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.

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.

Diagnosis and Treatment of Central Precocious Puberty / 이화의대지

A notable secular trend in early puberty onset has been described over the past few decades. Also, the prevalence and incidence of precocious puberty is increasing not only in Korea, but also around the world. The manifestation of secondary sex characteristics before 8 years in girls and 9 years in boys is defined as precious puberty. The causes of precocious puberty can be classified as gonadotropin releasing hormone (GnRH)-dependent, also known as central precocious puberty (CPP), or GnRH-independent. Evaluation of patient with precocity requires detailed examination of the clinical manifestation, GnRH stimulation test, and imaging of the central nervous system if indicated. The standard treatment for CPP is GnRH agonist, which is beneficial for adequate pubertal development and preservation of final adult height. In this paper, we investigate the diagnosis and adequate treatment of CPP.

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.

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.

Ten-Year Trends of Metabolic Syndrome Prevalence and Nutrient Intake among Korean Children and Adolescents: A Population-Based Study

Purpose@#Metabolic syndrome (MetS) comprises a cluster of risk factors for future cardiovascular and metabolic diseases. Only a few recent studies have reported the trend in the prevalence of MetS in youth. This study aimed to analyze trends in the prevalence of MetS and nutrient intake in the last 10 years and investigate the changes in MetS components among Korean children and adolescents. @*Materials and Methods@#We analyzed the data of 9513 children and adolescents aged 10–19 years from the 2008–2017 Korean National Health and Nutrition Examination Surveys. Diagnosis of MetS was based on the International Diabetes Federation (IDF) and modified National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) criteria. @*Results@#Based on the IDF criteria, MetS prevalence increased from 1.53% in 2008 to 3.19% in 2017 (p=0.007). Based on the NCEPATP III criteria, MetS prevalence increased from 2.18% in 2008 to 3.19% in 2017; however, the increase was not statistically significant. Daily calorie and fat intakes increased significantly during the study period. Among the risk factors that MetS comprises, the prevalence rates of central obesity, low high-density lipoprotein cholesterol levels, and high fasting glucose levels increased significantly. @*Conclusion@#Over the last 10 years, the prevalence of MetS has grown significantly with increasing calorie and fat intake in Korean children and adolescents. Central obesity and high-density lipoprotein cholesterol and fasting glucose levels have worsened.Therefore, active support and close monitoring are required to control MetS and prevent further increase in the prevalence of cardiovascular diseases.

A case of primary hyperparathyroidism due to an intrathymic ectopic parathyroid adenoma in a 15-year-old boy

Hypercalcemia due to primary hyperparathyroidism (PHPT) is uncommon in children. PHPT is typically caused by a single parathyroid adenoma. Ectopic parathyroid adenomas account for 6%–16% of all parathyroid adenomas and are rare in children but should be considered in cases that present with hypercalcemia. We report the case of a 15-year-old boy with PHPT due to an intrathymic ectopic parathyroid adenoma. Neck ultrasonography and Tc-99m-sestamibi (MIBI) scanning with single-photon emission computed tomography/computed tomography (SPECT/CT) revealed ectopic parathyroid adenoma in the thymus. Video-assisted thoracoscopic surgery was performed to remove the ectopic parathyroid adenoma. Pathology showed intrathymic ectopic parathyroid adenoma. After surgery, the patient’s serum calcium level immediately normalized. Intact parathyroid hormone (iPTH) and alkaline phosphatase levels returned to normal ranges within 3 months. Delayed diagnosis of PHPT can cause end-organ damage; a timely diagnosis is especially critical to preserve bone and renal function. If ectopic parathyroid adenomas are well localized in preoperative imaging evaluation and intraoperative iPTH level decreases after resection, ectopic parathyroidectomy without bilateral neck exploration may be performed to avoid unnecessary morbidity.

Incidence and Prevalence of Type 1 Diabetes Mellitus among Korean Children and Adolescents between 2007 and 2017: An Epidemiologic Study Based on a National Database

Background@#The incidence of type 1 diabetes mellitus (T1DM) among children is high in Europe and the USA and relatively low in Asia, including Korea. The present study aimed to investigate the incidence and prevalence of childhood-onset T1DM in Korea and examine trends in incidence. @*Methods@#This study was conducted using the national registry data provided by the Health Insurance Review and Assessment Service in Korea from 2007 to 2017. We included children aged 0 to 14 years who were newly registered with a T1DM diagnosis each year (code E10). @*Results@#A total of 29,013 children were registered. The overall incidence of T1DM was 4.45 per 100,000 persons (girls, 4.93; boys, 4.01). The overall incidence of childhood-onset T1DM in Korea increased from 3.70 in 2008 to 4.77 in 2016 (P=0.002). The incidence of T1DM increased from 3.07 in 2008 to 4.89 in 2016 (P<0.001) among boys. Although the incidence of the disease increased significantly among boys aged 5–9 and 10–14 years, it remained constant among girls (4.39 in 2008, 4.64 in 2016). The overall prevalence of childhood-onset T1DM in Korea increased from 32.85 in 2007 to 41.03 per 100,000 persons in 2017 (girls, 35.54 to 43.88; boys, 32.85 to 41.03). @*Conclusion@#We calculated relatively accurate incidence and prevalence of childhood-onset T1DM from a nation-based registry. The incidence increased by 3% to 4% every year from 2007 to 2017. The increasing trend is noteworthy compared with previous reports.

Cushing syndrome with acute kidney injury due to ureteral stones in a 6-year-old boy

Cushing syndrome (CS) is rare in children. The clinical presentation of CS varies according to extent and duration of glucocorticoid excess, and urolithiasis is a common complication. We report the first case of a patient with CS associated with acute kidney injury (AKI) due to urolithiasis. A 6-year-old boy presented to the Emergency Department with seizure. On physical examination, he had clinical features of CS and high blood pressure. Brain computed tomography (CT) suggested posterior reversible encephalopathy syndrome due to hypertension. On evaluation of hypertension, laboratory tests suggested adrenocortical tumor, but abdominal CT suggested pheochromocytoma. During further evaluation, his condition deteriorated with AKI due to bilateral ureteral stones, for which the patient underwent continuous renal replacement therapy in the intensive care unit. After controlling hypercortisolism with etomidate and performing ureteral stent indwelling, an adrenal mass was resected and histologically confirmed as an adrenocortical adenoma. We review the clinical manifestations, diagnosis, and management of CS associated with urolithiasis and AKI. Early recognition and careful monitoring of urolithiasis in CS patients are important to avoid severe complications of urolithiasis.

Incidence and Prevalence of Type 1 Diabetes Mellitus among Korean Children and Adolescents between 2007 and 2017: An Epidemiologic Study Based on a National Database

Background@#The incidence of type 1 diabetes mellitus (T1DM) among children is high in Europe and the USA and relatively low in Asia, including Korea. The present study aimed to investigate the incidence and prevalence of childhood-onset T1DM in Korea and examine trends in incidence. @*Methods@#This study was conducted using the national registry data provided by the Health Insurance Review and Assessment Service in Korea from 2007 to 2017. We included children aged 0 to 14 years who were newly registered with a T1DM diagnosis each year (code E10). @*Results@#A total of 29,013 children were registered. The overall incidence of T1DM was 4.45 per 100,000 persons (girls, 4.93; boys, 4.01). The overall incidence of childhood-onset T1DM in Korea increased from 3.70 in 2008 to 4.77 in 2016 (P=0.002). The incidence of T1DM increased from 3.07 in 2008 to 4.89 in 2016 (P<0.001) among boys. Although the incidence of the disease increased significantly among boys aged 5–9 and 10–14 years, it remained constant among girls (4.39 in 2008, 4.64 in 2016). The overall prevalence of childhood-onset T1DM in Korea increased from 32.85 in 2007 to 41.03 per 100,000 persons in 2017 (girls, 35.54 to 43.88; boys, 32.85 to 41.03). @*Conclusion@#We calculated relatively accurate incidence and prevalence of childhood-onset T1DM from a nation-based registry. The incidence increased by 3% to 4% every year from 2007 to 2017. The increasing trend is noteworthy compared with previous reports.

Cushing syndrome with acute kidney injury due to ureteral stones in a 6-year-old boy

Cushing syndrome (CS) is rare in children. The clinical presentation of CS varies according to extent and duration of glucocorticoid excess, and urolithiasis is a common complication. We report the first case of a patient with CS associated with acute kidney injury (AKI) due to urolithiasis. A 6-year-old boy presented to the Emergency Department with seizure. On physical examination, he had clinical features of CS and high blood pressure. Brain computed tomography (CT) suggested posterior reversible encephalopathy syndrome due to hypertension. On evaluation of hypertension, laboratory tests suggested adrenocortical tumor, but abdominal CT suggested pheochromocytoma. During further evaluation, his condition deteriorated with AKI due to bilateral ureteral stones, for which the patient underwent continuous renal replacement therapy in the intensive care unit. After controlling hypercortisolism with etomidate and performing ureteral stent indwelling, an adrenal mass was resected and histologically confirmed as an adrenocortical adenoma. We review the clinical manifestations, diagnosis, and management of CS associated with urolithiasis and AKI. Early recognition and careful monitoring of urolithiasis in CS patients are important to avoid severe complications of urolithiasis.

A novel compound heterozygous mutation of the AIRE gene in a patient with autoimmune polyendocrine syndrome type 1

Autoimmune polyendocrine syndrome type 1 (APS-1), or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare, autosomal recessive autoimmune disease caused by a mutation of the autoimmune regulator (AIRE) gene. The main symptom triad in APS-1 comprises chronic mucocutaneous candidiasis, adrenal insufficiency, and hypoparathyroidism. Various autoimmune diseases and ectodermal abnormalities are also commonly associated with the syndrome. The treatment of APS-1 includes hormone replacement and symptom control. It is important to monitor such patients for clinical manifestations of their disease through regular follow-up. We report the case of a 10-year-old Korean girl with APS-1 due to a novel compound heterozygous mutation of the AIRE gene. This patient's main clinical manifestations were adrenal insufficiency and chronic mucocutaneous candidiasis. The patient had a previously known pathogenic variant of c.1513delG (p.Ala505ProfsTer16), and a newly discovered variant of c.1360dupC (p.His454ProfsTer50).

The impact of a quality improvement effort in reducing admission hypothermia in preterm infants following delivery / 소아과

PURPOSE: Hypothermia at admission is associated with increased mortality and morbidity in preterm infants. We performed a quality improvement (QI) effort to determine the impact of a decrease in admission hypothermia in preterm infants. METHODS: The study enrolled very low birth weight (VLBW) infants born at Gangnam Severance Hospital between January 2013 and December 2016. This multidisciplinary QI effort included the use of occlusive wraps, warm blankets, and caps; the delivery room temperature was maintained above 23.0℃, and a check-list was used for feedback. RESULTS: Among 259 preterm infants, the incidence of hypothermia (defined as body temperature <36.0℃) decreased significantly from 68% to 41%, and the mean body temperature on neonatal intensive care unit admission increased significantly from 35.5℃ to 36.0℃. In subgroup analysis of VLBW infants, admission hypothermia and neonatal outcomes were compared between the pre-QI (n=55) and post-QI groups (n=75). Body temperature on admission increased significantly from 35.4℃ to 35.9℃ and the number of infants with hypothermia decreased significantly from 71% to 45%. There were no cases of neonatal hyperthermia. The incidence of pulmonary hemorrhage was significantly decreased (P=0.017). Interaction analysis showed that birth weight and gestational age were not correlated with hypothermia following implementation of the protocol. CONCLUSION: Our study demonstrated a significant reduction in admission hypothermia following the introduction of a standardized protocol in our QI effort. This resulted in an effective reduction in the incidence of massive pulmonary hemorrhage.

Respiratory failure in a diabetic ketoacidosis patient with severe hypophosphatemia

Phosphate is essential in regulating human metabolic processes, and severe hypophosphatemia can induce neurologic and hematological complications and result in respiratory failure and cardiac dysfunction. Therefore, correction of severe hypophosphatemia can be pivotal in the management of diabetic ketoacidosis (DKA). We report the case of a 14-year-old female who was diagnosed with type 1 diabetes and referred to our institute for treatment of DKA. Although the patient received fluid and continuous insulin administration according to the current DKA treatment protocol, generalized tonic seizures and cardiac arrest developed. After cardiopulmonary resuscitation, the patient recovered and was stable. Within 16 hours after DKA treatment, the patient developed respiratory failure with severe hypophosphatemia that required mechanical ventilation. Concurrent neurologic evaluation revealed no specific abnormalities. The patient recovered without any complications after correcting the hypophosphatemia. We suggest vigilant monitoring of the phosphate level in DKA patients and active replacement when required.

Ca2 -activated K Currents of Pancreatic Duct Cells in Guinea-pig

There are numerous studies on transepithelial transports in duct cells including Cl and/or HCO3. However, studies on transepithelial K transport of normal duct cells in exocrine glands are scarce. In the present study, we examined the characteristics of K currents in single duct cells isolated from guinea pig pancreas, using a whole-cell patch clamp technique. Both Cl and K conductance were found with KCl rich pipette solutions. When the bath solution was changed to low Cl, reversal potentials shifted to the negative side, 75 4 mV, suggesting that this current is dominantly selective to K. We then characterized this outward rectifying K current and examined its Ca2 dependency. The K currents were activated by intracellular Ca2. 100 nM or 500 nM Ca2 in pipette significantly (P< 0.05) increased outward currents (currents were normalized, 76.8 7.9 pA, n=4 or 107.9 35.5 pA, n=6) at 100 mV membrane potential, compared to those with 0 nM Ca2 in pipette (27.8 3.7 pA, n=6). We next examined whether this K current, recorded with 100 nM Ca2 in pipette, was inhibited by various inhibitors, including Ba2, TEA and iberiotoxin. The currents were inhibited by 40.4 % (n=3), 87.0 % (n=5) and 82.5 % (n=9) by 1 mM Ba2, 5 mM TEA and 100 nM iberiotoxin, respectively. Particularly, an almost complete inhibition of the current by 100 nM iberiotoxin further confirmed that this current was activated by intracellular Ca2. The K current may play a role in secretory process, since recycling of K is critical for the initiation and sustaining of Cl or HCO3 secretion in these cells.