A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration.

The accumulation of misfolded and aggregated proteins is a hallmark of neurodegenerative proteinopathies. Although multiple genetic loci have been associated with specific neurodegenerative diseases (NDs), molecular mechanisms that may have a broader relevance for most or all proteinopathies remain poorly resolved. In this study, we developed a multi-layered network expansion (MLnet) model to predict protein modifiers that are common to a group of diseases and, therefore, may have broader pathophysiological relevance for that group. When applied to the four NDs Alzheimer's disease (AD), Huntington's disease, and spinocerebellar ataxia types 1 and 3, we predicted multiple members of the insulin pathway, including PDK1, Akt1, InR, and sgg (GSK-3ß), as common modifiers. We validated these modifiers with the help of four Drosophila ND models. Further evaluation of Akt1 in human cell-based ND models revealed that activation of Akt1 signaling by the small molecule SC79 increased cell viability in all models. Moreover, treatment of AD model mice with SC79 enhanced their long-term memory and ameliorated dysregulated anxiety levels, which are commonly affected in AD patients. These findings validate MLnet as a valuable tool to uncover molecular pathways and proteins involved in the pathophysiology of entire disease groups and identify potential therapeutic targets that have relevance across disease boundaries. MLnet can be used for any group of diseases and is available as a web tool at http://ssbio.cau.ac.kr/software/mlnet.

Comparison of the Triglyceride Glucose Index and Modified Triglyceride Glucose Indices to Predict Nonalcoholic Fatty Liver Disease in Youths.

OBJECTIVE: To assess the associations between the triglyceride glucose (TyG) index and modified TyG indices with nonalcoholic fatty liver disease (NAFLD) and evaluate their ability as predictors of NAFLD in youths. STUDY DESIGN: We analyzed the cross-sectional data of 3728 individuals aged 10-19 years using the Korea National Health and Nutrition Examination Survey, a nationally representative survey. Logistic regression analysis was performed, and ORs and 95% CIs of tertiles 2 and 3 for each variable for predicting NAFLD were calculated and compared with those of tertile 1 as the reference. Receiver operating characteristic (ROC) curves were plotted to evaluate the ability of each variable for NAFLD prediction. RESULTS: All TyG and modified TyG indices exhibited progressively increased ORs and 95% CIs for NAFLD across all tertiles (all P < .001). In addition, all TyG and modified TyG indices significantly predicted NAFLD through ROC curves. All modified TyG indices were superior to the TyG index for predicting NAFLD in all subjects and in males. Among females, the TyG-waist-to-height ratio was superior to the TyG index, TyG-body mass index (BMI), and TyG-waist circumference (WC), and the TyG-BMI SDS and TyG-WC were superior to the TyG index. CONCLUSIONS: The TyG and modified TyG indices are markers for NAFLD prediction in youths, and the modified TyG indices are superior to the TyG index. Modified TyG indices have the potential to be simple and cost-effective markers in screening for NAFLD in youths.

Trends of Dyslipidemia in Korean Youth According to Sex and Body Mass Index: Based on the Korea National Health and Nutrition Examination Survey (2007-2018).

OBJECTIVE: To assess trends of dyslipidemia among youth, we investigated secular trends in serum lipid levels from 2007 to 2018 and the current prevalence of dyslipidemia in Korean children and adolescents. STUDY DESIGN: This cross-sectional study investigated lipid profiles of 10 734 youths aged 10-18 years using data from phases IV-VII of the Korea National Health and Nutritional Examination Survey. We assessed age-, sex-, and body mass index (BMI)-adjusted mean levels of lipids at each survey. RESULTS: Mean levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) levels increased from phase IV to VII. Among boys, the prevalence of acceptable levels of total cholesterol, LDL-C, and non-HDL-C decreased significantly (P = .005, P = .001, and P < .001, respectively). In girls, the prevalence of acceptable levels of total cholesterol, LDL-C, HDL-C, and non-HDL-C decreased significantly (P = .003, P = .005, P = .008, and P = .013, respectively). In BMI- and age-specific analyses, worsening trends in total cholesterol, LDL-C, and non-HDL levels were more apparent in youths with a normal BMI and young age. CONCLUSIONS: Dyslipidemia trends are worsening in Korean youth, even in those with a normal BMI and young age. Thus, future cardiovascular disease risk may increase and comprehensive management plans are required for youth with overweight or obesity and those with a normal BMI and young age.

Adolescents with thyroid nodules: retrospective analysis of factors predicting malignancy.

Thyroid nodules are less common in children than in adults. However, pediatric thyroid nodules have a higher rate of malignancy compared to those in adults, and increased risk of metastasis and recurrence. In the present study, we analyzed the clinical features as well as laboratory and thyroid ultrasound (US) findings of children and adolescents with thyroid nodules to identify predictive factors of thyroid cancer. We retrospectively analyzed 275 patients with thyroid nodules under 18 years of age who visited Severance Children's Hospital between January 2005 and May 2017. Among them, 141 patients who underwent ultrasonography-guided fine needle aspiration biopsy (FNAB), and four patients without FNAB who underwent surgical resection, were included in this study. The remaining 125 patients without FNAB and five patients with follow-up loss after FNAB were excluded. Clinical, laboratory, and US data were evaluated in 145 patients to establish the potential predictive factors of thyroid cancer. Thyroid malignancies were observed in 101 patients. Grade 2 goiters were seen more often in benign nodule group. Hypoechoic nodules, nodules with microcalcifications, abnormal lymph nodes, and irregular margins were findings significantly associated with thyroid cancer. The findings of hypoechoic nodule, nodule with microcalcifications, and abnormal lymph nodes showed statistical significance in predicting thyroid cancer.Conclusion: Hypoechoic nodules, nodules with microcalcifications, and abnormal lymph nodes are predictive factors for thyroid cancer in children. Therefore, further diagnostic evaluations, including FNAB, should be considered in patients with such findings.What is Known:• Thyroid nodules are less common in children than in adults, but pediatric thyroid nodules have a higher rate of malignancy, and also have increased risk of metastasis and recurrence.• Research on ways to predict thyroid cancer have mostly been accomplished in adult patients, and the application of risk stratification system has not been fully satisfactory in children, which requires further studies in pediatric thyroid nodules.What is New:• Hypoechoic nodules, nodules with microcalcifications, and abnormal lymph nodes are predictive factors for thyroid cancer in Korean children.

The analysis of endocrine disruptors in patients with central precocious puberty.

BACKGROUND: A few studies have reported a positive association between phthalate exposure and pubertal timing, but several conflicting reports exist. The main objective of the study was to determine whether phthalate exposure was associated with central precocious puberty in girls. METHODS: This was a multicenter case-control study wherein 47 girls with central precocious puberty (CPP) and 47 controls (26 pre-pubertal girls and 21 pubertal girls) were enrolled. No obese girls were included. Five phthalate metabolites (creatinine adjusted) and bisphenol A (BPA) were measured in the first spot urine samples of these 94 girls in the early morning. RESULTS: The median values of monobenzyl phthalate (MBzP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and mono-n-butyl phthalate (MnBP) were 3.1, 29.3, 18.0, 15.4, and 25.2 µg/g creatinine in the CPP group, 4.3, 53.7, 35.7, 29.1, and 66.0 µg/g creatinine in the pre-pubertal control group, and 1.7, 28.7, 21.4, 12.1, and 33.3 µg/g creatinine in the pubertal control group, respectively. The urinary concentration of the five phthalates was significantly lower in the CPP group than in the pre-pubertal control group (P < 0.001). Conversely, there was no significant difference in the urinary concentration of the five phthalates between the CPP and pubertal control groups (P values: 0.077 for MBzP, 0.733 for MECPP, 0.762 for MEHHP, 0.405 for MEOHP, and 0.981 for MnBP). In addition, the BPA level was not significantly different between the CPP and pubertal control groups (BPA median values: 0.63 µg/g creatinine, the CPP group; 1.7 µg/g creatinine, the pubertal control group; P value = 0.092). CONCLUSIONS: Our study showed that there was no significant difference in the urinary phthalate levels between the CPP and pubertal control groups. Moreover, phthalate metabolites were significantly lower in the CPP group than in the pre-pubertal control group. Further investigation about endocrine disruptors and pubertal progression is needed.

Effectiveness and safety of pamidronate treatment in nonambulatory children with low bone mineral density.

PURPOSE: Nonambulatory pediatric patients may have low bone mineral density (BMD) and increased risk of pathologic fractures. Though bisphosphonate therapy is the mainstream medical intervention in these children, clinical data regarding this treatment are limited. Therefore, this study aimed to evaluate the effectiveness and safety of bisphosphonate therapy in such children. METHODS: We conducted a retrospective study of 21 nonambulatory children (Gross Motor Function Classification System level V) with BMD z-score ≤ -2.0 who were treated with intravenous pamidronate for at least 1 year. These patients received pamidronate every 4 months at a dose of 1.0 to 3.0 mg/kg for each cycle and had regular follow-ups for at least 1 year. The main outcome measures were changes in BMD, risk rate of fracture, biochemical data, and adverse events. RESULTS: The average duration of pamidronate treatment was 2.0±0.9 years, and the mean cumulative dose of pamidronate according to body weight was 7.7±2.5 mg/kg/yr. After treatment, the mean lumbar spine bone mineral content, BMD, and height-for-age-z-score-adjusted BMD z-score (BMDhazZ) significantly improved. The relative risk of fracture after treatment was 0.21 (p=0.0032), suggesting that pamidronate treatment reduced fracture incidence significantly. The increase in the average dose per body weight in each cycle significantly increased the changes in BMDhazZ. CONCLUSION: Pamidronate treatment improved the bone health of nonambulatory children with low bone density without any significant adverse events. Independent of cumulative dosage and duration of treatment, the effectiveness of pamidronate increased significantly with an increase in the average dose per body weight in subsequent cycles.

Association between early glycemic management and diabetes complications in type 1 diabetes mellitus: A retrospective cohort study.

AIMS: To investigate the association between early HbA1c levels near diagnosis and future glycemic management, and analyzed risk factors of complications in people with T1DM. METHODS: This retrospective cohort study included 201 children and adolescents with T1DM. Patient data including sex, age at diagnosis, duration of disease, HbA1c levels, HbA1c variability during the follow-up period, and diabetes complications and comorbidities were collected. RESULTS: The mean follow-up period of patients was 16.4 years. HbA1c levels in all three examined time points after diagnosis (first year, second year, and first two years) were significantly associated with recent HbA1c level, and second-year HbA1c was most closely correlated with recent HbA1c level. Elevated second-year HbA1c was a risk factor of diabetic ketoacidosis (DKA) and retinopathy, and increased variability of HbA1c was significantly related to various microvascular complications. When HbA1c is stratified into quartiles, the subjects of each quartile trend to stay within that quartile over the follow-up period. CONCLUSIONS: Early HbA1c levels were closely associated with recent HbA1c levels and diabetes complications in patients with T1DMs. Strict glucose management after diagnosis and reducing variability of HbA1c may prevent future diabetes complications and comorbidities.

Comparison of growth response and adverse reaction according to growth hormone dosing strategy for children with short stature: LG Growth Study.

OBJECTIVE: Growth hormone (GH) dosage in children is conventionally determined either by body weight (BW) or body surface area (BSA). However, there is no consensus on the calculation method for proper GH treatment dose. We aimed to compare growth response and adverse reactions between BW- and BSA-based GH treatment doses for children with short statures. DESIGN: Data from 2284 GH-treated children were analyzed. Distributions of BW- and BSA-based GH treatment doses and their association with growth response parameters, including changes in height, height standard deviation score (SDS), body mass index (BMI), and safety parameters, such as changes in insulin-like growth factor (IGF)-I SDS and adverse events, were investigated. RESULTS: The mean BW-based doses were close to the recommended dose's upper limit in participants with GH deficiency and idiopathic short stature, while they were below the recommended dose in patients with Turner syndrome (TS). As age and BW increased, BW-based dose decreased, whereas BSA-based dose increased. Gain in height SDS was positively associated with BW-based dose in the TS group and negatively associated with BW in all groups. Despite having a lower BW-based dose, the overweight/obese groups had a higher BSA-based dose and higher frequencies of children with high IGF-I and adverse events than those of the normal-BMI group. CONCLUSIONS: In children of older age or with high BW, BW-based doses can be overdosed in terms of BSA. and BW-based dose positively correlated with height gain only in the TS group. BSA-based doses represent an alternative dosing strategy in children who are overweight/obese.

Bone Age Estimation and Prediction of Final Adult Height Using Deep Learning.

PURPOSE: The appropriate evaluation of height and accurate estimation of bone age are crucial for proper assessment of the growth status of a child. We developed a bone age estimation program using a deep learning algorithm and established a model to predict the final adult height of Korean children. MATERIALS AND METHODS: A total of 1678 radiographs from 866 children, for which the interpretation results were consistent between two pediatric endocrinologists, were used to train and validate the deep learning model. The bone age estimation algorithm was based on the convolutional neural network of the deep learning system. The test set simulation was performed by a deep learning program and two raters using 150 radiographs and final height data for 100 adults. RESULTS: There was a statistically significant correlation between bone age interpreted by the artificial intelligence (AI) program and the reference bone age in the test set simulation (r=0.99, p<0.001). In the test set simulation, the AI program showed a mean absolute error (MAE) of 0.59 years and a root mean squared error (RMSE) of 0.55 years, compared with reference bone age, and showed similar accuracy to that of an experienced pediatric endocrinologist (rater 1). Prediction of final adult height by the AI program showed an MAE of 4.62 cm, compared with the actual final adult height. CONCLUSION: We developed a bone age estimation program based on a deep learning algorithm. The AI-derived program demonstrated high accuracy in estimating bone age and predicting the final adult height of Korean children and adolescents.

Effect of long-acting growth hormone treatment on endogenous growth hormone secretion in prepubertal patients with idiopathic short stature: A preliminary study.

Long-acting growth hormone (LAGH) is emerging to be a new preparation for treatment of short stature. We aimed to determine whether 12-month treatment with LAGH in patients with idiopathic short stature has an effect on the nocturnal endogenous growth hormone (GH) secretion and metabolic consequences and efficacy. Participants included 10 GH-naïve prepubertal children with idiopathic short stature (ISS). One patient was withdrawn due to own decline during study. Participants were randomized on a 1:1 ratio to receive either a daily GH (0.37 mg/kg/week) or once-weekly LAGH (0.7 mg/kg/week) over a 12-month period. Nocturnal endogenous GH secretory profiles obtained from 12-h blood samplings at 30-min interval were assessed at baseline and 2 weeks after the completion of GH treatment. Post-treatment changes in height velocity, height standard deviation score (SDS), metabolic parameters, and adverse events were measured. A total of 4 patients received LAGH, and 5 patients received daily GH. Nocturnal endogenous GH secretory profiles, such as mean serum GH concentrations, frequency, amplitude, interpulse interval of spontaneous GH secretory bursts, and mass of GH released per secretory burst were similar at baseline and after 12-month treatment in both groups. The efficacy and safety after LAGH treatment for 12 months were similar to those of daily GH. In conclusions, these findings indicated that LAGH does not suppress endogenous GH secretion, and can be used for treatment of non-GH deficient short stature with similar efficacy and safety compared to daily GH. These may contribute to define and develop treatment and follow-up protocols for LAGH use in ISS patients.

Insulin Requirement and Complications Associated With Serum C-Peptide Decline in Patients With Type 1 Diabetes Mellitus During 15 Years After Diagnosis.

Objective: C-peptide is conventionally used in assessing pancreatic function in patients with diabetes mellitus. The clinical significance of this molecule during the course of type 1 diabetes mellitus (T1DM) has been recently revisited. This study aimed to investigate the natural course of C-peptide in T1DM patients over the period of 15 years and analyze the association between the residual C-peptide and diabetes complications. Methods: This retrospective study included a total of 234 children and adolescents with T1DM. Patient data including sex, age at diagnosis, anthropometric measures, daily insulin dose, serum HbA1c, post-prandial serum C-peptide levels, lipid profiles, and diabetic complications at the time of diagnosis and 1, 3, 5, 10, and 15 years after diagnosis were retrospectively collected. Results: Among the 234 patients, 101 were men and 133 were women, and the mean patient age at initial diagnosis was 8.3 years. Serum C-peptide decreased constantly since the initial diagnosis, and showed a significant decline at 3 years after diagnosis. At 15 years after diagnosis, only 26.2% of patients had detectable serum C-peptide levels. The subgroup with older patients and patients with higher BMI standard deviation score showed higher mean serum C-peptide, but the group-by-time results were not significant, respectively. Patients with higher serum C-peptide required lower doses of insulin and had fewer events of diabetic ketoacidosis. Conclusion: Serum C-peptide decreased consistently since diagnosis of T1DM, showing a significant decline after 3 years. Patients with residual C-peptide required a lower dose of insulin and had a lower risk for diabetic ketoacidosis.

Serum kisspeptin levels mainly depend on ovarian expression of Kiss1 mRNA in female rats.

The hypothalamic kisspeptin/KISS1 receptor system is essential for puberty onset and reproductive development. Although serum kisspeptin might be associated with puberty, its levels, according to developmental stage, and its origin still remain unclear. This study evaluated the changes in serum kisspeptin levels during puberty and the corresponding Kiss1 mRNA and protein expression in various organs of female rats to identify the source of serum kisspeptin. Tissues from several organs, including the ovaries and anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) in the hypothalamus, were obtained for assessing Kiss1 mRNA and protein expressions. Serum kisspeptin levels progressively increased with developmental stages until the peripubertal stage. The ovaries showed the highest Kiss1 expression among the organs examined. Next, we explored the changes in serum kisspeptin levels and hypothalamic Kiss1 expression in ovariectomized and estradiol-treated ovariectomized rats. Serum kisspeptin levels decreased regardless of estradiol treatment; Kiss1 expression was enhanced by ovariectomy and estradiol treatment in the ARC, while it was decreased by ovariectomy and enhanced by estradiol in the AVPV, suggesting that serum kisspeptin may be associated with pubertal development and mainly depended on ovarian Kiss1 expression. Thus, serum kisspeptin levels are associated with puberty and may serve as a downstream marker of ovarian reproductive function.

Comparison of the Modified TyG Indices and Other Parameters to Predict Non-Alcoholic Fatty Liver Disease in Youth.

We investigated the modified triglycerides-glucose (TyG) indices and other markers for non-alcoholic fatty liver disease (NAFLD) in 225 participants aged 10-19 years, and the participants were divided into subgroups according to their NAFLD grade. We performed logistic regression analysis and calculated the odds ratios (ORs) with 95% confidence intervals (CIs) of tertiles 2 and 3 for each parameter, with those of tertile 1 as a reference. The area under the receiver operating characteristic (ROC) curve was calculated to compare the parameters for identifying NAFLD. TyG and modified indices, aspartate transaminase-to-platelet ratio index (APRI)-body mass index (BMI), APRI-BMI standard deviation score (SDS), APRI waist-to-hip ratio, fibrosis-4 index (FIB)-4, and hepatic steatosis index (HSI) were higher in participants with NAFLD than in those without NAFLD. The ORs and 95% CIs for NAFLD progressively increased across tertiles of each parameter. TyG and modified TyG indices, FIB-4, HSI, and modified APRIs, except APRI waist-to-height ratio, predicted NAFLD significantly through ROC curves. Modified TyG indices, APRI-BMI SDS, and HSI were superior to the other markers for NAFLD prediction. Modified TyG indices, APRI-BMI SDS, and HSI appear to be useful for assessing NAFLD in youths.

Trends in Prediabetes and Non-Alcoholic Fatty Liver Disease Associated with Abdominal Obesity among Korean Children and Adolescents: Based on the Korea National Health and Nutrition Examination Survey between 2009 and 2018.

Investigations on the trends of prediabetes and non-alcoholic fatty liver disease (NAFLD) among children are scarce. We aimed to analyze the trends of prediabetes and NAFLD, as well as their association, among Korean children and adolescents from 2009 to 2018. This study investigated the prevalence of prediabetes, NAFLD, and abdominal obesity among 6327 children and adolescents aged 10-18 years according to age, sex, and body mass index (BMI) using a nationally representative survey. The prevalence of prediabetes, NAFLD, and abdominal obesity increased from 5.14%, 8.17%, and 5.97% respectively, in 2009 to 10.46%, 12.05%, and 10.51% respectively, in 2018. In age-specific analyses, an adverse trend in NAFLD was significant only in participants aged 16-18 years while the prevalence of prediabetes worsened significantly in all age groups. In BMI-specific analyses, the prevalence of prediabetes and NAFLD increased significantly only in participants with normal BMI. In logistic regression analysis, the odds ratio of prediabetes for NAFLD was 1.85 and those of abdominal obesity for prediabetes and NAFLD was 1.85 and 9.34, respectively. Our results demonstrated that the prevalence of prediabetes and NAFLD was increasing in association with abdominal obesity in Korean children and adolescents.

Association of hypercalciuria with vitamin D supplementation in patients undergoing ketogenic dietary therapy.

Background: Ketogenic dietary therapy (KDT) is used as an effective treatment for epilepsy. However, KDT carries the risk of bone health deterioration; therefore, vitamin D supplementation is required. Vitamin D replacement therapy in KDT has not been established because it may be related to hypercalciuria/urolithiasis, which are common adverse effects of KDT. Hence, this study aimed to evaluate the dose-dependent association between vitamin D3 and hypercalciuria/urolithiasis in patients undergoing KDT and dose optimization for renal complications. Materials and methods: Overall, 140 patients with intractable childhood epilepsy started 3:1 KDT (lipid to non-lipid ratio) at the Severance Children's Hospital from January 2016 to December 2019. Regular visits were recommended after KDT initiation. Participants were assessed for height, weight, serum 25-hydroxyvitamin D (25-OH-D3) level, parathyroid hormone level, and ratio of urinary excretion of calcium and creatinine (Uca/Ucr). Kidney sonography was conducted annually. Patients who already had urolithiasis and were taking hydrochlorothiazide before KDT, failed to maintain KDT for 3 months, did not visit the pediatric endocrine department regularly, did not take prescribed calcium and vitamin D3 properly, or needed hospitalization for > 1°month because of serious medical illness were excluded. Data from patients who started diuretic agents, e.g., hydrochlorothiazide, were excluded from that point because the excretion of calcium in the urine may be altered in these patients. Result: In total, 49 patients were included in this study. Uca/Ucr ratio significantly decreased with increasing levels of 25-OH-D3 (p = 0.027). The odds ratio for hypercalciuria was 0.945 (95% confidence interval, 0.912-0.979; p = 0.002) per 1.0 ng/mL increment in 25-OH-D3 level. Based on findings of receiver operating characteristic curve analysis and Youden's J statistic, the cut-off 25-OH-D3 level for preventing hypercalciuria was > 39.1 ng/mL at 6 months. Furthermore, the vitamin D3 supplementation dose cut-off was > 49.5 IU/kg for hypercalciuria prevention. Conclusion: An inverse relationship between Uca/Ucr ratio and 25-OH-D3 level was noted, which means that vitamin D supplementation is helpful for preventing hypercalciuria related to KDT. We suggest that the recommended 25-OH-D3 level is > 40 ng/mL for hypercalciuria prevention and that KDT for children with epilepsy can be optimized by vitamin D3 supplementation at 50 IU/kg.

Metabolic Impacts of Discontinuation and Resumption of Recombinant Human Growth Hormone Treatment during the Transition Period in Patients with Childhood-Onset Growth Hormone Deficiency.

BACKGROUND: Discontinuing growth hormone (GH) treatment during the transition to adulthood has been associated with adverse health outcomes in patients with childhood-onset growth hormone deficiency (CO-GHD). This study investigated the metabolic changes associated with interrupting GH treatment in adolescents with CO-GHD during the transition period. METHODS: This study included 187 patients with CO-GHD who were confirmed to have adult GHD and were treated at six academic centers in Korea. Data on clinical parameters, including anthropometric measurements, metabolic profiles, and bone mineral density (BMD) at the end of childhood GH treatment, were collected at the time of re-evaluation for GHD and 1 year after treatment resumption. RESULTS: Most patients (n=182, 97.3%) had organic GHD. The median age at treatment discontinuation and re-evaluation was 15.6 and 18.7 years, respectively. The median duration of treatment interruption was 2.8 years. During treatment discontinuation, body mass index Z-scores and total cholesterol, low-density lipoprotein, and non-high-density lipoprotein (HDL) cholesterol levels increased, whereas fasting glucose levels decreased. One year after GH treatment resumption, fasting glucose levels, HDL cholesterol levels, and femoral neck BMD increased significantly. Longer GH interruption (>2 years, 60.4%) resulted in worse lipid profiles at re-evaluation. The duration of interruption was positively correlated with fasting glucose and non-HDL cholesterol levels after adjusting for covariates. CONCLUSION: GH treatment interruption during the transition period resulted in worse metabolic parameters, and a longer interruption period was correlated with poorer outcomes. GH treatment should be resumed early in patients with CO-GHD during the transition period.

Regulation of synaptic Rac1 activity, long-term potentiation maintenance, and learning and memory by BCR and ABR Rac GTPase-activating proteins.

Rho family small GTPases are important regulators of neuronal development. Defective Rho regulation causes nervous system dysfunctions including mental retardation and Alzheimer's disease. Rac1, a member of the Rho family, regulates dendritic spines and excitatory synapses, but relatively little is known about how synaptic Rac1 is negatively regulated. Breakpoint cluster region (BCR) is a Rac GTPase-activating protein known to form a fusion protein with the c-Abl tyrosine kinase in Philadelphia chromosome-positive chronic myelogenous leukemia. Despite the fact that BCR mRNAs are abundantly expressed in the brain, the neural functions of BCR protein have remained obscure. We report here that BCR and its close relative active BCR-related (ABR) localize at excitatory synapses and directly interact with PSD-95, an abundant postsynaptic scaffolding protein. Mice deficient for BCR or ABR show enhanced basal Rac1 activity but only a small increase in spine density. Importantly, mice lacking BCR or ABR exhibit a marked decrease in the maintenance, but not induction, of long-term potentiation, and show impaired spatial and object recognition memory. These results suggest that BCR and ABR have novel roles in the regulation of synaptic Rac1 signaling, synaptic plasticity, and learning and memory, and that excessive Rac1 activity negatively affects synaptic and cognitive functions.

Two cases of 17α-hydroxylase/17,20-lyase deficiency caused by the CYP17A1 mutation.

17α-hydroxylase/17,20-lyase deficiency, caused by mutations in the cytochrome P450 family 17 subfamily A member 1 gene (CYP17A1), is an extremely rare form of congenital adrenal hyperplasia that is characterized by diverse phenotypes resulting from specific mutations. Here, we report 2 phenotypic females with 17α-hydroxylase/17,20-lyase deficiency: one with the 46,XX karyotype presenting primary amenorrhea and sexual infantilism, and the other with the 46,XY karyotype presenting a disorder of sexual development. In both cases, the serum levels of adrenocorticotropic hormone, 11-deoxycorticosterone, and gonadotropin were elevated, whereas the levels of testosterone and dehydroepiandrosterone were reduced. Next-generation sequencing revealed one patient with compound heterozygosity for p.Trp17Ter (c.51G>A) and p.His373Leu (c.1118A>T), and the other with homozygosity for p.His373Leu (c.1118A>T). This report further describes 2 cases of 17α-hydroxylase/17,20-lyase deficiency in patients who harbored a p.His373Leu substitution, commonly found in Korean individuals, and presented diverse phenotypes.

Identification of a novel point mutation in DAX-1 gene in a patient with adrenal hypoplasia congenita.

X-linked adrenal hypoplasia congenita caused by a mutation in NR0B1/DAX-1 is a rare inherited disorder. Patients with adrenal hypoplasia congenita are usually diagnosed with primary adrenal insufficiency in infancy or early childhood and present hypogonadotropic hypogonadism during adolescence. Our patient first presented with adrenal crisis at the age of 2 months, which was managed with glucocorticoids and mineralocorticoids. At the age of 17 years, testicular volumes of 5 mL each and a stretched penile length of 4 cm were noted. A combined pituitary function test showed a peak luteinizing hormone level of 2.68 mIU/mL, testosterone 13.5 ng/dL, confirming hypogonadotropic hypogonadism. After whole-exome sequencing, a new variant of DAX-1, c.881T>C (p.Leu294Pro), was found. He was diagnosed with X-linked adrenal hypoplasia congenita and then treated with human choriogonadotropin for the induction of spermatogenesis as well as with steroid replacement therapy.

Management of Central Precocious Puberty in Children with Hypothalamic Hamartoma.

Hypothalamic hamartoma (HH) is a rare, congenital, and benign lesion of the tuber cinereum, typically presenting with central precocious puberty (CPP), gelastic seizure, and developmental delay. This study aimed to investigate CPP in HH patients and compare clinical features between before and after gonadotropin-releasing hormone (GnRH) agonist treatment. A total of 30 HH patients under 18 years of age who visited Severance Children's Hospital between January 2005 and May 2020 were retrospectively reviewed. Fourteen patients were male (46.7%) and sixteen (53.3%) were female, with a mean age at diagnosis was4.2 ± 2.9 years. During follow-up, 24 patients (80.0%) were diagnosed with CPP, 15 patients (50.0%) had gelastic seizure, and 13 patients (43.3%) had developmental delay. The gelastic seizure was significantly associated with sessile type HH rather than pedunculated type HH (85.7% vs. 18.8%, p = 0.001). After GnRH agonist treatment, discrepancies between bone age and chronological age decreased (3.3 ± 1.3 years to 2.0 ± 1.7 years, p = 0.002). Additionally, height standard deviation score for bone age was increased, and predicted adult height increased significantly in females, while males showed an increasing trend. Clinical symptoms of HH were closely associated with the location of HH, and GnRH agonist treatment was safe and effective in the management of CPP caused by HH.