Volume 31, Issue 11

Background Although carotid intima media thickness (CIMT) is an established marker of endothelial dysfunction, limited data exist on relative laboratory biomarkers in youngsters with type 1 diabetes mellitus (T1DM). Our aim was to study CIMT and the biomarkers of the osteoprotegerin (OPG)/RANKL system in young T1DM patients and controls, and also in subgroups of patients with increased risk for endothelial dysfunction, such as those with overweight/obesity, poor metabolic control or the presence of microalbuminuria. Methods CIMT and OPG/RANKL of 56 T1DM children and adolescents were compared to 28 healthy controls. Results Anthropometric, laboratory, CIMT and OPG/RANKL measurements were similar between patients and controls. Overweight/obese patients had greater CIMT than the normal weight ones (0.50 vs. 0.44 mm, p=0.001). Microalbuminuric patients had greater CIMT (0.49 vs. 0.44 mm, p=0.035) than the normoalbuminuric ones, with no difference in terms of OPG/RANKL. In the microalbuminuric group, OPG (r=−0.90, p=0.036) and RANKL (r=−0.92, p=0.024) were significantly negatively associated with CIMT. Following linear regression analysis, in the total patients group, microalbuminuria was the only factor significantly associated with CIMT (beta±SE: 0.050±0.021, p=0.035), body mass index (BMI)-z-scores were negatively associated with OPG (beta±SE: −0.25±0.12, p=0.05), while in the microalbuminuric group, CIMT was negatively associated with OPG (beta±SE: −0.070±0.019, p=0.036). During the forward stepwise procedure, microalbuminuria and age were the only variables negatively associated with RANKL (b=−0.334, p=0.034, b=−35.95, p=0.013, respectively). Conclusions In T1DM pediatric patients, overweight/obesity and microalbuminuria were associated with greater CIMT and with impaired OPG/RANKL levels, as biochemical indices of calcification of the atherosclerotic plaque.

Background Abdominal obesity (AO) is linked to inflammation and insulin resistance (IR). However, there is limited information on whether preschoolers with AO present these risk factors. We evaluated the association between AO and cardiovascular risk factors in preschoolers. Methods We enrolled 232 children (2–5 years), of whom 50% had AO. Serum total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), high-density lipoprotein-cholesterol (HDL-c), triglycerides (TG), apolipoprotein B (Apo-B) and apolipoprotein A-1 (Apo-A1), glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-1β, monocyte chemoattractant protein (MCP-1/CCL2), leptin, adiponectin, vascular cell adhesion molecule (VCAM-1/CD106) and intercellular adhesion molecule (ICAM-1/CD54) were measured. The homeostatic model assessment of IR (HOMA-IR) was calculated. We analyzed these variables according to the presence of AO and other metabolic syndrome (MetS) components. Results A total of 75.8% of children with AO had one or more risk factors for MetS. Children with AO had significantly higher body mass indexes (BMIs), insulin, HOMA-IR, TG, very low-density lipoprotein-cholesterol (VLDL-c) and TC/HDL-c ratio and lower HDL-c, compared to children without AO; but there were no differences in inflammatory markers. After adjusting for BMI, sex and age, the differences between groups were not significant for any variable. Waist circumference (WC) was correlated with insulin (r=0.547; p<0.001), TG (r=0.207; p=0.001), ICAM-1 (r=0.213; p=0.039), hs-CRP (r=0.189; p=0.015) and glucose (r=0.187; p=0.004). After adjusting for BMI, age and sex, AO plus one MetS component contributed to individual variation in glucose, insulin, HOMA-IR and TG. Conclusions AO in preschool children is associated with greater IR and atherogenic lipid profiles, although these findings seem to be more related to general obesity than just central obesity. In addition, our data suggest that IR may precede the elevation of systemic cytokines in obese children, unlike findings in adults. More studies in pediatric populations are needed to elucidate these associations.

Background Elevated body mass index (BMI) is associated with hypogonadism in men but this is not well described in adolescents. The aim is to evaluate gonadal dysfunction and the effects of weight loss after gastric banding in obese adolescent boys. Methods Thirty-seven of 54 boys (age 16.2±1.2 years, mean BMI 48.2 kg/m 2 ) enrolled at the Center for Adolescent Bariatric Surgery at Columbia University Medical Center had low total testosterone for Tanner 5 <350 ng/dL. Sixteen had long-term hormonal data for analysis at baseline (T0), 1 year (T1) and 2 years (T2) post-surgery. T-tests, chi-squared (χ 2 ) tests, correlation and linear mixed models were performed. Results At T0, the hypogonadal group had higher systolic blood pressure (SBP) (75th vs. 57th percentile, p=0.02), fasting insulin (19 vs. 9 μIU/mL, p=0.0008) and homeostatic index of insulin resistance (HOMA-IR) (4.2 vs. 1.9, p=0.009) compared to control group. Total testosterone was negatively correlated with fasting insulin and HOMA-IR. In the long-term analysis, BMI, weight, waist circumference (WC), and % excess weight decreased at T1 and T2 compared to T0. Mean total testosterone at T0, T1 and T2 were 268, 304 and 368 ng/dL, respectively (p=0.07). There was a statistically significant negative correlation between BMI and testosterone after 2 years (r=−0.81, p=0.003). Conclusions Low testosterone levels but unaltered gonadotropins are common in this group and associated with insulin resistance. While a significant increase in testosterone was not found over time, the negative relationship between BMI and testosterone persisted, suggesting there may be an optimal threshold for testosterone production with respect to BMI. Long-term studies are needed.

Background The extent of the obesity epidemic among youth is an important public health statistic which provides an indication of the future burden of non-communicable diseases. Many developing countries, including Albania, do not have systematic and repeated monitoring systems in operation. Methods The Balkan Survey of Inactivity in Children study is a population-based cross-sectional survey including Albanian children living in the four Balkan nation-states of Albania, Kosovo, FYR Macedonia and Montenegro. In total, 19,850 children from 49 schools were approached. The LMS method was used to provide body mass index (BMI), height, weight and waist circumference reference centiles for boys and girls. The World Health Organisation (WHO) and International Obesity Task Force (IOTF) age- and sex-specific BMI cut-points were applied to evaluate adiposity levels. Results A sample of 18,460 participants aged 6–16 years old was available for creation of the BMI for age and sex reference centiles. The prevalence of overweight (including obesity) in the full sample was 21% (95% CI: 20%–21%) according to IOTF cut-off points and 28% (95% CI: 28%–29%) at WHO cut-off points. Overweight/obesity levels where higher in boys than in girls irrespective of the cut-off points applied (p<0.001). Noticeable between-country differences were observed with a prevalence of overweight/obesity of 40% (95% CI: 38%–42%) in Montenegro but only 20% (95% CI: 19%–21%) in Kosovo (WHO cut-off points). Conclusions Overweight/obesity is highly prevalent in Albanian children and adolescents. The apparent sex and country differences may inform public health actions.

Background Studies in adults have shown a relationship between high blood pressure and hyperuricemia, but few studies have investigated this association in children and adolescents. The aim of the present study was to associate urate concentration with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in schoolchildren. Methods This cross-sectional study used a sample of 2335 schoolchildren in basic education between 7 and 17 years old. Blood pressure was classified by percentile according to Brazilian parameters for sex and age, reclassified into two categories: normal and borderline/hypertension. Blood collection to obtain serum for urate concentration analysis was performed after a 12-h fast. Values above 5.5 mg/dL were considered hyperuricemia. Descriptive data were presented in frequency and percentage. Linear regression and Poisson regression (prevalence ratio [PR]) was used to test the association between urate concentration and blood pressure. Results Urate concentration was weakly associated with SBP (β: 0.05; 95% CI: 0.02–0.08) and DBP (β: 0.03; 95% CI: 0.01–0.05) z-scores. Schoolchildren with hyperuricemia had a higher prevalence of high SBP (PR: 1.12; p<0.001) and DBP (PR: 1.08; p<0.001). Conclusions Elevated urate concentration is associated with altered blood pressure in schoolchildren.

Background The aim of the study was to evaluate high-sensitivity C-reactive protein (hs-CRP) and fibrinogen in non-obese normoinsulinemic adolescent girls with polycystic ovary syndrome (PCOS) and their relationship with anthropometric and lipid parameters. Methods The study comprised a total of 26 adolescent girls newly diagnosed with PCOS and 12 healthy controls with regular ovulatory menstrual cycles. The concentration of hs-CRP, fibrinogen, anthropometric measurements, and biochemical and hormonal testing were assessed. Results PCOS adolescent girls had significantly higher levels of hs-CRP and fibrinogen compared to healthy controls. In univariate regression analysis, statistically significant associations of hs-CRP and fibrinogen levels of PCOS patients have been shown with body mass index (BMI), waist circumference (WC), hip circumference (HC) and low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio, while hs-CRP levels were also associated with cholesterol and LDL. In the multivariate regression model, we found that hs-CRP levels were predicted by BMI (β=0.541, p<0.001) and LDL (β=0.507, p=0.014), while fibrinogen levels were predicted by BMI (β=0.449, p=0.004). Conclusions We have shown an association of proinflammatory indices hs-CRP and fibrinogen with anthropometric and lipid parameters of adolescent women with PCOS. The inflammatory markers might be useful in monitoring normal-weight adolescent women with PCOS in an effort to timely prevent unfavorable changes in body mass and lipid profile.

Background Adolescents having early puberty (EP) are more likely to have obesity and increased cardiometabolic and inflammatory markers and atherosclerosis risk. We aimed to assess the indirect and mediated effects of leptin and adiposity on the relation between EP and cardiometabolic and inflammatory markers in European adolescents. Methods A sample of 511 adolescents with EP (12.5–17.5 years) from the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross-sectional study was studied. To assess whether leptin levels and adiposity mediate the relation between EP and several biomarkers, linear regression models for mediation analyses were performed. Results EP was positively associated with the atherogenic index (Ath-I) (β=0.174; 95%CI 0.029–0.265) and negatively associated with the C-reactive protein (CRP) (β=−0.284; 95%CI −0.542 to −0.028) in girls. These associations were fully mediated by leptin levels (9.5%) and adiposity (44%), respectively. Moreover, EP has indirect effects on the apolipoprotein A-1 (ApoA-1) levels through adiposity in girls (for body mass index [BMI], β=0.014; 95%CI 0.005–0.028, and for waist circumference [WC], β=0.011; 95%CI 0.003–0.024), and on ApoA-1 (β=0.012; 95%CI 0.004–0.025), apolipoprotein B (ApoB) (β=−0.004; 95%CI −0.011 to −0.0004) and CRP (β=−0.265; 95%CI −0.819 to −0.047) through abdominal fat in boys. Conclusions Leptin levels and adiposity seem to play an important indirect and mediation role in the association between EP and cardiometabolic and inflammatory markers in adolescents. Weight control should be recommended in order to control the impaired cardiometabolic and inflammatory status arising in early pubertal adolescents.

Background Current literature suggests that diet is involved in either the development of premenstrual syndrome (PMS) or contributes to symptom severity, but to date, there are no studies evaluating eating attitudes of adolescents with PMS. The aim of this study was to evaluate dietary intake and eating attitudes in adolescents with PMS. Methods This study was conducted with 383 adolescents (214 with and 169 without PMS), aged 13–19 years. PMS was diagnosed using the premenstrual syndrome scale (PMSS). The Food Frequency Questionnaire (FFQ) and 24-h dietary recall were used to assess dietary intake. The Eating Attitudes Test-26 (EAT-26) and Three Factor Eating Questionnaire-Revised 18 (TFEQ-R18) were used to evaluate eating attitudes. Anthropometrical measurements and bone mineral content were measured. Results PMS prevalence was 55.9% according to PMSS subscales. Disordered eating attitudes determined by EAT-26 was detected in 23.8% in the PMS group and 11.8% of the control group (p<0.05). In the PMS group, total TFEQ-R18 score, emotional eating behavior and uncontrolled eating behavior scores were significantly higher (p<0.001). Whereas no significant difference in dietary intake, anthropometrical measurements or bone mineral content was observed between the two groups. Conclusions This is the first study documenting that not dietary intake but eating attitudes can be associated with PMS in adolescents. It is important to understand the relationship between disordered eating behaviors and PMS as both conditions may trigger the other.

Background Thyroid function in children with leukemia during the first year after hematopoietic stem cell transplantation (HSCT) was investigated. Methods The medical records of 186 subjects [111 boys and 75 girls; lymphoid=75, myeloid=111; median age at HSCT was 10.7 (0.8–21.8) years old] were reviewed retrospectively. Results In children with leukemia, T 3 decreased at 1 month (p<0.001) and recovered 9 months to the levels before HSCT. TSH decreased at 1 month (p<0.001), recovered at 3 months and increased at 12 months (p<0.001) to the levels before HSCT. The incidence of euthyroid sick syndrome (ESS, 23.2%, 15.5%, 5.9%, 5.2%, 3.9%, p for trend <0.001) decreased and subclinical hypothyroidism (SH, 0%, 3.9%, 14.8%, 22.1%, 21.3%, p for trend <0.001) increased at 1, 3, 6, 9 and 12 months after HSCT. Out of 55 patients developing ESS during 3 months after HSCT, 54 recovered to normal thyroid function within 5 months without medication. Among the total 186 subjects, 21 patients have been treated with levothyroxine. Both height and weight standard deviation scores continued to decrease over 1 year after HSCT. Conclusions In children with leukemia, one-quarter had ESS at 1 month and one-fifth had SH at 12 months and continued growth impairments were observed during 1 year after HSCT. Most of the ESS patients recovered to normal within 5 months without medication. More long-term follow-up of thyroid function and growth in children with leukemia after HSCT is crucial.

Background The present study compared the administration of levothyroxine (LT4) before breakfast and bedtime in school children diagnosed with hypothyroidism and analyzed the effects of timing on thyroid functioning and patient satisfaction. Methods A total of 163 children with acquired hypothyroidism (125 females and 38 males) between 8 and 18 years of age and taking LT4 for at least 3 months were enrolled in the study. The timing of administration of the drug of all subjects was shifted to bedtime. The levels of thyroid hormone and blood lipid, anthropometric measurements, Pediatric Quality of Life Inventory, Morisky Medication Adherence Scale and hypothyroidism symptoms scores were analyzed and compared at the beginning of the study and 3 months later after the shift in the timing of drug administration. Results There was no difference between the bedtime and morning regimens of LT4 with respect to thyroid hormone levels, quality of life, drug adherence and symptoms of hypothyroidism. At the end of the study, 45 of 70 new-onset treated subjects preferred the bedtime regimen. Also, drug adherence was found to be better in these patients. Conclusions We found no difference between the bedtime and morning regimens in both new-onset and long-standing treated patients. In naive patients, consideration of patient’s preference for timing of drug administration may increase their adherence to medication. Therefore, we suggest that choice of drug administration timing should be based on the preference of patients.

Background Children with non-acquired (na) growth hormone deficiency (GHD) diagnosed over decades in one center may provide perspective insight. Methods naGHD is divided into idiopathic GHD (IGHD), GHD of known cause (cGHD) and GHD neurosecretory dysfunction (NSD); time periods: <1988 (I); 1988–1997 (II); 1998–2007 (III); 2008–2015 (IV). Descriptive analyses were performed at diagnosis and during first year GH treatment. Results Patients (periods, N): I, 87; II, 141; III, 356; IV, 51. In cGHD (all), age, maximum GH, insulin-like growth factor-I (IGF-I), and insulin-like growth factor-binding protein-3 (IGFBP-3) (5.1 years, 3.6 μg/L, −5.3 standard deviation score [SDS], −3.7 SDS) were lower than in IGHD (all) (6.8 years 5.8 μg/L, −2.5 SDS, −1.0 SDS), but not height (−3.1 vs. −3.2 SDS). Characteristics of NSD were similar to that of IGHD. Patients with IGHD – not cGHD – diagnosed during 2008–2015 (IV) were the youngest with most severe GHD (maxGH, IGF-I, IGFBP-3), and first year height velocity (HV) and ∆ IGF-I (10.5 cm/year, 4.0 SDS) but not ∆ height SDS were the highest on recombinant human growth hormone (rhGH) (27 μg/kg/day). Conclusions Although during 1988–2007 patient characteristics were similar, the recently (>2008) stipulated more stringent diagnostic criteria – HV before testing, sex steroid priming, lower GH cut-off – have restricted diagnoses to more severe cases as they were observed before the rhGH era.

Background Pituitary cysts have been speculated to cause endocrinopathies. We sought to describe the prevalence and volumetry of pituitary cysts in patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS). Methods Six hundred and eighteen children evaluated for growth failure at the Division of Pediatric Endocrinology at New York Medical College between the years 2002 and 2012, who underwent GH stimulation testing and had a brain magnetic resonance imaging (MRI) prior to initiating GH treatment were randomly selected to be a part of this study. High resolution MRI was used to evaluate the pituitary gland for size and the presence of a cyst. Cyst prevalence, cyst volume and percentage of the gland occupied by the cyst (POGO) were documented. Results Fifty-six patients had a cyst, giving an overall prevalence of 9.1%. The prevalence of cysts in GHD patients compared to ISS patients was not significant (13.5% vs. 5.7%, p=0.46). Mean cyst volume was greater in GHD patients than ISS patients (62.0 mm 3 vs. 29.4 mm 3 , p=0.01). POGO for GHD patients was significantly greater (p=0.003) than for ISS patients (15.3%±12.8 vs. 7.1%±8.0). Observers were blinded to patient groups. Conclusions GHD patients had a significantly greater volume and POGO compared to ISS patients. This raises the question of whether cysts are implicated in the pathology of growth failure.

Background The short stature homeobox-containing ( SHOX ) gene strongly affects height. Therefore, a better understanding of SHOX haploinsufficiency could be advantageous to early diagnosis and treatment. We investigated the rate of SHOX haploinsufficiency in patients of short stature and documented their anthropometric measurements. Methods Between 2010 and 2017, we evaluated 86 patients (70 females, 16 males; age 4.3–18 years) with clinical diagnoses of short stature and Madelung deformity (MD). Clinical abnormalities are presented for patients with MD with and without SHOX haploinsufficiency as determined by fluorescence in situ hybridisation (FISH). Results According to our inclusion criteria, 78 of 86 patients (70 females, 16 males) had short stature (height <−2.5 standard deviation [SD]) and a family history suggestive of short stature. Eight patients had short stature, a family history suggestive of short stature and MD. MD was obvious in eight children in radiographic examinations. Although five of these had no deletion of SHOX , three had deletion of this gene. The deletion detection rate was 37.5% in the individuals with short stature and MD, i.e. Leri-Weill dyschondrosteosis syndrome (LWS), whilst no deletions were detected in the individuals with only short stature. One individual responded well to growth hormone (GH) treatment for the first 2 years but then developed an intolerance with persistently elevated insulin-like growth factor-1 (IGF-1) levels. Conclusions As we likely missed cases due to our methodology, the routine analysis for SHOX screening should be firstly multiplex ligation-dependent probe amplification (MLPA). The incidence of MD may have been higher in the cohort if X-rays were performed in all individuals. GH treatment was not well tolerated in one case due to persistently elevated IGF-1 levels, and long-term evaluations of patients with SHOX deficiency are required.

Background Children with hypochondroplasia (HCH), who have FGFR3 mutations c.1620C>A or c.1620C>G (p.Asn540Lys) appear to have a more severe phenotype than those with HCH without these mutations. We describe the change in height, leg length and body proportions in a retrospective cohort of children with HCH related-p.Asn540Lys mutation and we compared them with Argentine population. Methods Anthropometric measurements were initially taken and followed up by the same observer, with standardized techniques. Sitting height/height and head circumference/height ratio were calculated as a body disproportion indicator. In order to make a comparison with the Argentine population height average, centiles of height, leg length and body proportions were estimated by the LMS method. Results The sample consisted of 57 HCH children (29 males and 28 females) between the ages of 0–18 years. The median (interquartile range) number of measurements per child was 8 (4.3, 13) for height, 7 (4, 12) for sitting height and 7.5 (4, 12.8) for head circumference. Leg length increased from 17 cm at birth to approximately 54 cm in adolescents, 25 cm shorter than the leg length in non-HCH populations. Sitting height increased from 39 cm at birth to 81 cm in adolescents, 7 cm below mean in non-HCH adolescents. Mean (range) adult height were 143.6 cm (131–154.5) and 130.8 cm (124–138) for males and females, respectively. Conclusions The disharmonic growth between the less affected trunk and the severely affected limbs determine body disproportion in HCH.

Background Cushing’s syndrome (CS) or hypercortisolism results from disruption of the hypothalamus-pituitary-adrenal (HPA) axis with the resultant increase in the circulating serum and urinary cortisol levels and lack of cortisol circadian rhythm. The resultant effects cause the physical manifestation of hypercortisolism. The appearance of Cushing’s disease in children is insidious, the most common features being growth failure, obesity, early puberty and facial appearance. Case presentation We report a case of a 7-year-old male with a very unusual course of the disease, which could have led to diagnostic delays.

Background Familial apo C-II deficiency is a rare hereditary disorder frequently caused by lipoprotein lipase ( LPL ) and APOC2 gene mutations. To date, less than 30 patients with familial apo C-II deficiency with 24 different mutations have been identified in the literature. Here, we describe two familial chylomicronemia syndrome cases in infants with two novel mutations of the APOC2 gene. Case presentation Case 1, a 46-day-old female, was admitted to our hospital for evaluation due to the lipemic appearance of the blood sample. A clinical examination revealed hepatomegaly and lipemia retinalis. Triglyceride level of 6295 mg/dL was decreased with a strict low-fat diet, medium-chain triglycerides (MCT) oil-rich formula and omega-3 fatty acid supplementation. Due to low adherence to the diet, TG elevation was detected and fresh frozen plasma (10 mL/kg/day) was administered for 2 days. A novel homozygous p.Q25X (c.73C>T) mutation in the APOC2 gene was detected. Case 2, a 10-month-old female patient, referred to our center for the differential diagnosis of hyperlipidemia as her blood sample could not be assessed due to its lipemic appearance. Laboratory examinations showed a TG level of 4520 mg/dL which was reduced with a low-fat diet, MCT oil-rich formula and omega-3 fatty acid supplementation. Hepatosteatosis and splenomegaly were determined using abdominal sonography. A novel homozygous IVS2+6T>G (c.55+6T>G) mutation in the APOC2 gene was identified. Conclusions We describe two novel homozygous mutations (p.Q25X [c.73C>T] and IVS2+6T>G [c.55+6T>G]) in the APOC2 gene in infants with hyperchylomicronemia. To the best of our knowledge, Case 1 is the youngest patient with familial apo C-II deficiency in the literature to date.