Volume 29, Issue 11

Background: Reports on the secular trend of pubertal onset indicate a recent earlier start especially in girls. Bisphenol A (BPA), which posses estrogenic activity, might be a cause of advanced puberty. The objective of the study was to determine the association between BPA and advanced puberty. Methods: A cross-sectional study was conducted in patients with advanced puberty (n=41) compared to age-matched controls (n=47). Anthropometric measurements, estradiol, basal and gonadotropin releasing hormone (GnRH)-stimulated follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels, uterine sizes, ovarian diameters and bone ages were obtained. Urinary BPA concentrations were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MSMS) with the lower limit of quantification (LLOQ) of 0.05 ng/mL. Results: The median adjust-BPA concentration in advanced puberty group was higher than in control groups [1.44 vs. 0.59 μg/g creatinine (Cr): p<0.05]. We also found that the median adjust-BPA concentration in girls with advanced puberty who were overweight/obese, was greater than in the normal pubertal overweight/obese girls (1.74 vs. 0.59 μg/g Cr: p<0.05), and was in the same trend among normal weight girls with advanced and normal puberty (0.83 vs. 0.49 μg/g Cr: p=0.09), but not statistically significant. Conclusions: The present findings suggest that BPA exposure appears to be related to an earlier age at onset of puberty especially in obese girls.

Background: Triptorelin is an established treatment for central precocious puberty (CPP) as 1- and 3-month formulations. The current triptorelin 22.5 mg 6-month formulation is approved for prostate cancer therapy. This is the first study in patients with CPP. Methods: The efficacy and safety of the triptorelin 6-month formulation in CPP were investigated. The primary objective was to evaluate the efficacy in achieving luteinizing hormone (LH) suppression to pre-pubertal levels at month 6. This was an international, non-comparative phase III study over 48 weeks. Eighteen medical centers in the US, Chile and Mexico participated. Forty-four treatment naïve patients (39 girls and five boys) aged at treatment start 2–8 years for girls and 2–9 years for boys with an advancement of bone age over chronological age ≥1 year were to be included. Triptorelin was administered im twice at an interval of 24 weeks. LH, follicle stimulating hormone (FSH) (basal and stimulated), estradiol (girls), testosterone (boys), auxological parameters, clinical signs of puberty and safety were assessed. Results: Forty-one patients (93.2%) showed pre-pubertal LH levels (stimulated LH ≤5 IU/L) at month 6 and maintained LH suppression through month 12. The percentage of patients with LH suppression exceeded 93% at each time point and reached 97.7% at month 12. No unexpected drug-related adverse events were reported. Conclusions: The triptorelin 6-month formulation was safe and effective in suppressing the pituitary-gonadal axis in children with CPP. The extended injection interval may improve compliance and increase comfort in the management of CPP.

Background: Peak gonadotropin-releasing hormone or agonist (GnRHa) stimulated luteinizing hormone (LH) testing with leuprolide acetate (LA) is commonly used to document suppression during therapy for central precocious puberty (CPP). The objective of the study was to investigate suitability of using basal LH levels to monitor GnRHa treatment and to determine optimal transition from 1-month to 3-month LA formulations via a post hoc analysis of a randomized, open-label, 6-month study. Methods: A total of 42 children with CPP, pretreated with 7.5-, 11.25-, or 15-mg 1-month LA formulations were randomized to 11.25- or 30-mg 3-month LA. Basal LH/peak-stimulated LH levels were measured at weeks 0, 4, 8 and 12. Positive/negative predictive values and sensitivities/specificities were determined for basal LH vs. LH-stimulation results. Results: Pretreatment with any 1-month formulation for the most part did not affect continuation of suppression after transitioning to 3-month formulation (mean peak-stimulated LH levels remained < 4 IU/L). Basal LH predicted suppression escape (basal LH-level cutoff ≥ 0.6 IU/L predicted 70% of those failing suppression). Tolerability was similar, regardless of dose. Conclusions: Our data indicate that a basal level of <0.60 IU/L is adequate for monitoring suppression approximately two-thirds of the time. Furthermore, the effectiveness and safety of 3-month LA treatments are not influenced by previous CPP therapies.

Background: Studies have suggested the triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) as a surrogate marker of insulin resistance. However, few studies have examined the association between TG/HDL-C and insulin resistance in the general adolescent population. This study aimed to examine the association between TG/HDL-C and insulin resistance in a nationally representative sample of Korean adolescents. Methods: A total of 2649 participants aged 12–18 years were selected from the 2007 to 2010 Korean National Health and Nutrition Examination Survey (KNHANES). Insulin resistance was defined as the homeostatic model assessment of insulin resistance (HOMA-IR) values greater than the 80th percentile. Results: The mean values of most cardiometabolic variables increased proportionally with TG/HDL-C quartiles. Compared to individuals in the lowest TG/HDL-C quartile, the odds ratio for insulin resistance for individuals in the highest quartile was 2.91 in boys and 2.38 in girls after adjusting for confounding variables. Conclusions: This study suggests that TG/HDL-C could be a convenient marker for identifying Korean adolescents with insulin resistance.

Background: Childhood obesity is associated with abnormal glucose metabolism and type 2 diabetes mellitus (T2DM). This study evaluated the prevalence of abnormal glucose metabolism in asymptomatic obese children and adolescents, and determined the percentage of T2DM development after 3–6 years of follow-up. Methods: During 2007–2013, 177 obese children and adolescents who had normal fasting plasma glucose (FPG<100 mg/dL) were given an oral glucose tolerance test (OGTT). The participants were classified into four groups: normal glucose tolerance (NGT), NGT-hyperinsulinemia (NGT-HI), impaired glucose tolerance (IGT), and diabetes mellitus (DM). Blood chemistries, including FPG, glycated hemoglobin, and lipid profiles, and liver function test were performed every 6–12 months or when the patient developed any symptom or sign indicative of diabetes. Results: Glucose metabolism alterations were detected in 81.4% of the participants: 63.8% with NGT-HI, 15.3% with IGT, and 2.3% with T2DM. The median levels of homeostasis model assessment-insulin resistance (HOMA-IR) in patients with IGT (8.63) were significantly greater than those in the patients with NGT (4.04) (p<0.01). During the follow-up, 22 patients (14.4%) developed T2DM significantly more from the IGT group (nine of 33 cases, 27.3%) than the NGT-HI group (12 of 108 cases, 11.1%) (p=0.022). The predicting parameters for T2DM conversion were weight status, body mass index (BMI), FBG, fasting insulin, alanine transaminase (ALT) levels, and HOMA-IR. Conclusions: Glucose metabolism alteration was commonly found among obese adolescents. Factors associated with T2DM development were greater weight status and the severity of insulin resistance as shown by higher HOMA-IR levels.

Background: Metabolic syndrome (MetS) is a chronic and multifactorial syndrome characterized by a low-grade chronic inflammation, and a major risk factor for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). In our study, we aimed to investigate the serum levels of high sensitive C-reactive protein (hs-CRP), haptoglobin (Hp), α 2 -macroglobulin (α 2 -MG), platelet factor-4 (PF-4), fetuin-A, serum amyloid P (SAP) and α 1 -acid glycoprotein (AGP) in an adolescent population with MetS. Methods: This study was performed in 43 (18 males, 25 females) MetS adolescents between the ages of 13 and 17 years (14.70±1.15) and 43 lean controls were matched for age and sex. The serum levels of Hp, α 2 -MG, PF-4, fetuin-A, SAP and AGP were measured by using a multi-ELISA technique. Results: Serum Hp, fetuin-A (p<0.01) and PF-4, hs-CRP, SAP, AGP (p<0.001) values of the MetS subjects were significantly higher than those of the controls. No difference was found in serum α 2 -MG levels between the MetS and control groups (p=0.184). Conclusions: This finding suggests the possibility of using these markers in diagnosis of MetS in adolescents to prevent future complications.

Background: Current pediatric guidelines for heterozygous familial hypercholesterolemia (HeFH) propose pharmacotherapy (PT) with statins from age 8 to 10 years; however, schemes with absorption inhibitors combined with statins, could be started earlier. The aim of the study was to show the 10-year results of a combined treatment protocol. Methods: Prospective, descriptive and analytical study. Pediatric patients (n=70; mean age at PT initiation 9.3 years [range, 2–17.5]) with HeFH who required PT between 2005 and 2015 were included. All patients ≥10 years, with LDL >190 mg/dL or >160 mg/dL with one cardiovascular risk factor (CVRF) or >130 mg/dL with two or more CVRF; and those patients 5–10 years and with LDL-C >240 mg/dL or a family history of a cardiovascular event before 40 years, were medicated. After a period on a lipid-lowering diet (LLD), all patients were started on ezetimibe. Patients who did not achieve the treatment goal were given statins. The variables were: age, age at PT initiation, duration of PT, initial LDL-C, mean LDL-C during ezetimibe monodrug therapy, mean LDL-C during combined PT, and percentage of LDL decrease. Results: LDL-C levels were: Baseline: 235 mg/dL±55; after 3 months on ezetimibe: 167 mg/dL±47 (decrease: −27.62%). In 18 patients who did not reach the treatment goal atorvastatin was added and their LDL-C decreased −41.5% (p: 0.02). Overall, mean final LDL-C was 155 mg/dL±30.4 (range, 98–257) and treatment goals were reached in 74% of the patients. No severe side effects were reported. Conclusions: Combined and sequential treatment starting at early ages was shown to be safe and effective over this follow-up period.

Background: The aim of this study was to analyze the prevalence of attention deficit hyperactivity disorder (ADHD) in children and adolescents with type 1 diabetes mellitus (T1DM) in Germany. Methods: Two different representative German databases – IMS®-Disease Analyzer, a database that includes diagnoses as well as other information, and IMS®-LRx, a database that documents prescriptions – were used to conduct a retrospective analysis. We searched the LRx database for patients who received both insulin and ADHD-specific medication. Results: In 2014, 677,587 children and adolescents aged 0–18 years were treated by a pediatrician and documented in the Disease Analyzer database. Of these patients, 16,833 received the International Statistical Classification of Diseases and Related Health Problems (ICD-10) diagnosis of ADHD (2.5%) and 3668 patients were treated for T1DM (0.1%). Of these 3668 patients, a total of 153 children were also diagnosed with ADHD (4.2%; p<0.05). In the LRx database, the overall prevalence of children in Germany who received both drugs for the treatment of ADHD and insulin in 2014 amounted to 2.9%. Diagnosis of ADHD is 2.4–3.3 times more frequent in boys than in girls. The highest prevalence was seen in the age group of 12–15 years (3.5%) and the lowest in the age group of 6–11 years (2.5%). Conclusions: Children with diabetes suffer from ADHD significantly more frequently than children without diabetes. The prevalence of medically treated children with ADHD and diabetes is similar to that documented in a recent report by the Barmer GEK health insurance body. However, it is possible that children with T1DM are much more frequently seen by medical care providers and are thus more likely to be evaluated and receive an appropriate diagnosis.

Background: Data on stature in Iranian children and adolescents at national level are limited. The purpose of this study was to investigate the association of short stature with life satisfaction (LS) and self-rated health (SRH) in children and adolescents. Methods: Data were obtained from a nationwide survey entitled childhood and adolescence surveillance and prevent i on of adult non-communicable disease (CASPIAN IV). Participants were 14,880 children and adolescents, aged 6–18 years, who were selected using multistage, cluster sampling method from rural and urban areas of 30 provinces of Iran. LS and SRH were evaluated for every participant by the validated questionnaire prepared based on the global school-based student health survey of the World Health Organization (WHO). Height was measured according to the standard protocol. Short stature was defined as height less than −2 standard deviation (SD) below the mean height for age and sex. Results: Overall, 13,484 participants with a mean (SD) age of 12.5 (3.36) years (49.24% girls, 50.75% boys) completed the study (response rate 90.6%). The prevalence of short stature, poor SRH and life dissatisfaction was 9%, 20.04% and 20.09%, respectively. Although in the univariate model, participants with short stature had significantly lower odds of LS [odds ratio (OR): 0.83, 95% confidence interval (CI): 0.71–0.97] and good SRH (OR: 0.79, 95% CI: 0.68–0.92), in the multivariate model, only the association of short stature with good SRH remained statistically significant (OR: 0.82, 95% CI: 0.69–0.98). Conclusions: Results of the present study show that participants with short stature are at the greater risk of poor SRH and decreased LS in comparison with the subjects with normal height.

The 22q13 deletion syndrome or Phelan-McDermid syndrome is a neurodevelopmental disorder associated with developmental delay, hypotonia, delayed or absent speech, autistic-like behavior, normal to accelerated growth and dysmorphic faces. We report the occurrence of central precocious puberty in a boy diagnosed with Phelan-McDermid syndrome. At the age of 1 year, our patient presented with increased testicular volume for his age, bone age advancement and growth acceleration. Stimulated gonadotropin levels demonstrated a premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. Central precocious puberty was treated with gonadotropin-releasing hormone (GnRH) analog. Molecular diagnosis with array-comparative genomic hybridization (CGH) revealed a major deletion of 5.8 Mb at the 22q13 chromosomal region and a 25 kb duplication at the 9q34.3 region that included the NOTCH-1 gene. On the background of 22q13 deletion syndrome and data from animals on the effect of abnormal NOTCH-1 gene expression on kisspeptin neuron formation, we discuss the probable role of Notch signaling in the premature activation of the HPG axis.

Adrenocortical carcinoma (ACC) is a rare malignancy in childhood. Affected children with ACC mostly present with virilization, but not the pure form of Cushing’s syndrome. A 9-year-old Japanese girl was hospitalized, because of the unstable emotions and excessive weight gain. She was diagnosed as having Cushing’s syndrome and a left adrenal tumor. The adrenalectomy led to the pathological diagnosis of ACC without metastasis. There was no mutation of PRKACA in the tumor-derived DNA, or p53 in peripheral blood-derived DNA. Testosterone and dehydroepiandrosterone sulfate (DHEA-S) levels were normal throughout the clinical course. On the other hand, these levels were elevated in all five reported cases of preadolescent ACC children with isolated Cushing’s syndrome. The exceptional secretory behavior of ACC gave a diagnostic precaution of the rare pediatric cancer.

Kearns-Sayre syndrome (KSS) is characterized by external ophthalmoplegia, retinal pigmentation and cardiac conduction defects due to mitochondrial DNA (mtDNA) deletions. Short stature and growth hormone (GH) deficiency have been reported in KSS, but data on GH treatment is limited. We describe the clinical presentation, phenotype evolution, and response to GH in a patient with KSS and report data on eight additional KSS patients from the KIGS database. Our patient with KSS and GH deficiency achieved a final adult height at −0.8 SDS. In the KIGS database GH treatment resulted in mean improvement in height from −3.9 to −2.9 SDS in patients with KSS. Two patients did not show growth improvement. Our data shows improvement in height SDS in our patient and mixed results in eight additional patients from the KIGS database after treatment with GH. Heterogeneity in responsiveness may relate to presence of GH deficiency or severity of underlying mitochondrial dysfunction.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive bone marrow failure syndrome typically characterized by neutropenia and pancreatic dysfunction, although phenotypic presentations vary, and the endocrine phenotype is not well-described. We report a unique case of a patient with SDS who initially presented with hypoglycemia and micropenis in the newborn period and was diagnosed with congenital hypopituitarism. We are not aware of any other cases of SDS documented with this combination of complex endocrinopathies.