 45,Xp (n=10), 45,Xm (n=15), and 45,X/46,X,+mar(Y) (Xm_Yseq) (n=8). Results: The mean baseline Z_Ht did not differ according to Xp or Xm origin, however the mean baseline Z_Ht was higher in the Xm_Yseq group than in Xm group, after adjusting for bone age delay and midparental Z_Ht (P=0.04). There was no difference in the height response to GH between the 3 groups. The height response to GH decreased progressively each year (P<0.001), such that the third- year increase in Z_Ht was not significant. This third-year decrease in treatment response was unaffected by Xp, Xm, and Xm_Yseq groups. Increasing GH dosage from the second to third-year of treatment positively correlated with the increase in Z_Ht (P=0.017). Conclusion: There was no evidence of X-linked imprinted genes and/or Yseq affecting height response to 3 years of GH therapy. Increasing GH dosages may help attenuate the decrease in third-year GH response in TS patients with 45,X and/or 46,X/+mar(Y). [ABSTRACT FROM AUTHOR]

Purpose: A gonadotropin-releasing hormone stimulation test (GnRHST) is the gold standard in diagnosing central precocious puberty (CPP). The aim of this study was to investigate the diagnostic accuracy of basal gonadotropin levels for girls with suspected precocious puberty and to evaluate the factors affecting positive results of the GnRHST. Methods: Korean girls with early pubertal development who visited the clinic during 2010-2012 were included. Auxological and biochemical tests were evaluated and a standard GnRHST was performed. A peak luteinizing hormone (LH) level of ≥5 IU/L was considered a positive response during the GnRHST. Results: A total of 336 girls were included. The positive responses were observed in 241 girls (71.7%), and negative responses were found in 95 girls (28.3%). In the logistic regression analysis, the coefficient of the basal LH and basal LH/follicular stimulating hormone (FSH) ratio was 4.23 (P<0.001) and 21.28 (P<0.001), respectively. Receiver operating characteristic analysis showed that the basal LH/FSH ratio is a better predictor of the pubertal result after the GnRHST than the basal LH (area under the curve was 0.745 and 0.740, respectively; P=0.027). Among 189 girls with a basal LH of <0.1 IU/L, 105 (55.6%) had positive responses. Conclusion: An elevated level of the basal LH and basal LH/FSH ratio was a significant predicting factor of positive responses during the GnRHST. However a GnRHST was still necessary for diagnostic confirmation of CPP because more than half of the girls with a basal LH level below the detection limit revealed to have CPP . [ABSTRACT FROM AUTHOR]

Central precocious puberty (CPP) is caused by premature activation of the hypothalamic-gonadal axis, and must be treated adequately. In particular, CPP that occurs at a relatively young age or in boys is likely to be caused by an organic lesion. Hypothalamic hamartoma (HH) is the most common organic cause of CPP. The present case report describes an 11-month-old female infant who presented with vaginal bleeding and rapidly progressive secondary sex characteristics from the age of 6 months. She was diagnosed with CPP following the detection of HH via magnetic resonance imaging. The infant girl was successfully treated with gonadotropin-releasing hormone agonist. After 6 months, her breast had regressed and clinical and radiological follow-up demonstrated stable findings with no evidence of tumor growth or secondary sexual characteristics until the fourth year after the initiation of treatment. This patient is the one of the youngest infants presenting with CPP and HH in Korea; treatment was successful over a relatively long follow-up period.