Volume 30, Issue 5

The objective of the work was to prepare an update on imaging methods for bone evaluation during childhood and adolescence. The text was based on original and review articles on imaging methods for clinical evaluation of bone mass in children and adolescents up to 20 years old. They were selected from BIREME and PUBMED by means of the following keywords: bone density; osteoporosis/diagnosis; densitometry; tomography; ultrasonography; magnetic resonance imaging; and radiogrammetry and published in Portuguese or English, in the last 10 years (2006–2016). The article was organized into topics with the description of peculiarities, advantages and disadvantages of each imaging method and their possible clinical applicability. Despite the emergence of new technologies, dual energy X-ray absorptiometry (DXA) remains the gold standard method for low bone mass diagnosis in all age groups. However, interpretation is complex in children and adolescents and demands skilled people. Quantitative computed tomography (QCT) [central QCT, peripheral QCT (pQCT) and high resolution-pQCT (HR-pQCT)] and magnetic resonance imaging (MRI) evaluate real bone density, but are not yet available for routine use. Quantitative bone ultrasound (QUS) shows good perspectives for its use in primary prevention actions. Automated radiogrammetry shows promise as a method able to flag individuals who might benefit from a complete bone assessment, but the clinical value of the measures still needs to be established.

Background: Understanding risk factors that may vary culturally can help improve preventive strategies for obesity. This is the first cross-sectional study aimed to determine the risk factors for overweight/obesity in children aged 2–6 years in a central Anatolian city in Turkey. Methods: A total of 1582 children (1351 healthy, 231 overweight/obese) aged 2–6 years were included from the Anthropometry of Turkish Children aged 0–6 years database. Age, gender, birth weight, birth order, mother’s age, mother’s body mass index (BMI), weight gain of mothers during pregnancy, presence of gestational diabetes, breastfeeding duration, history of formula feeding, mother’s and father’s education, mother’s job, monthly income, smoking at home and physical activity, sleep duration and duration of television (TV) watching of the children were evaluated as independent risk factors. Logistic regression analyses were performed to investigate risk factors for overweight/obesity. Results: Having a high family income compared to bad [odds ratio (OR)=1.96; 95% confidence interval (CI): 1.237–3.106], increased the time of watching TV during the weekend (OR=1.094; 95% CI: 1.032–1.159), and similar physical activity level according to their peers compared to less (OR=2.957; 95% CI: 1.056–8.282) were found to be significantly associated with a higher risk of overweight/obesity in children aged 2–6 years old. Conclusions: The early childhood period seems to be important in the establishment of healthy behavioral patterns, especially limitation of TV watching and encouragement of physical activity. Obesogenic environment in families with high incomes need to be revealed.

Background: Obesity is genetically heterogeneous and highly heritable, although polymorphisms explain the phenotype in only a small proportion of obese children. We investigated the presence of copy number variations (CNVs) in “classical” genes known to be associated with (monogenic) early-onset obesity in children. Methods: In 194 obese Caucasian children selected for early-onset and severe obesity from our obesity cohort we screened for deletions and/or duplications by multiplex ligation-dependent probe amplification reaction (MLPA). As we found one MLPA probe to interfere with a polymorphism in SIM1 we investigated its association with obesity and other phenotypic traits in our extended cohort of 2305 children. Results: In the selected subset of most severely obese children, we did not find CNV with MLPA in POMC, LEP, LEPR, MC4R, MC3R or MC2R genes. However, one SIM1 probe located at exon 9 gave signals suggestive for SIM1 insufficiency in 52 patients. Polymerase chain reaction (PCR) analysis identified this as a false positive result due to interference with single nucleotide polymorphism (SNP) rs3734354/rs3734355. We, therefore, investigated for associations of this polymorphism with obesity and metabolic traits in our extended cohort. We found rs3734354/rs3734355 to be associated with body mass index-standard deviation score (BMI-SDS) (p = 0.003), but not with parameters of insulin metabolism, blood pressure or food intake. Conclusions: In our modest sample of severely obese children, we were unable to find CNVs in well-established monogenic obesity genes. Nevertheless, we found an association of rs3734354 in SIM1 with obesity of early-onset type in children, although not with obesity-related traits.

Background: We assessed nationwide trends in extreme obesity prevalence and its impact on metabolic syndrome in Korean youth. Methods: Data from 19,593 youth (10,271 boys) aged 2–19 were obtained from the Korean National Health and Nutrition Examination Surveys (2001–2014). The prevalence of extreme obesity and the odds ratio of metabolic syndrome were calculated. Questionnaires on body weight perceptions and weight control behaviors were administered. Results: The prevalence of extreme obesity increased significantly among boys (p<0.05). The odds ratios of extreme obesity on metabolic syndrome compared with obesity were 3.781 and 1.979 in boys and girls, respectively. Obese teenage girls with appropriate weight perception attempted to lose weight more frequently than obese teenage boys did. Conclusions: Although the prevalence of childhood obesity in Korea was similar since early 2000s, extreme obesity prevalence has increased, especially among teenage boys. Considering greater morbidity risks, preventing progression to extreme obesity is crucial.

Background: Little is known regarding the relationships among circulating brain-derived neurotrophic factor (BDNF) levels and glucose or insulin in children and adolescents. The objective of this study was to investigate whether circulating BDNF levels would change during the oral glucose tolerance test (OGTT). Methods: We performed the OGTT and measured the serial changes in BDNF levels in both plasma and serum. Results: There were 22 subjects in the normal type (N) group and 20 in the borderline/diabetic type (B/D) group, defined by the results of the OGTT. Serum levels of BDNF were almost five times higher and plasma levels gradually decreased during the OGTT, whereas serum levels showed no significant change. The reduction of plasma BDNF level changes from baseline to 120 min were significantly different between the N and B/D groups (36.3% vs. 20.8%, p=0.023). Conclusions: Our results showed that plasma levels of BDNF are more sensitive to acute changes in glucose or insulin levels than serum.

Background: Vitamin D deficiency has been associated with adverse health outcomes. We examined genetic and environmental determinants of serum 25(OH)D 3 and 1,25(OH) 2 D 3 in childhood. Methods: The study sample consisted of 322 healthy Australian children (predominantly Caucasians) who provided a venous blood sample. A parental interview was conducted and skin phototype and anthropometry measures were assessed. Concentrations of 25(OH)D 3 and 1,25(OH) 2 D 3 were measured by selective solid-phase extraction-capillary liquid chromatography-tandem mass spectrometry. These concentrations were deseasonalised where relevant to remove the effect of month of sampling. Results: Deseasonalised log 25(OH)D 3 and 1,25(OH) 2 D 3 concentrations were only moderately correlated (r=0.42, p<0.001). The following predicted both 25(OH)D 3 and 1,25(OH) 2 D 3 : UVR 6 weeks before the interview, natural skin and eye colour, height and vitamin D allelic metabolism score. The following predicted 25(OH)D 3 only: lifetime sunburns and vitamin D allelic synthesis score. Overall, 43.5% and 25.6% of variation in 25(OH)D 3 and 1,25(OH) 2 D 3 could be explained. After accounting for 25(OH)D 3 concentrations, higher UVR 6 weeks before the interview and vitamin D allelic metabolism score further predicted 1,25(OH) 2 D 3 concentrations. Conclusions: Environmental factors and genetic factors contributed to both vitamin D metabolite concentrations. The intriguing finding that the higher ambient UVR contributed to higher 1,25(OH) 2 D 3 after accounting for 25(OH)D 3 concentrations requires further evaluation.

Background: Vitamin D (VD) deficiency (VDD) is still a population-based health problem that affects people at different ages. The aim of this study was to evaluate VD prophylaxis for the prevention of VDD in (3–36)-month-old infants and children. Methods: Infants and children aged between 3 and 36 months, with different etiologies, admitted to outpatient and inpatient clinics from October 2010 to October 2011 at the Children’s Hospital of Erciyes University, were enrolled for the study. Their VD intake (if used; time of initiation, dosage and compliance) and nutritional status (breast-fed, formula or complementary fed) were noted. In order to study seasonal VD changes, the levels of serum calcium, phosphorus and magnesium, alkaline phosphatase activity (PLA), plasma parathyroid hormone (PTH) and 25 hydroxyvitamin 25(OH)D levels were measured at the beginning of VD supplementation during the four seasons. Results: A total of 316 subjects were enrolled in the study, consisting of 202 (63.9%) outpatient and 114 (26.1%) inpatient groups. From these subjects, 304 (96.2%) were supplemented with VD; whereas 12 (3.8%) were not. Out of the subjects supplemented with VD, 237 (75%) initiated VD after the second week of life, 267 (87.8%) were given three drops of VD daily and 209 (66.1%) had taken VD regularly. The plasma 25(OH)D levels were found to be lower in the inpatient group than the outpatient group (29.35 ng/mL and 34.35 ng/mL, respectively). The plasma 25(OH)D levels were lower during the spring and winter. VDD and VD insufficiency (VDI) was found in 31 (9.8%) and 30 (9.5%) subjects, respectively. Conclusions: The plasma 25(OH)D levels were lower in inpatient and breast-fed only subjects and in winter and spring. The national VD augmentation program seems to be beneficial for the prevention of VDD, but VDD/VDI seems to still be an important health problem.

Background: In this study we evaluated whether vitamin B12 deficiency affects neonatal screening (NS) for congenital hypothyroidism (CH). Methods: A cross-sectional study conducted from 2010 to 2011. A total of 10,740 infants were born in our hospital in this period. Thyroid-stimulating hormone (TSH) was tested for NS and neonates with abnormal screening results (TSH>20 mIU/L) were re-examined. Two hundred and twenty-nine re-called subjects (re-call rate 2.3%) were compared to 77 randomly selected newborns with normal TSH screening among these term newborns in terms of serum TSH, free T4, vitamin B12 and homocysteine status. Results: Of the 229 re-called subjects, 11 infants with CH and 21 infants with transient TSH elevation were detected. In the normal TSH screening group, only two infants were diagnosed with transient TSH elevation. Mean serum B12 levels were 126.4±48.7 pg/mL and 211.9±127.9 pg/mL in the positive TSH-screening group and the control group, respectively. There was a significant difference between positive and normal TSH-screening groups in regard to serum TSH, free T4, serum B12 and homocysteine levels. Conclusions: We found a significant vitamin B12 deficiency in positive TSH-screening infants. Beside the crucial role of vitamin B12 in newborns, deficiency seems to increase the recall rates of infants in an NS program for CH.

Background: Impaired heart functions in newborns with hypothyroidism should be reversed by levothyroxine substitution therapy. The aim of the study was to investigate heart functions with congenital hypothroidism (CH) in newborns and changes after levothyroxine substitution therapy, measured with tissue Doppler echocardiography and conventional echocardiography. Methods: The study included 30 neonates with CH and 34 healthy controls. Echocardiography were performed at baseline, 2nd week and 6th month of therapy. Results: Heart systolic function was normal. Mitral E velocities and mitral E/A ratios were significantly lower in patients at baseline. Tei indices were significantly higher in patients and a significant negative correlation was detected between free thyroxine levels and Tei indices.When early and late post-treatment echocardiography findings are compared, a non-significant difference was detected. Conclusions: Neonates with CH may exhibit systolic and diastolic heart dysfunction, which can be reversed by early L-T4 substitution treatment. The Tei index index should be measured in addition to conventional echocardiography.

Background: During puberty there is a physiologic increase in adrenal and ovarian androgens. It has been suggested that the somatotrophic axis may be related to the development of hyperandrogenism and anovulation in non-obese adult women with polycystic ovarian syndrome (PCOS). The objective of the study was to investigate whether ovarian androgen secretion in young postmenarchal girls is related to the function of their somatotropic axis. Methods: This was a cross-sectional study of adolescent girls. We studied non-obese adolescent girls with hyperandrogenism (HA; n = 21) matched with control girls (C; n = 25) for chronological age, age at menarche and body mass index. We obtained a fasting blood sample for measurement of serum glucose, insulin, 17-hydroxyprogesterone (17OH-Prog), dehydroepiandrosterone-sulfate (DHEA-S), androstenedione, sex hormone-binding globulin (SHBG), total testosterone, IGF-I, IGF-II, IGFBP-1, IGFBP-3, ghrelin, leptin, AMH (antiMüllerian hormone), luteinizing hormone (LH) and follicle stimulating hormone (FSH) during the follicular phase of the menstrual period. We performed an oral glucose tolerance test to determine blood glucose, insulin and ghrelin levels and urine samples to measure urinary GH (growth hormone) levels. Results: As expected, the hyperandrogenic girls had significantly higher Ferriman scores, basal total testosterone, free androgen index (FAI), androstenedione, AMH, and basal LH levels compared with the girls in controls. Serum IGF-I, IGF-II, IGFBP-3 and urinary GH did not differ between HA and C. There was a correlation between urinary GH and FAI in all girls (r 0.29, p < 0.05). In addition, in HA girls FAI correlated with insulin, homeostasis model assessment (HOMA) and ghrelin. Conclusions: We observed a correlation between urinary GH and FAI in the hyperandrogenic and control girls, suggesting that the function of the somatotrophic axis may influence the secretion of androgens in adolescent girls.

Background: The aim of this study was to determine the serum levels of kisspeptin and ghrelin (GAH), as well as the relationship of these two peptides with each other in premature thelarche (PT) and premature adrenarche (PA) cases and to investigate the possibility of using these peptides as markers in the differentiation of puberty disorders. Methods: A PT group aged 1–8 years (n = 40), a PA group aged 1–9 years (n = 23, female/male = 20/3) and control groups consistent with each of the previous groups in terms of age and gender were created for the study. Kisspeptin and ghrelin levels were measured with ELISA methods from blood samples drawn while fasting in the morning. Results: When the PT group was compared with the controls, the plasma kisspeptin levels of the cases were significantly higher than the control group (165.47 ± 15.45 pmol/L, 96.82 ± 12.33 pmol/L, p = 0.005, respectively). Kisspeptin levels in the PA group did not show a difference with the control group (121.36 ± 17.99 pmol/L, 95.52 ± 11.54 pmol/L, p = 0.249, respectively). No significant difference could be found when GAH levels in the PT and PA groups were compared with controls. No significant correlation was found between kisspeptin and GAH levels in the PT and PA groups. Conclusions: Our results indicate that kisspeptin plays an important role in the PT, but GAH is not associated with puberty disorders.

Background: Data on genotype-phenotype correlation in children is limited. Hence, we studied the prevalence of germline mutations and genotype-phenotype correlation in children with pheochromocytoma (PCC)/paraganglioma (PGL) and compared it with adult PCC/PGL cohort. Methods: A total of 121 consecutive, unrelated, index PCC/PGL patients underwent genetic testing for five PCC/PGL susceptibility genes ( RET , VHL , SDHB , SDHD and SDHC ) and were evaluated for clinical diagnosis of neurofibromatosis type1 (NF1). Results: Thirty patients (12 boys, 18 girls) presented at ≤20 years of age (mean age of 15.9±3.8 years). Children were more frequently symptomatic and more frequently had bilateral PCC than adults. Fourteen (46.7%) PCC/PGL children had germline mutations ( VHL 10 [33.3%], SDHB 2 [6.6%], and SDHD 2 [6.6%]). Overall germline mutations (46.7% vs. 26.4%, p=0.04) and VHL mutations (33.3% vs. 10.9%, p=0.026) were significantly more common in children than in adults. In children with VHL mutations, bilateral PCC were more frequent than in adults with VHL mutations. Within the paediatric cohort, bilateral PCC (60% vs. 5%, p=0.002), PCC+sPGL (30% vs. 0%, p=0.03) and occurrence of a second PCC/PGL (30% vs. 0%, p=0.03) were significantly more frequent among children with VHL mutations than others. Conclusions: All PCC/PGL children should be screened for germline mutations with first priority for VHL gene testing. Paediatric PCC/PGL patients with VHL mutations should be thoroughly evaluated for bilateral PCC and PCC+sPGL at initial presentation and closely followed up for occurrence of a second PCC/PGL.

Background: Early diagnosis and expeditious treatment of newborns with congenital hypothyroidism (CH) is necessary to avoid mental retardation. Methods: A survey of 44 practitioners in the southern US was conducted to better understand common practices regarding neonatal CH and the findings were compared with current guidelines in the US and Europe. Results: Responses indicated some consensus that 10–15 μg of thyroid hormone/kg/day was the appropriate dosage. However, despite guidelines advocating their use, practitioners reported that they did not commonly use imaging or laboratory tests, though experienced providers apparently used them more often. Conclusions: Together, these results show moderate adherence to published guidelines for treating and diagnosing CH. Further research is needed to determine why providers deviate from these guidelines and to generalize these results to other populations.

Background: The objective of this study is to bring attention to the importance of differential diagnosis in adolescent patients with skeletal involvement and hypercalcemia. Case: A 17-year-old male patient with a complaint of severe leg pain was admitted to our hospital. Seven months before he had a fracture of his distal humerus after falling on to his left shoulder and was treated conservatively. Five months previously, he had a rupture of his quadriceps tendon. Magnetic resonance imaging (MRI) was performed for the quadriceps tendon rupture and was evaluated as polyostotic fibrous dysplasia (PFD). Doctors decided to operate for the ruptured tendon but they detected severe hypercalcemia in the pre-operative blood tests and noticed that the main disease was primary hyper-parathyroidisim (PHPT) which was caused by a giant parathyroid adenoma. Conclusions Giant parathyroid adenoma can present in adolescent patients with multiple bone lesions and severe hypercalcemia. PHPT should be considered in the differential diagnosis of pathological bone fractures and benign bone tumors in every age. This may prevent patients from miss or delayed diagnosis of PHPT.

Although hyperglycemia is common in neonates, especially preterm infants, a diagnosis of neonatal diabetes mellitus (NDM) is rarely made. NDM can be permanent (45%), transient (45%) or syndromic (10%). Of the 95% of identifiable mutations for NDM, methylation defects in 6q24, KCNJ11 , ABCC8 , and INS account for the majority. Two cases of transient NDM in extremely preterm, 24 weeks’ gestational age (GA) triplets, due to a missense mutation c.685G>A in the KCNJ11 gene are presented. Both patients were successfully transitioned from insulin to Glyburide (Glibenclamide) at 2 months of age. Comprehensive genetic testing with targeted next-generation sequencing and 6q24 methylation analysis helps identify monogenic diabetes early, thereby improving metabolic and glycemic control when patients with potassium channel mutations are started on sulfonylurea (SU) treatment.

Pseudohypoaldosteronism (PHA) comprises a diverse group of rare diseases characterized by sodium and potassium imbalances incorrectly attributed to a defect in aldosterone production. Two different forms of PHA have been described, type I (PHAI) and type II (PHAII). PHAI has been subclassified into renal and systemic. Given the rarity and heterogeneity of this group of disorders we report three patients who carry PHA and a brief revision of current literature focused on the comparative analysis of PHAI and PHAII. Cases 1 and 2 presented with hyponatremia, hyperkalemia, metabolic acidosis and elevated plasma aldosterone and plasma renin activity in the neonatal period. Sequence analysis of the NRC2 gene demonstrated a novel heterozygous c.403C>T mutation in case 1 and a complete deletion in case 2, confirming the diagnosis of renal PHAI. Case 3 was a 4-year-old with hypertension, hyperkalemia, metabolic acidosis, normal plasma aldosterone and decreased plasma renin activity. Sequence analysis of the CUL3 gene demonstrated a previously unreported heterozygous c.1377+2T>3 mutation, confirming the diagnosis of PHAII-E. We highlight the importance of the determination of plasma aldosterone and plasma renin activity in the context of persistent sodium and potassium imbalances in children.

Cushing’s syndrome is rare in childhood and is usually caused by a pituitary adenoma. Primary hyperfunction of adrenal glands is less frequent, particularly primary pigmented nodular adrenocortical disease (PPNAD). It occurs usually in children and adolescents, with female preponderance, while Cushing’s disease has increased frequency in prepubertal males. A case of a 6-year-old boy is presented with isolated non-familiar PPNAD. The clinical pattern involved Cushingoid appearance, hypertension, virilization and depressive mood. Laboratory analyses showed loss of circadian rhythm of cortisol, undetectable adrenocorticotropic hormone (ACTH) level, impaired fasting glucose, polycythemia and elevated white blood count (WBC). Radiology investigation revealed a slightly enlarged medial branch of the left adrenal gland and a normal right one, so a unilateral adrenalectomy was performed. Pathohistology described multiple dark brownish pigmented nodules of various sizes confined to the cortex. Contralateral adrenalectomy was done 3 months later. Follow-up of 3 years was uneventful, except for one adrenal crisis during an intercurrent respiratory illness.