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.

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.

2022 Clinical practice guidelines for central precocious puberty of Korean children and adolescents.

The Committee of Central Precocious Puberty of Korean Pediatrics and Adolescents of the Korean Society of Pediatric Endocrinology has newly developed evidence-based 2022 clinical practice guidelines for central precocious puberty in Korean children and adolescents. These guidelines provide the grade of recommendations, which includes both the strength of recommendations and the level of evidence. In the absence of sufficient evidence, recommendations are based on expert opinion. These guidelines have been revised and supplement the previous guidelines "Clinical Guidelines for Precocious Puberty 2011," and are drawn from a comprehensive review of the latest domestic and international research and the grade of recommendation appropriate to the domestic situation. This review summarizes the newly revised guidelines into 8 key questions and 27 recommendations and consists of 4 sections: screening, diagnosis, treatment, and long-term outcome of central precocious puberty.

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.

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.

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.

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.

Hypertriglyceridemia with acute pancreatitis in a 14-year-old girl with diabetic ketoacidosis.

Diabetic ketoacidosis (DKA) is a medically fatal condition in poorly controlled hyperglycemia or newly diagnosed diabetes mellitus. Severe hypertriglyceridemia (HTG) is an uncommon complication of DKA and can be associated with acute pancreatitis (AP). We present the clinical manifestations, laboratory findings, and management of AP associated with HTG in a 14-year-old girl with DKA. The patient, with a 7-year history of type 2 diabetes presented with epigastric pain, 1 month after stopping insulin injection. DKA, severe HTG, and AP were diagnosed based on the laboratory and imaging tests. She recovered from DKA after conventional treatment for DKA, and her triglyceride (TG) level was reduced from 10,867 mg/dL to the normal range after 7 days of admission without antilipid medication. Given that her C-peptide level was not too low and considering her negative diabetes-related antibodies and high TG level, targeted gene panel sequencing was performed on the genes associated with diabetes and HTG. We identified a heterozygous mutation, c.4607C>T (p. Ala1537Val), in ABCC8 related to maturityonset diabetes of the young (MODY) 12. To our knowledge, this is the first reported case of HTG-induced AP with DKA in a patient with MODY. In addition, we reviewed the literature for pediatric cases of HTG with DKA. In patients with DKA, timely awareness of severe HTG related to insulin deficiency is crucial for improving the consequences of AP. We recommend considering AP in all DKA patients presenting with severe HTG to ensure early and proper management.

Statin Use and COVID-19 Infectivity and Severity in South Korea: Two Population-Based Nationwide Cohort Studies.

BACKGROUND: Basic studies suggest that statins as add-on therapy may benefit patients with COVID-19; however, real-world evidence of such a beneficial association is lacking. OBJECTIVE: We investigated differences in SARS-CoV-2 test positivity and clinical outcomes of COVID-19 (composite endpoint: admission to intensive care unit, invasive ventilation, or death) between statin users and nonusers. METHODS: Two independent population-based cohorts were analyzed, and we investigated the differences in SARS-CoV-2 test positivity and severe clinical outcomes of COVID-19, such as admission to the intensive care unit, invasive ventilation, or death, between statin users and nonusers. One group comprised an unmatched cohort of 214,207 patients who underwent SARS-CoV-2 testing from the Global Research Collaboration Project (GRCP)-COVID cohort, and the other group comprised an unmatched cohort of 74,866 patients who underwent SARS-CoV-2 testing from the National Health Insurance Service (NHIS)-COVID cohort. RESULTS: The GRCP-COVID cohort with propensity score matching had 29,701 statin users and 29,701 matched nonusers. The SARS-CoV-2 test positivity rate was not associated with statin use (statin users, 2.82% [837/29,701]; nonusers, 2.65% [787/29,701]; adjusted relative risk [aRR] 0.97; 95% CI 0.88-1.07). Among patients with confirmed COVID-19 in the GRCP-COVID cohort, 804 were statin users and 1573 were matched nonusers. Statin users were associated with a decreased likelihood of severe clinical outcomes (statin users, 3.98% [32/804]; nonusers, 5.40% [85/1573]; aRR 0.62; 95% CI 0.41-0.91) and length of hospital stay (statin users, 23.8 days; nonusers, 26.3 days; adjusted mean difference -2.87; 95% CI -5.68 to -0.93) than nonusers. The results of the NHIS-COVID cohort were similar to the primary results of the GRCP-COVID cohort. CONCLUSIONS: Our findings indicate that prior statin use is related to a decreased risk of worsening clinical outcomes of COVID-19 and length of hospital stay but not to that of SARS-CoV-2 infection.

Assessment of vitamin D, exercise, and lipid profile associated with excessive daytime sleepiness in school children.

Previous research reported associations of excessive daytime sleepiness (EDS) with a low vitamin D level, obesity, and sexual maturity. The aim of this study was to identify the association and rank the importance of these with EDS. This study examined 618 children who were 10-12 year-old. The pediatric daytime sleepiness scale (PDSS) was used to evaluate EDS and sleep patterns. EDS was defined as a total PDSS score above 17. We ranked the importance of the relationship of these factors with EDS using random forest analysis. EDS (n = 111, 18%) was positively associated with more advanced pubertal stage in girls, chronic cough, urticaria, and allergic rhinitis. Multivariable analysis with adjustment for confounding indicated that children with low level of 25-hydroxyvitaminD3 (25(OH)D3 (<20 ng/mL) and high-density lipoprotein-cholesterol (HDL-C) (<40 mg/dL) levels had an increased risk of EDS (25(OH)D3:adjusted odds ratio [aOR] = 1.73; 95% confidence interval [CI]: 1.06 to 2.81; P = 0.028; HDL-C: aOR = 2.84; 95% CI: 1.05 to 7.68; P = 0.039). Random forest analysis indicated that 25(OH)D3 level, exercise, and body mass index (BMI) were over three. This study indicated high levels of 25-(OH)D3 and HDL-C and performing regular exercise decreased the risk of EDS.

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.

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.

Response to vitamin D replacement in overweight and normal weight children with vitamin D deficiency.

PURPOSE: It is well known that obesity is related to vitamin D deficiency (VDD). We investigated the response to vitamin D replacement in normal-weight and overweight children. METHODS: This was a prospective study including 62 Korean children with VDD. VDD was defined as a serum 25-hydroxycholecalciferol (25(OH)D) concentration <20 ng/mL. Overweight was defined as a body mass index (BMI)≥the 85th percentile (n=21), and normal weight as a BMI between the 5th and 84th percentiles (n=41). All participants received vitamin D3 supplementation (2,000 IU/day) for 8 weeks. The serum levels of 25(OH)D, PTH and biochemical parameters were measured before and after treatment. RESULTS: The mean age was 10.0±1.4 years in normal-weight children and 10.0±2.1 years in overweight children (P=0.93). After 8 weeks of treatment, 61.9% of normal-weight children and 47.6% of overweight children achieved vitamin D sufficiency (P =0.30). The mean serum 25(OH)D levels after vitamin D replacement were 33.8±7.6 ng/mL and 30.3±6.6 ng/mL in normal-weight and overweight children, respectively (P =0.10). The mean calcium/creatinine ratios after treatment were 0.09±0.07 and 0.08±0.06 in the normal-weight and overweight groups, respectively, and no hypercalciuria was found. In multiple regression analysis, the response to vitamin D replacement was influenced by the BMI (ß=-1.0, P=0.03) and sex (ß=-4.0, P=0.04). CONCLUSION: Eight weeks of vitamin D replacement (2,000 IU/day) is sufficient to overcome vitamin D deficiency in normal-weight and overweight children without any complications.

Variable Clinical Characteristics and Molecular Spectrum of Patients with Syndromes of Reduced Sensitivity to Thyroid Hormone: Genetic Defects in the THRB and SLC16A2 Genes.

BACKGROUND/AIMS: Syndromes of reduced sensitivity to thyroid hormone can be caused by innate resistance to thyroid hormone (RTH), thyroid hormone cell transporter defects, or thyroid hormone metabolism defects. This study was performed to describe clinical, endocrinological, and molecular characteristics of patients with disorders associated with impaired sensitivity to thyroid hormone due to THRB or SLC16A2 mutations. METHODS: This study included 5 probands (1 male and 4 females) with RTH and 6 patients with Allan-Herndon-Dudley syndrome (AHDS). Clinical features and endocrine findings were reviewed retrospectively. Molecular analysis of two candidate genes, THRB or SLC16A2, confirmed the diagnosis. RESULTS: Among RTH patients, median age at diagnosis was 5.6 years. Three patients were classified as having generalized RTH, whereas the other 2 patients were regarded as having isolated pituitary RTH. Three novel heterozygous mutations and 2 known mutations in THRB were identified from 5 independent pedigrees. All mutations were located in the major ligand-binding domain. In AHDS patients, delayed development was apparent between 3 and 6 months of age. Direct sequencing of SLC16A2 identified 6 hemizygous missense mutations in each patient: p.I188N, p.G221R, p.A224V, p.G276R, p.W398R, and p.G401R. CONCLUSIONS: This study identified 3 novel mutations in THRB in RTH patients and 1 novel mutation in SLC16A2 in AHDS patients. Routine neonatal screening based on the TSH assay has a limited role in detecting RTH or AHDS. Therefore, genetic testing of the candidate genes THRB and SLC16A2 should be performed for diagnosis of RTH and AHDS in patients with the suggestive clinical phenotype.

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 triglyceride-to-high density lipoprotein cholesterol ratio in overweight Korean children and adolescents.

PURPOSE: The triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-C) ratio has recently been reported as a biomarker of cardiometabolic risk in obese children and adolescents. The purpose of this study is to describe the TG/HDL-C ratio and related factors in overweight and normal weight Korean children and to evaluate whether the high TG/HDL-C ratio is associated with insulin resistance in overweight children and adolescents. METHODS: Data from 255 overweight (aged 8.7±2.0 years) and 514 normal weight (aged 8.9±1.8 years) children and adolescents were evaluated. Glucose, insulin, total cholesterol (TC), HDL-C and TG levels were measured after overnight fasting, and the TG/HDL-C ratio, non-HDL-C and the homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. RESULTS: The TG/HDL-C ratio was higher in overweight group compared to normal weight group (P<0.001). Among overweight children and adolescents, alanine aminotransferase (P=0.018), non-HDL-C (P<0.001), and HOMA-IR (P=0.004) were different between the TG/HDL-C ratio tertile groups. The prevalence of elevated HOMA-IR was increased with increasing TG/HDL-C ratio tertiles (P for trend=0.003). On regression analysis adjusted for age and sex, the BMI (ß=0.402, P=0.001) and TG/HDL-C ratio (ß=0.251, P=0.014) were independently associated with HOMA-IR (adjusted R2=0.324). The TG/HDL-C ratio of 2.0 or more showed higher sensitivity (55.6%) and specificity (72.9%), when compared to TC (≥200 mg/dL), non-HDL-C (≥145 mg/dL), and LDL-C (≥130 mg/dL) for identifying overweight children with elevated HOMA-IR. CONCLUSIONS: The TG/HDL-C ratio is independently associated with insulin resistance in overweight children and adolescents, and it can be useful in identifying those at higher cardiometabolic risk.

Diurnal variation of gonadotropin levels in girls with early stages of puberty.

PURPOSE: Pubertal gonadotropin secretion shows circadian pattern and the luteinizing hormone (LH) levels tend to rise in later stages of puberty in girls. We studied the usefulness of basal LH in the evaluation of central precocious puberty with emphasis on the influence of sampling time. METHODS: Medical records of 334 girls that underwent gonadotropin-releasing hormone stimulation test (GnRHST) were reviewed. Auxological and laboratory data were compared between those with early morning (EM, before 10 AM) and late morning/afternoon (LM/A, after 10 AM) basal samples. RESULTS: Among those in sexual maturity rating (SMR) 2, EM samples showed higher basal LH (P=0.004) compare to LM/A samples, whereas those in SMR 3 showed no difference in LH levels between EM and LM/A samples. Among girls with pubertal response, EM group showed higher basal LH (P=0.031) and follicular stimulating hormone (P=0.008) than LM/A group. The EM basal LH was more closely related with the peak stimulated LH than the LM/A basal LH did (rs=0.871 vs. rs=0.524). The optimal basal LH cutoffs to predict a pubertal response to GnRHST were 0.11 IU/L with a sensitivity of 66.7% and a specificity of 78.7% in EM group, and 0.07 IU/L with a sensitivity of 60.0% and a specificity of 78.9% in LM/A group, respectively. CONCLUSIONS: In girls with early stages of puberty, EM basal LH is a more sensitive screening tool than the LM/A basal LH. Diurnal variation should be considered in evaluating children with precocious puberty.

Delayed diagnosis of 22q11 deletion syndrome due to late onset hypocalcemia in a 11-year-old girl with imperforated anus.

Neonatal hypocalcemia and congenital heart defects has been known as the first clinical manifestation of the chromosome 22q11.2 deletion syndrome (22q11DS). However, because of its wide clinical spectrum, diagnosis of 22q11DS can be delayed in children without classic symptoms. We report the case of a girl with the history of imperforate anus but without neonatal hypocalcemia or major cardiac anomaly, who was diagnosed for 22q11DS at the age of 11 after the onset of overt hypocalcemia. She was born uneventfully from phenotypically normal Korean parents. Imperforate anus and partial cleft palate were found at birth, which were surgically repaired thereafter. There was no history of neonatal hypocalcemia, and karyotyping by GTG banding was normal. At the age of 11, hypocalcemia (serum calcium, 5.0 mg/dL) and decreased parathyroid hormone level (10.8 pg/mL) was noted when she visited our Emergency Department for fever and vomiting. The 22q11DS was suspected because of her mild mental retardation and velopharyngeal insufficiency, and a microdeletion on chromosome 22q11.2 was confirmed by fluorescence in situ hybridization. The 22q11DS should be considered in the differential diagnosis of hypocalcemia at any age because of its wide clinical spectrum.

Waist-to-height ratio as a screening tool for obesity and cardiometabolic risk.

The waist-to-height ratio (WHtR), calculated by dividing the waist circumference (WC) by height, has recently gained attention as an anthropometric index for central adiposity. It is an easy-to-use and less age-dependent index to identify individuals with increased cardiometabolic risk. A WHtR cutoff of 0.5 can be used in different sex and ethnic groups and is generally accepted as a universal cutoff for central obesity in children (aged ≥6 years) and adults. However, the WHtR has not been validated in preschool children, and the routine use of WHtR in children under age 6 is not recommended. Prospective studies and meta-analysis in adults revealed that the WHtR is equivalent to or slightly better than WC and superior to body mass index (BMI) in predicting higher cardiometabolic risk. In children and adolescents, studies have shown that the WHtR is similar to both BMI and WC in identifying those at an increased cardiometabolic risk. Additional use of WHtR with BMI or WC may be helpful because WHtR considers both height and central obesity. WHtR may be preferred because of its simplicity and because it does not require sex- and age-dependent cutoffs; additionally, the simple message 'keep your WC to less than half your height' may be particularly useful. This review article summarizes recent publications on the usefulness of using WHtR especially when compared to BMI and WC as a screening tool for obesity and related cardiometabolic risks, and recommends the use of WHtR in clinical practice for obesity screening in children and adolescents.

Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management.

Sitosterolemia is an autosomal recessive disorder characterized by increased plant sterol levels, xanthomas, and accelerated atherosclerosis. Although it was originally reported in patients with normolipemic xanthomas, severe hypercholesterolemia have been reported in patients with sitosterolemia, especially in children. Sitosterolemia is caused by increased intestinal absorption and decreased biliary excretion of sterols resulting from biallelic mutations in either ABCG5 or ABCG8, which encode the sterol efflux transporter ABCG5 and ABCG8. Patients with sitosterolemia show extreme phenotypic heterogeneity, ranging from almost asymptomatic individuals to those with severe hypercholesterolemia leading to accelerated atherosclerosis and premature cardiac death. Hematologic manifestations include hemolytic anemia with stomatocytosis, macrothrombocytopenia, splenomegaly, and abnormal bleeding. The mainstay of therapy includes dietary restriction of both cholesterol and plant sterols and the sterol absorption inhibitor, ezetimibe. Foods rich in plant sterols include vegetable oils, wheat germs, nuts, seeds, avocado, shortening, margarine and chocolate. Hypercholesterolemia in patients with sitosterolemia is dramatically responsive to low cholesterol diet and bile acid sequestrants. Plant sterol assay should be performed in patients with normocholesterolemic xanthomas, hypercholesterolemia with unexpectedly good response to dietary modifications or to cholesterol absorption inhibitors, or hypercholesterolemia with poor response to statins, or those with unexplained hemolytic anemia and macrothrombocytopenia. Because prognosis can be improved by proper management, it is important to find these patients out and diagnose correctly. This review article aimed to summarize recent publications on sitosterolemia, and to suggest clinical indications for plant sterol assay.