The association between phthalate exposure and pubertal development.

Antiandrogenic effect of phthalates have been reported; however, results regarding the effect of phthalate exposure in pubertal children have been inconsistent. We aimed to investigate the relationship between phthalate exposure and pubertal development, especially whether high molecular weight phthalates (HMWP) and low molecular weight phthalates (LMWP) are differently associated in boys and girls. Urinary phthalate metabolites (4 HMWPs and 3 LMWPs) in Korean children (236 boys and 202 girls, aged 10 to 12 years) were measured. The association between phthalate levels and pubertal development (pubertal stages self-reported by parents and sex steroid levels) was analyzed by generalized linear regression after adjusting for age, body mass index z score, and premature birth and/or low birth weight. Both the highest quartile of HMWP (Q4 vs Q1, adjusted odds ratio [OR], 0.238; 95% confidence interval [CI], 0.090-0.627; p = 0.004) and LMWP (Q4 vs Q1, adjusted OR, 0.373; 95% CI, 0.151-0.918; p = 0.032) were inversely associated with pubertal stages in boys, whereas the highest quartile of LMWP (Q4 vs Q1, adjusted OR, 2.431; 95% CI, 1.024-5.768; p = 0.044) was significantly related to advanced pubertal stages in girls. Testosterone levels in boys were significantly lower at the highest quartile of HMWP (adjusted ß = - 0.251; 95% CI, - 0.476 to - 0.027; p = 0.028). However, in girls, we could not find any significant relationship between HMWP or LMWP and estradiol levels. CONCLUSIONS: Our results suggest that phthalate exposure, especially exposure to the HMWP, may have inverse association with male pubertal development. Further investigation is required to verify the relationship of phthalate exposure and pubertal development in girls. WHAT IS KNOWN: • Exposure to phthalates may have antiandrogenic effects. • Studies on the association between phthalates and pubertal development have yielded inconsistent results. WHAT IS NEW: • Phthalate levels were inversely associated with self-reported pubertal stages in boys. • Exposure to phthalates might have a negative influence on male pubertal development.

Sex differences in body composition affect total airway resistance during puberty.

BACKGROUND: During puberty, changes in body composition due to sex hormones are associated with lung mechanics. However, little is known about the mediation effect of sex differences in body composition during puberty with total airway resistance. METHODS: We prospectively recruited 620 children (10-12 years old) from the general population and conducted a cross-sectional study. This study assessed pubertal status according to the five Tanner stages using a questionnaire, line drawings, and each subject's blood sex hormone profile. Both the impulse oscillation system for total lung mechanics and multifrequency bioelectrical impedance for body composition analyses were conducted. The effects of puberty on body composition and subsequent total lung resistance were evaluated using mediation analysis. RESULTS: Among the 503 children enrolled, there were 261 males (51.9%) and 242 females (48.1%). In males, higher testosterone levels corresponded with reduced total lung resistance (ß = -0.13, 95% CI = -0.21 to -0.05, p < 0.001), and the proportion of the mediating effect through the muscle-fat ratio was 19% (95% CI = 4 to 59, p = 0.02). In contrast, in females, pubertal status reduced total lung resistance (ß = -0.27, 95% CI = -0.58 to -0.05, p = 0.04), however, the proportion of the mediating effect through the body mass index was -51% (95% CI = -244 to -4%, p = 0.04). CONCLUSION: The muscle-fat ratio in adolescent males had a synergistic effect with testosterone on improving total airway resistance, whereas improvements in lung resistance by pubertal status were partially masked by body mass index in adolescent females. In conclusion, body composition changes during puberty between males and females have differing effects on total airway resistance.

High Prevalence of Nonalcoholic Fatty Liver Disease Among Adolescents and Young Adults With Hypopituitarism due to Growth Hormone Deficiency.

OBJECTIVE: To investigate the prevalence of nonalcoholic fatty liver disease (NAFLD) in adolescents and young adults with hypopituitarism and to examine the associations of growth hormone (GH) deficiency with the occurrence of NAFLD. METHODS: A cross-sectional study for the determination of NAFLD prevalence included 76 patients with childhood-onset hypopituitarism and 74 controls matched by age and body mass index (BMI). We investigated the prevalence of NAFLD in adolescent and young adult patients with hypopituitarism as well as the age- and BMI-matched controls. Among patients with hypopituitarism, anthropometric, clinical, and biochemical assessments using transient elastography and magnetic resonance imaging were performed. Logistic regression was used to identify the factors associated with NAFLD. RESULTS: The adolescents and young adults with hypopituitarism exhibited higher prevalence of NAFLD than the age- and BMI-matched controls. Among patients with hypopituitarism, obesity and obesity-related metabolic derangements were significantly associated with liver steatosis and fibrosis, whereas lower insulin-like growth factor (IGF)-I standard deviation score (SDS) and IGF-I/IGF-binding protein 3 molar ratios were associated with steatosis. In regression analyses adjusted for BMI SDS, steatosis was found to be associated with a lower IGF-I SDS and IGF-I/IGF-binding protein 3 molar ratios, whereas liver fibrosis was found to be associated with a lower IGF-I SDS. CONCLUSION: Our results suggest that GH deficiency contributes to the occurrence of NAFLD, along with obesity and obesity-related metabolic changes. Because NAFLD occurs early in patients with hypopituitarism, the surveillance, weight control, and timely replacement of deficit hormones, including GH, are essential.

Incidence and Prevalence of Central Precocious Puberty in Korea: An Epidemiologic Study Based on a National Database.

OBJECTIVES: To investigate the prevalence and incidence of central precocious puberty in Korea using claims data provided by the Health Insurance Review and Assessment Service in Korea as the population-based epidemiologic study. STUDY DESIGN: In this national registry-based, longitudinal, epidemiologic study, patients who were registered with an International Classifications of Diseases, Tenth Revision diagnosis of central precocious puberty (E22.8 according to International Classifications of Diseases, Tenth Revision) and treated with gonadotropin-releasing hormone agonist were included. We assessed the age- and sex-specific prevalence and incidence rates of central precocious puberty in Korea from 2008 to 2014. RESULTS: A total of 37 890 girls and 1220 boys were newly registered with a diagnosis of central precocious puberty from 2008 to 2014. The overall incidence of central precocious puberty during the study period was 122.8 per 100 000 persons (girls, 262.8; boys, 7.0). The overall prevalence of central precocious puberty during the study period was 193.2 per 100 000 persons (girls, 410.6; boys, 10.9). The incidence and prevalence of central precocious puberty steeply increased during the study period in both girls and boys. CONCLUSIONS: This epidemiologic study, based on a national registry that included Korean children, demonstrated that the incidence and prevalence rates of central precocious puberty were high and increased steeply during the study period. Further investigations to determine the underlying causes for this rapid increase in central precocious puberty are needed.

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.

Erythromelalgia with a linear pattern in a 12-year-old girl.

Erythromelalgia is a rare clinical syndrome characterized by erythema, increased temperature, and severe burning pain that can be aggravated by warmth or relieved by cold. Erythromelalgia occurs either as a primary, idiopathic form, or secondary to a number of diseases and conditions. Although fairly well studied in adults, the characteristics, pathogenesis, and natural history are poorly characterized in the pediatric age group. Different therapeutic options have been tried, but no optimal treatment has been suggested for erythromelalgia. We report a rare case of linear erythromelalgia in a 12-year-old girl involving her central body from the peripheral extremities, which seemed to be secondary due to vasculitis. Clinical progress waxed and waned on maintenance aspirin and propranolol.

Familial male-limited precocious puberty due to an activating mutation of the LHCGR: a case report and literature review.

Familial male-limited precocious puberty (FMPP) is a rare form of gonadotropin-independent precocious puberty that is caused by an activating mutation of the LHCGR gene. Herein, we report a case of FMPP with a mutation of the LHCGR gene in a Korean boy with familial history of precocious puberty through 3 generations. A 16-month-old boy presented with signs of precocious puberty, including pubic hair, acne, and increased growth velocity. The patient's grandfather and father had a history of precocious puberty and profound short stature. On physical examination, the patient had prepubertal testes with pubic hair development appropriate for Tanner stage II. The stretched penile length was 7 cm (>2 standard deviation score), and observed bone age was that of a 4-year-old boy. Laboratory findings showed high serum testosterone (5.74 ng/mL [appropriate for Tanner IV-V]; normal range, <0.05 ng/mL) with suppressed luteinizing hormone (<0.07 mIU/mL) and normal serum level of follicular stimulating hormone (0.56 mIU/mL; normal range, 0.38-1.11 mIU/mL). Genetic testing revealed a pathogenic variant of LHCGR (c.1730 C>T (p.Thr577Ileu)), confirming FMPP. Bicalutamide and anastrozole were administered, and pubertal progression was sufficiently suppressed without any specific side effects. To our knowledge, this is the first case of genetically confirmed FMPP in Korea.

Dried blood spot-based free sterol signatures in sitosterolemia diagnostics.

BACKGROUND: Sitosterolemia is a rare inherited lipid metabolic disorder characterized by increased levels of plant sterols and accelerated atherosclerosis. Although early detection is beneficial for the prevention of disease progression, it is largely underdiagnosed by routine screening based on conventional lipid profiles. MATERIALS AND METHODS: A gas chromatography-mass spectrometry (GC-MS)-based profiling has been developed and validated to measure the levels of biologically active free sterols, including five endogenous sterols and three plant sterols (sitosterol, campesterol, and stigmasterol) in dried blood spot (DBS). RESULTS: Within- and between-run precisions were 1.4-11.1 % and 2.2-14.1 %, respectively, while the accuracies were all 86.3 ∼ 121.9 % with the correlation coefficients (r2) > 0.988 for all the sterols. In the patients (four girls and two boys, 6.5 ±â€¯2.8 years), sitosterol levels were significantly increased, with an optimal cut-off value of 2.5 µg/mL distinguishing them from ninety-three age-matched healthy children. A cut-off value of 31.9 was differentiated the patients from six ABCG5/ABCG8 heterozygous carriers. In addition, the molecular ratios of sitosterol to cholesterol, desmosterol, and 7-dehydrocholesterol provided excellent cut-off values of 26.3, 67.6, and 21.6, respectively, to distinguish patients from both healthy controls and heterozygous carriers. CONCLUSIONS: The novel DBS-based GC-MS profiling of free sterols accurately identified patients with sitosterolemia, with a performance comparable to that of a serum assay. The DBS profiling could be more feasible method in clinical practice as well as population screening programs, and it can provide diagnostic cut-off values for individual plant sterols.

Slower progression of central puberty in overweight girls presenting with precocious breast development.

PURPOSE: Overweight (OW)/obese girls tend to have an earlier pubertal onset than girls with normal weight. However, only a few studies have reported the progression of puberty in these girls. This study aimed to identify risk factors for rapid pubertal progression in OW/obese girls presenting with precocious breast development. METHODS: This retrospective cohort study reviewed the medical records of 110 OW (body mass index [BMI] ≥85th percentile for age and sex) and 213 nonoverweight (NW, BMI <85th percentile for age and sex) girls who presented with breast budding before 8 years of age. OW girls were divided into 2 subgroups: girls with central puberty progression before 9 years of age (OW-RP) and those without (OW-SP). RESULTS: Progression to central puberty before the age of 9 was more common in NW girls than in OW girls (83.8 % vs. 65.2 % in NW vs. OW group, p<0.001), and progression-free survival for 1, 2, and 3 years was higher in the OW group (p<0.001). In a subgroup analysis of OW girls, the OW-RP subgroup had more advanced bone age (BA) at the first visit (p=0.047) and higher initial luteinizing hormone (LH, p=0.010) levels than the OW-SP subgroup. Being NW (p=0.001) and having more advanced BA (p=0.023) at the initial workup were the risk factors for pubertal progression before age 9. CONCLUSION: Pubertal progression seems to be slower in OW girls than in NW girls presenting with precocious breast development. However, it can progress rapidly in OW girls with particularly pronounced BA advancement and high LH levels at the initial workup.

Assessment of Neurodevelopment and Growth in Congenital Hypothyroidism: Serial 6-Year Follow-up Study of 408 Patients.

CONTEXT: The link between congenital hypothyroidism (CH) and neurodevelopment is suggested, yet studies applying quantifiable measures are lacking. Moreover, socioeconomic disparities and subtle variation in timing of approach make the relationship difficult to detect. OBJECTIVE: To evaluate associations between CH and abnormalities in neurodevelopment and growth and determine the critical period for intervention. METHODS: We utilized a nationwide database to conduct a longitudinal analysis of 919 707 children. Exposure to CH was identified using claims-based data. The primary outcome of interest was suspected neurodevelopmental disorder, as measured using the Korean Ages & Stages Questionnaires (K-ASQ) administered annually from 9 to 72 months of age. Secondary outcomes were height and BMI z-scores. After randomly matching cases and controls at a 1:10 ratio, we employed inverse probability of treatment weighting and generalized estimating equation models for our analyses. We conducted subgroup analysis based on the age of treatment initiation. RESULTS: The prevalence of CH in our population was 0.05% (n = 408). Relative to the control group, the CH group had higher risk of suspected neurodevelopmental disorders (propensity score-weighted odds ratio: 4.52; 95% CI: 2.91, 7.02), and significantly increased risk in each of the 5 K-ASQ domains. No time interactions were noted at any rounds for the outcomes according to when the neurodevelopmental assessment was conducted (all P for interaction >.05). The CH group also had higher risk for low height-for-age z-score, but not for elevated BMI-for-age z-score. In subgroup analysis, delayed medication for CH correlated with worse neurodevelopmental outcomes. CONCLUSION: The CH group had worse neurodevelopmental outcomes and reduced height-for-age z-score. Outcomes were worse when onset of treatment was increasingly delayed.

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.

Growth hormone deficiency in a boy with Wiedemann-Steiner syndrome: A case report and review.

Wiedemann-Steiner syndrome (WSS) is a rare genetic disorder characterized by a broad phenotypic spectrum, including facial dysmorphism, hypertrichosis, hypotonia, short stature, and developmental delay. Mutations in the lysine (K)-specific methyltransferase 2A (KMT2A) gene are known to cause WSS. A 2 year-old boy with a short stature visited our pediatric endocrinology clinic for a diagnostic examination. In addition to his short stature, he had other symptoms characteristic of WSS including dysmorphic features and developmental delay. Whole-exome sequencing was performed in order to diagnose any underlying genetic condition; the test detected the presence of the mutant variant of KMT2A:c.731T>G(p.Leu244*). Since the patient showed a decreased growth velocity after 18 months of age, a growth hormone provocation test was performed to check for growth hormone (GH) deficiency. The patient's peak GH level was found to be 6.96 ng/mL and recombinant human GH treatment was started. This case of WSS along with growth hormone deficiency (GHD) in a pediatric patient is the first report of its kind in Korea, to the best of our knowledge. WSS should be considered as a possibility in pediatric patients with short stature, especially in the presence of additional clinical symptoms, such as dysmorphic features and developmental delay.

Machine learning-based prediction of response to growth hormone treatment in Turner syndrome: the LG Growth Study.

Background Growth hormone (GH) treatment has become a common practice in Turner syndrome (TS). However, there are only a few studies on the response to GH treatment in TS. The aim of this study is to predict the responsiveness to GH treatment and to suggest a prediction model of height outcome in TS. Methods The clinical parameters of 105 TS patients registered in the LG Growth Study (LGS) were retrospectively reviewed. The prognostic factors for the good responders were identified, and the prediction of height response was investigated by the random forest (RF) method, and also, multiple regression models were applied. Results In the RF method, the most important predictive variable for the increment of height standard deviation score (SDS) during the first year of GH treatment was chronologic age (CA) at start of GH treatment. The RF method also showed that the increment of height SDS during the first year was the most important predictor in the increment of height SDS after 3 years of treatment. In a prediction model by multiple regression, younger CA was the significant predictor of height SDS gain during the first year (32.4% of the variability). After 3 years of treatment, mid-parental height (MPH) and the increment of height SDS during the first year were identified as significant predictors (76.6% of the variability). Conclusions Both the machine learning approach and the multiple regression model revealed that younger CA at the start of GH treatment was the most important factor related to height response in patients with TS.

Hypertriglyceridemia in Obese Children and Adolescents.

The increasing prevalence of obesity in children and adolescents is a serious public health concern. Hypertriglyceridemia is common in obese children and adolescents, and elevated triglyceride (TG) level is a known biomarker of cardiometabolic risk. Results from genetic studies suggest that TG and TG-rich lipoproteins and, more specifically, remnant cholesterol are in the causal pathway of cardiovascular disease. However, simultaneous measurement of all remnants has not yet been established, and plasma TG level can be used as a useful marker of remnant cholesterol. Adipose tissue dysfunction, including impaired adipocyte TG storage and release of fatty acids, mediates the development of obesity-related complications. The prevalence of hypertriglyceridemia increases in overweight or obese children and is associated with other cardiometabolic risk factors. Recently, the TG/high-density lipoprotein cholesterol (HDL-C) ratio was recognized as a marker of structural vascular changes and insulin resistance in obese youth. Recent guidelines recommend universal lipid screening with nonfasting non-HDL-C measurement in children at 9-11 years of age; however, fasting lipid profiles should be measured in obese children and overweight adolescents and in those with high non-HDL-C in universal screening. The primary approach to lower TG in children includes dietary and lifestyle modifications; however, children with severe hypertriglyceridemia should also be referred to a pediatric lipid specialist.

The effect of neonatal hypothyroidism and low family income on intellectual disability: A population-based cohort study.

BACKGROUND: To investigate relationships among neonatal hypothyroidism, family income, and intellectual disability, as well as the combined effects of neonatal hypothyroidism and low family income on intellectual disability. METHODS: Data were extracted from the National Health Insurance Service-National Sample Cohort from 2002 to 2011. This retrospective study included 91,247 infants. The presence of intellectual disability was based on the disability evaluation system in Korea. Newborn hypothyroidism was identified from diagnosis and prescription codes. Family income was determined from average monthly insurance premiums. Cox proportional hazards models were used to calculate adjusted hazard ratios. RESULTS: Of the 91,247 infants, 208 were considered to have intellectual disability (29.18 cases per 100,000 person-year). The risk of intellectual disability was higher in infants with hypothyroidism than in those without hypothyroidism (hazard ratio = 5.28, P: < .0001). The risk of intellectual disability was higher in infants with low family income than in those with high family income (hazard ratio = 2.32, P: < .0001). The risk of intellectual disability was higher in infants with hypothyroidism and low family income than in those without hypothyroidism and with high family income (hazard ratio = 36.05, P: < .0001). CONCLUSIONS: Neonatal hypothyroidism and low family income were associated with the risk of intellectual disability in Korea. Additionally, neonatal hypothyroidism and low family income significantly increased the risk of intellectual disability. Public health policymakers should consider providing additional resources for alleviating neonatal hypothyroidism among low-income families.

Clinical manifestations of Rathke's cleft cysts and their natural progression during 2 years in children and adolescents.

PURPOSE: Rathke's cleft cyst (RCC) is an asymptomatic benign lesion. With increased interest in pediatric endocrinology, the prevalence of RCCs in children is also increasing. However, the clinical relevance and proper management of RCC is not well defined in children. Therefore, we investigated the clinical manifestations and radiologic features of RCC in children and adolescents, as well as the natural progression of RCC. METHODS: We retrospectively reviewed the medical records of 91 children and adolescents with RCC diagnosed with magnetic resonance imaging (MRI) in Severance Children's Hospital from January 2006 to December 2015. The clinical, hormonal, and imaging findings were analyzed in patient groups classified according to age. The size of each cyst was assessed in sixty patients who underwent follow-up MRI during the 2 years. RESULTS: Female patients were predominant (64 vs. 27). The common clinical features at presentation were endocrine dysfunction (59.3%), headache (23.0%), and dizziness (4.4%). Symptoms related to endocrine disorders were more frequent in younger patients. In 7 patients managed surgically, the cysts were significantly larger and more frequently located in the suprasellar region. Of 60 nonsurgical patients with a follow-up MRI performed within 2 years after the diagnosis, the RCC size increased in about 26.7% (n=16). CONCLUSIONS: Although 94.4% of the patients with RCC had clinical symptoms, surgery was performed in only about 7.5% of patients. RCC is associated with pituitary insufficiency, thus, baseline and follow-up endocrine function tests are required. Additionally, regular MRI follow-up is required in long-term period to monitor change in size.

Insulin resistance and bone age advancement in girls with central precocious puberty.

PURPOSE: Precocious puberty has significantly increased recently. While obesity is associated with puberty timing, the relationship between obesity and central precocious puberty (CPP) remains controversial. The purpose of this study was to determine whether insulin resistance is associated with bone age (BA) advancement in girls with CPP. METHODS: We retrospectively analyzed the records of 804 girls referred for puberty evaluation. Anthropometric measurements, BA, sex hormone, sex hormone binding globulin (SHBG), and insulin levels, lipid profiles, and gonadotropin releasing hormone stimulation tests were assessed. Insulin resistance parameters were calculated using the homeostasis model assessment-insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) models. RESULTS: BA, BA advancement, free estradiol index, insulin, and HOMA-IR increased significantly in girls with high body mass index (BMI) compared with that of girls with low BMI in cases of CPP. HOMA-IR was positively correlated with BA advancement and BMI but negatively correlated with SHBG. QUICKI was negatively correlated with BA advancement and BMI and positively correlated with SHBG. When HOMA-IR increased by 1, the odds for BA advancement increased 120% after adjusting for age and BMI (P=0.033). CONCLUSIONS: Insulin resistance could be associated with BA advancement in girls with CPP.

A 1-month-old infant with chylomicronemia due to GPIHBP1 gene mutation treated by plasmapheresis.

Chylomicronemia is a severe type of hypertriglyceridemia characterized by chylomicron accumulation that arises from a genetic defect in intravascular lipolysis. It requires urgent and proper management, because serious cases can be accompanied by pancreatic necrosis or persistent multiple organ failure. We present the case of a 1-month-old infant with chylomicronemia treated by plasmapheresis. His chylomicronemia was discovered incidentally when lactescent plasma was noticed during routine blood sampling during a hospital admission for fever and irritability. Laboratory investigation revealed marked triglyceridemia (>5,000 mg/dL) with high chylomicron levels. We therefore decided to perform a therapeutic plasmapheresis to prevent acute pancreatitis. Sequence analysis revealed a homozygous novel mutation in exon 4 of GPIHBP1: c.476delG (p.Gly159Alafs). Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) stabilizes the binding of chylomicrons near lipoprotein lipase and supports lipolysis. Mutations of GPIHBP1, the most recently discovered gene, can lead to severe hyperlipidemia and are known to make up only 2% of the monogenic mutations associated with chylomicronemia. The patient maintains mild hypertriglyceridemia without rebound after single plasmapheresis and maintenance fibrate medication so far. Here, we report an infant with chylomicronemia due to GPIHBP1 mutation, successfully treated by plasmapheresis.

Diabetes mellitus due to agenesis of the dorsal pancreas in a patient with heterotaxy syndrome.

Heterotaxy syndrome (HS) is a congenital disorder resulting from an abnormal arrangement of visceral organs across the normal left-right axis in the embryonic period. HS is usually associated with multiple anomalies, including defects of the major cardiovascular system and the extracardiovascular system such as intestinal malrotation, abnormal lung lobulation, bronchus anomalies, and pancreatic dysplasia. Although pancreatic dysplasia is occasionally accompanied with HS, the occurrence of diabetes mellitus (DM) due to pancreatic dysplasia in HS is rarely reported. We here report a case involving 13-year-old girl with DM caused by agenesis of the dorsal pancreas and HS diagnosed on the basis of the presence of a double-outlet right ventricle with bilateral pulmonary stenosis and intestinal malrotation with duodenal cyst. Timely diagnosis and treatment with insulin improved glycemic control.